Psychopharmacological Issues in Geriatrics [1 ed.] 9781681080345, 9781681080352

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Psychopharmacological Issues in Geriatrics Edited By

Unax Lertxundi Pharmacy Service Araba´s Mental Health Network C/Alava 43 01006 Vitoria-Gasteiz Araba/Álava Spain

Juan Medrano Ezkerraldea - Enkarterri Mental Health Community Services Bizkaia´s Mental Health Network Portugalete Bizkaia/Vizcaya Spain

& Rafael Hernández Internal Medicine Araba´s Mental Health Network C/Alava 43 01006 Vitoria-Gasteiz Araba/Álava Spain

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CONTENTS Foreword

i

Preface

iii

List of Contributors

vii

CHAPTERS 1.

Historical Perspective of Psychotropic Drug Use Juan Medrano

2.

Evolution of Psychotropic Drug Use in Elderly Patients: Pharmaceuticals Emerging as Environmental Contaminants Unax Lertxundi and Beatriz Corcostegui

17

Age-Related Pharmacokinetic/Pharmacodynamic Changes in Psychopharmacological Drugs Arantxa Isla Ruiz, María Ángeles Solinís Aspiazu and Alicia Rodríguez-Gascón

31

3.

3

4.

Clinically Relevant Psychopharmacological Interactions in the Elderly Ainhoa Urrutia, Javier Peral and Jesús Ángel Padierna

49

5.

Potentially Inappropriate Medication in Elderly Rafael Hernández, Ane Gómez de Segura, Juan Medrano, Beatriz Corcóstegui and Unax Lertxundi

65

6.

Pharmacovigilance in Geropsychiatry Carmelo Aguirre and Montserrat García

111

7.

Anxiolytics and Hypnotics Juan Medrano

133

8.

Mood Stabilizers Juan Medrano

155

9.

Antidepressants Juan Medrano

187

10. Antipsychotics Juan Medrano

217

11. Antipsychotics in Dementia Juan Medrano

241

12. Antipsychotic Use in Parkinson’s Disease Saioa Domingo-Echaburu

273

13. Antipsychotic Polypharmacy in Elderly Patients Amaia Lopez de Torre

287

14. Drugs Used in Substance Use Disorders Juan Medrano

305

15. Drugs Used in the Treatment of Dementia and Neurocognitive Disorders Juan Medrano Subject Index

325 333

i

FOREWORD In a beautiful passage of “Alice in Wonderland”, Lewis Carroll wrote: “In a Wonderland they lie, dreaming as the days go by, dreaming as the summers die. Ever drifting down the stream, lingering in the golden gleam. Life, what is it but a dream?. May be that any of us could have dreamed to be for ever Alice, a lovely little girl living in a Wonderland. However, life is not a dream at all, and people, even Alice, usually become old and ailing with time. Although biomedical research has prolonged human life, it is not possible to live forever, and we cannot avoid unpleasant feelings such as ache, anxiety, depression and fear, especially in aging. The latin sentence “Post iucundam iuventutem, post molestam senectutem, nos habebit humus” (we will become dust after a funny youth and an annoying elderly), that is a part of an old song of our students in the University, indicates that the real problem is what to do with elderly, in which those “thousand natural shocks that flesh is heir to”, as was well expressed by Shakespeare, are even more unpleasant. After a long life, aged men and women will be suffering in many cases due to pain in osteoarthritis, sadness in depression, communication disability in Parkinson disease and other dyskinesias, as well as to social isolation and cognitive impairment in dementia. Moreover, anxiety caused by social exclusion, the loss of relatives and friends and the terrible fear of death, “the undiscovered country, from whose bourn no traveler returns” make difficult in the elderly “to take arms against a sea of troubles, and by opposing end them” as was said by prince Hamlet. Although death is denied by modern culture, our passing “through nature to eternity” should be helped by biomedical research in order to soften unpleasant feelings and moods that are linked in many cases to aging. The issues in psychopharmacology focused on the elderly, which are clearly exposed in the present work, can contribute to an improvement in life quality, especially in the case of aged people. Oblivion in institutions with elevated costs that we can hardly afford is not a social lasting solution for aged people, and soon the elevated economic and social cost of assistance to elderly will be unbearable. Then, the “land full of wonder, mystery, and danger”, as it is said in the famous novel by Lewis Carroll, could become a terrible place, even if “some say, to survive it”. Aggressive behavior, amnesia, cognitive and sensory deficits, paralysis, hallucinations, delirium and seizures in older people, as well as neurologic damage following to ictus and cerebrovascular pathology, and neurodegenerative diseases, can be deleterious for the health of those youngers charged with the responsibility towards older parents and relatives, leading to sadness, frustration and even desperation in caregivers, many of them women, that will be deprived to enjoy there own life. This is very well described by William Makepeace Thackeray in his novel “Vanity Fair”, when he tells about the character of Amelia nursing her dying mother: “Ceaseless slavery meeting with no reward; constant gentleness and kindness met by cruelty as constant; love, labour, patience, watchfulness, without even so much as the acknowledgement of a

ii

good word; all this, how many of them have to bear in quiet, and appear abroad with cheerful faces as if they felt nothing”. The present work comes to describe a partial solution to the suffering of older people and their caregivers, as a useful clinical tool in order to improve the pharmacological management of central nervous system pathology in the elderly. Enrique Echevarria Phisyology Department University of the Basque Country Victoria-Gasteiz Spain

iii

PREFACE Demographic evolution will extensively increase the number of subjects aged 65 years and beyond in the upcoming years. This demographic trend raises an important new challenge for healthcare professionals. Changes in organ functions, homeostatic mechanisms and receptor responsiveness impair drug distribution, metabolism and excretion, and reduce the effectiveness of medicines. Good clinical trial data in this age group are often lacking, under-treatment is common, and increasingly fragility can make drug administration difficult. As a consequence, medication management is much more challenging in the elderly than in younger adult patients. Pathophysiologic alterations occurring in the passing to middle age to old age are known to modify the response to drugs, including phycotropic drugs. The use of drugs in the general population and especially in the elderly has dramatically increased over the last decades, with older people aged 65 consuming about four times as many drugs as the rest of the population. Psychotropic drugs prescription in particular is becoming a major public health issue as its use is continuously increasing. One (frequently inadverted) risk of such use is the envionmental impact of pharmaceuticals. After their use, drugs are excreted in their native form or as metabolites and enter aquatic systems via different ways. Although there is some information about the environmental impact of certain drugs, knowledge about what happens with the vast majority of them is simply lacking. Other deleterious consequences are drug interactions and inappropriate drug prescription. In this sense, the elderly population suffers more drug-drug interactions, drug-disease interactions and adverse drug reactions than other age groups derived from the high number of drugs administered. Polypharmacy and potentially inappropriate medication is a common finding in the elderly and it is considered a public health issue related to morbidity, mortality and health care resource use. Avoiding the use of inappropriate drugs and high risk drugs is an important, simple and effective strategy to reduce the problems associated with medication in the elderly. Specific considerations about pharmacovigilance in elderly patients are widely described. In this sense, medications are brought to market with limited experience regarding their adverse effects, given the small number of people who have taken them during pre-marketing clinical tests. This is particularly true with elderly patients. As a result of this conditioning factor, in particular during the years leading up to the appearance of a new medication, health professionals (basically the physician) should pay special attention to: both identifying adverse effects of medications and reporting them in order to maintain a favorable risk-benefit balance always. In the second part of the book, a comprehensive and actualized review of the main specific classes of psychopharmacological agents used in geriatric patients is provided, including antipsychotics, anxiolytics & hypnotics, mood stabilizers and antidepressants. Even though anxiolytics & hypnotics are relatively a safe group that can provide rapid symptomatic amelioration, most of them are associated to the development of addiction and pose specific problems in old age. Therefore, the peculiars of these compounds and the characteristics

iv

of the elderly make especially accurate the classical recommendation to prescribe these drugs for short periods of time only. The following chapter reviews the different drugs labeled as mood stabilizers and where available introduces some considerations on their use in old age. Given the lack of controlled trials enrolling elderly bipolar patients, most information derives from application to geriatric patients’ characteristics of those data obtained in studies with other age groups, and also from decades of clinical experience, especially with lithium. Antidepressants are drugs used for the treatment of depression and many other psychiatric conditions. Albeit belonging to different chemical families and with a number of mechanisms of action, all of them enhance neurotransmitters at the synaptic cleft. They have a range of adverse effects and effectiveness compared with placebo, according to meta-analysis, is poor. However, they have shown to be efficacious in the elderly. Second-generation antidepressants are safer and better tolerated, but not devoid of side effects, something not to be forgotten when treating a population in which frailty and polypharmacy are common. Antipsychotics are those psychiatric drugs primarily used for the treatment of psychosis, mainly schizophrenia. Since their introduction, they have been used in a host of indications, but apart from mood disorders and somatoform disorders or insomnia in some European countries, most nonpsychosis uses are off-label. Antipsychotics are associated to serious adverse effects, which call for a careful use, especially in the elderly. Dementia is a common off-label use of antipsychotics. However, there are neither controlled studies, nor theoretical grounds supporting their use, especially in the treatment of behavioral disorder, where antipsychotics behave mainly as the “major traqnuillizers” they once were meant to be. As a result, treating dementia with antipsychotics could be a case in point of an irrational use of drugs. Untoward effects linked to antipsychotics when used in dementia are extensively reviewed. Some guidelines to make its use less irrational is also provided. One disease were antipsychotic use can be problematic is Parkinson’s Disease (PD), can because they can worsen parkinsonism by diminishing dopaminergic transmission in the nigrostriatal pathways. Prior to the introduction of clozapine there was no effective treatment for PD psychosis, and by the time being, is the only antipsychotic that has level I evidence to support its use in PD patients. Several open label studies on quetiapine for the treatment of psychosis in PD have been reported. Some of them showed quetiapine to be effective without worsening motor function while in others it was reported as ineffective although well tolerated. The simultaneous use of more than one antipsychotic in the management of psychiatric diseases has become a common practice worldwide. Although some theoretical bases have been suggested supporting this practice known as antipsychotic polypharmacy (APP), there is more personal experience than evidence-based behind it. APP is more frequent among young men. Nevertheless, some authors have estimated an APP prevalence in patients aged 65 or more up to 25% or even higher in the outpatient setting. Antipsychotics in the elderly are mainly used in the management of dementia-related behavioural alterations and schizophrenia but, as guidelines recommend, they should be used for short-term treatments. This limitation of duration of treatment has been associated with a wide range of potential risks like cerebrovascular events, hip fracture,

v

pneumonia, QT prolongation, metabolic disorders or even death. These risks are boosted when geriatric population and high dosage derived from polypharmacy are considered. In this concern, some special considerations should be taken into account: optimal antipsychotic election according to patient´s morbidities and other medications in order to avoid interactions, maximal daily dosage, optimal follow-up intervals and recommendations, among others. Another chapter will discuss the currently used drugs in of proposed for the treatment of substance use disorders, which are under-recognized in the elderly. The lack of studies focused on elderly populations call for a cautious, careful use of pharmacological agents, which must always be accompanied by psychosocial approaches. Dementia is a devastating illness for which currently there is no curative treatment. In the last twenty years, acetylcholinesterase inhibitors have been approved in the mild to moderate stages of the illness to delay the progression of Alzheimer’s disease, the most prevalent form of dementia, while memantine has been approved in later stages. Clinical experience shows that drug treatment of cognitive symptoms is of little benefit, but there is evidence that both acetylcholinesterase inhibitors and memantine could be helpful to alleviate the behavioral and psychological symptoms of dementia, especially in variants where other alternatives, such as antipsychotics, can be detrimental.

Unax Lertxundi Pharmacy Service Araba´s Mental Health Network C/Alava 43 01006 Vitoria-Gasteiz Araba/Álava Spain

Juan Medrano Ezkerraldea - Enkarterri Mental Health Community Services Bizkaia´s Mental Health Network Portugalete Bizkaia/Vizcaya Spain

& Rafael Hernández Internal Medicine Araba´s Mental Health Network C/Alava 43 01006 Vitoria-Gasteiz Araba/Álava Spain

vii

List of Contributors Ainhoa Urrutia

Pharmacy Service, Galdakao-Usánsolo Hospital, Barrio Labeaga s/n, 48960 Galdakao, Bizkaia/Vizcaya, Spain

Alicia Rodríguez-Gascón

Pharmacokinetics, Nanotechnology and Gene Therapy Group, Pharmananogene Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain

Amaia López de Torre

Pharmacy Service, Galdakao-Usansolo Hospital, Barrio Labeaga s/n, 48960 Galdakao, Bizkaia/Vizcaya, Spain

Ane Gómez de Segura

Pharmacy Service Araba´s Mental Health Network, Vitoria-Gasteiz, Araba/Álava, Spain

Arantxa Isla Ruiz

Pharmacokinetics, Nanotechnology and Gene Therapy Group, Pharmananogene Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain

Beatriz Corcóstegui

Pharmacy Service, Bizkaia´s Mental Health Network, Bizkaia, Spain

Carmelo Aguirre

Basque Country Pharmacovigilance Unit, Galdakao-Usansolo Hospital, BarrioLabeaga s/n, 48960 Galdakao, Bizkaia/Vizcaya, Spain

Javier Peral

Pharmacy Service Galdakao-Usansolo Hospital, Barrio Labeaga s/n, 48960 Galdakao, Bizkaia/Vizcaya, Spain

Jesús Ángel Padierna

Psychiatry Service, Galdakao-Usansolo Hospital, Barrio Labeaga s/n, 48960 Galdakao, Bizkaia/Vizcaya, Spain

Juan Medrano

Ezkerraldea - Enkarterri Mental Health Community Services, Bizkaia´s Mental Health Network, Portugalete, Bizkaia, Spain

Maria Ángeles Solinís Aspiazu

Pharmacokinetics, Nanotechnology and Gene Therapy Group, Pharmananogene Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain

Monserrat García

Basque Country Pharmacovigilance Unit, Galdakao-Usansolo Hospital, Barrio labeaga s/n, 48960 Galdakao, Bizkaia/Vizcaya, Spain

Rafael Hernández

Internal Medicine, Araba´s Mental Health Network, C/Alava 43 01006, Vitoria-Gasteiz, Araba/Álava, Spain

Saioa Domingo-Echaburu

Pharmacy Service, Alto Deba Integrated Health Organization, Avda, Nafarroa, 16, 20500 Arrasate Gipuzkoa/Guipuzcoa, Spain

Unax Lertxundi

Pharmacy Service, Araba´s Mental Health Network, Vitoria-Gasteiz, Araba, Spain

Psychopharmacological Issues in Geriatrics, 2015, 3-15

3

CHAPTER 1

Historical Perspective of Psychotropic Drug Use Juan Medrano* Ezkerraldea - Enkarterri Mental Health Community Services, Bizkaia´s Mental Health Network, Portugalete, Bizkaia, Spain Abstract: This chapter divides the history of Psychopharmacology into three different eras. The first, Empiric Psychopharmacology, was that of the serendipitous discovery of diverse molecules in the 1950s, in which the main current classes of compounds were roughly created. A second era, Scientific Psychopharmacology, was defined by the purposeful design of agents based on pathophysiological hypothesis developed from the identified mechanisms of action of the first psychiatric drugs. A third, modern era, of disenchantment, is marked by a growing criticism of Psychopharmacology and its commercial dimension. Finally, some remarks are made on the possible future of Psychopharmacology.

Keywords: Acetylcholinesterase inhibitors, Antipsychotics, Anxiolytics, Ataractics, Benzodiazepines, Berger, Frank, Cade, John, Catecholamine hypothesis of depression, D. Jean, D. Pierre, Discontinuation syndrome, Dopaminergic hypothesis of schizophrenia, Evidence Based Medicine (EBM), Kühn, Roland, Laborit, Henri, MAOI antidepressants, Meprobamate, Me-too, Mood stabilizers, Neuroleptics, Nootropics, Schou, Mogens, Supersensitivity psychosis, Tranquillizers, Tricyclic antidepressants. 1. EMPIRICAL PSYCHOPHARMACOLOGY: SERENDIPITY AND LARGE ACTION

THE

YEARS

OF

Any historical account of Psychopharmacology should start in 1949, with John Cade’s seminal paper on lithium therapeutic action on mania. Cade was not intending to use lithium as a treatment, but rather he utilized lithium urate as the most hydrosoluble urate in a series of experiments based on an erroneous hypothesis [1]. Even though Cade reported successful treatments of manic patients with lithium, both the toxicity linked to the compound and the relative opacity of the Australian journal where the original paper was published *Corresponding author Juan Medrano: Ezkerraldea - Enkarterri Mental Health Community Services, Bizkaia´s Mental Health Network, Portugalete, Bizkaia/Vizcaya; Spain; Tel: 3444596505; Fax: 3444596511; E-mail: [email protected] Unax Lertxundi, Juan Medrano and Rafael Hernández (Eds.) All rights reserved-© 2015 Bentham Science Publishers

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contributed to a scarce awareness of the prospects of the drug. In the 1950s and 1960s, lithium was patiently and stubbornly developed by a group of Danish psychiatrists, prominently Mogens Schou, for the prophylaxis of acute episodes of manic depressive illness, but the compound was not approved by the FDA until 1970, long after other drugs were routinely used not only in the US, but all over the world. This gap between the original communication and the extensive clinical application of lithium explains why the introduction of chlorpromazine in France in 1952 is the usual starting point in most outlines of the History of Psychopharmacology. Originally, chlorpromazine, a compound related to the antihistaminic promethazine, was employed by a surgeon, Henri Laborit, who while attempting to find a gangliopegic agent discovered it provoked a peculiar tranquilization unrelated to the effect of other sedatives. Laborit communicated such a serendipitous finding to some psychiatrists, encouraging them to try the new product in agitated patients. In January 1952, chlorpromazine was administered to a patient with psychotic mania, obtaining a marked improvement which would be reported a couple of months later by Hamon et al., [2]. Soon after, Jean Delay, professor at the Saint-Anne Hospital in Paris and his collaborator Pierre Deniker became interested in the product and started to use it. A discovery, even more unexpected than that of Laborit’s, was that chlorpromazine which could make psychotic symptoms disappear in patients suffering from chronic conditions. Although this ability would prompt the recognition of the drug as a medicine particularly useful to treat psychosis, chlorpromazine was actually used in a range of doses in very different conditions, both psychiatric and somatic, which explains the choice of its trademark in France (Largactil: large action), by which the manufacturer aimed to convey the product’s versatility. A few years after the introduction of chlorpromazine, another drug, reserpine, was also found to be able to revert psychotic symptoms. Reserpine is also credited to have been the first drug to display antidepressant properties in a randomized clinical trial by Davies and Shepherd [3], something apparently striking, since reserpine would be later associated to deaths by suicide [4] but which on the other hand shows that in the infancy of Psychopharmacology drugs were neither used nor conceived of as specific remedies. Also in 1952, a tuberculostatic agent, iproniazid, was serendipitously found to have an antidepressant effect by physicians who noted that the patients administered the drug became “inappropriately happy”. Iproniazid was marketed in 1958, but had to be withdrawn just three years after, because of an extremely

Historical Perspective of Psychotropic Drug Use

Psychopharmacological Issues in Geriatrics 5

high incidence of hepatitis. The identification that iproniazid, in contrast to isoniazid, was able to inhibit the Mono Amine Oxidase (MAO), led to the discovery of new compounds sharing this action. Some of them were structurally related to iproniazid, but others not, like tranylcypromine, which had been synthetized in 1948 in attempt to produce an amphetamine analogue. After having been unsuccessfully tried for the treatment of nasal congestion, it was forgotten until its ability to inhibit MAO was discovered, which led to its introduction in the therapy of depression as another MAOI (MAO Inhibitor). In 1958, the Swiss psychiatrist Roland Kuhn tried in psychiatric inpatients a tricyclic product designed as a new chlorpromazine analogue. Kuhn found it was not useful to treat psychosis, but as he reported, imipramine could help people with endogenous depression showing the typical symptoms of mental and motor retardation, fatigue, feelings of heaviness, hopelessness, guilt, and despair. After imipramine, a host of new tricyclic compounds was synthetized and marketed. Also in the 1950s, Frank Berger synthetized meprobamate, the first agent specifically used to reduce anxiety. Devoid of the lethal potential of barbiturates, meprobamate would become a real blockbuster, until the advent a few years later of benzodiazepines, a chemical group which proved to have also hypnotic credentials. 2. SCIENTIFIC PSYCHOPARMACOLOGY: FROM SERENDIPITY AND LARGE ACTION TO INTENDED DESIGN AND SPECIFICITY As has been previously stated, chlorpromazine was initially used as an unspecific sedative agent. Laborit observed that the drug elicited a state of indifference which he labeled as ataraxia. All new products related to chlorpromazine were found to induce such a state and were accordingly named “ataractics”, a term that captured that their action resembled to a sort of “chemical lobotomy”. Shocking as the comparison seems 60 years later, it must be recalled that for years lobotomy had been a first-line treatment for psychosis and that in 1949, Egas Moniz had been awarded the Nobel Prize in Medicine for his “discovery of the therapeutic value of leucotomy in certain psychoses”. The tranquillizing action of chlorpromazine and some other compounds suggested tranquillizers as a suitable umbrella term. The arrival of meprobamate first, and benzodiazepines later, helped distinguish two groups, that of major tranquilizers, which comprised of chlorpromazine and related compounds, and the class of the so-called minor tranquillizers, encompassing those drugs selectively used for

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anxiety. Another remarkable property of chlorpromazine, from a clinical viewpoint, was its ability to induce parkinsonism and other extrapyramidal symptoms and signs. Noticeably, all drugs sharing chlorpromazine’s therapeutic action also shared its neurologic effects, a feature early recognized by practitioners which prompted Delay and Deniker as soon as 1955 to coin the term “neuroleptic” (seize the nervous system) to label the group. The term, which alludes to the various actions of all these drugs, both therapeutic and adverse, could therefore appear an unpropitious way to designate a group of drugs intended to help patients, but prevailed over that of antipsychotic, a name proposed by Lehman also in those years, which instead remarked a therapeutic action rather than an untoward one. This predominance, attributed to Delay’s reputation, can also stem from the fact that during decades it was assumed (also from Delay’s insights) that a collateral extrapyramidal toxicity was a prerequisite for antipsychotic action, a theory that could only be discarded with the advent of clozapine, a uniquely effective antipsychotic drug with minor or no neurological side effects. Such a variety of terms to name a group of medicines, as King and Voruganti point out [5], contrasts with the apparent certainty about the mechanisms of action of these drugs (see below). This outline will interchangeably employ the terms neuroleptic and antipsychotic, to avoid repetition, but this choice may also reflect a personal ambivalence clinically rooted in the classic concept of any drug as a pharmakon which could concurrently be a remedy or a poison. This ambivalence has not existed in the pharmacotherapy of depression, given that all the terms coined to designate the drugs used in this field are positively connoted. After other early alternatives, such as psychic energizer or thymoleptic were discarded, antidepressant is the universally accepted term to label the successors of iproniazid and imipramine. One of the consequences of the availability of drugs for the treatment of psychiatric disorders was the possibility of developing hypotheses about the etiopathogenesis of mental illnesses. As purported mechanisms of action were identified and attributed an ability to reverse symptoms, the logical following step seemed to deduce that the latter were caused by biochemical dysfunctions abated by drugs. Carlsson and Lindqvist [6] found that chlorpromazine and haloperidol increased brain 3-methoxytyramine, a major metabolite of dopamine, and proposed that these drugs block dopamine receptor, thereby increasing the production of its metabolites. The findings that dopamine agonists worsen psychotic symptoms and that the affinity of any given drug for dopamine receptors had a good correlation with its clinical efficacy, as well as the discovery that neuroleptic-induced parkinsonism was attributable to a blockade of D1 and D2

Historical Perspective of Psychotropic Drug Use

Psychopharmacological Issues in Geriatrics 7

receptor subtypes in the extrapyramidal motor systems, contributed to the success of the dopamine the hypothesis of schizophrenia, which ascribes symptoms of schizophrenia to a disturbed, hyperactive dopaminergic system. The model also allowed for an explanation of tardive dyskinesia through dopamine receptor sensitivity and a neuroleptic-induced mesolimbic supersensitivity psychosis that would explain the tendency to relapse in some patients [7]. On the other hand, evidence mounted that the antidepressant effects of both the MAO inhibitors and the tricyclics could be mediated through an increase of active catecholamines at adrenergic receptor and that reserpine-induced sedation in animals was associated to catecholamine depletion. Although in a seminal paper on the catecholamine hypothesis of depression Schildkraut [8] warned that it remained to be demonstrated that this findings had any relation to naturally occurring biochemical abnormalities which might be associated with the disease, the idea quickly took hold and was later refined by Carlsson et al., [9], who suggested that serotonin reuptake could be the mechanism by which tricyclics produced their mood-elevating effect, something that had already been conjectured by Schildkraut. For years all new compounds were either synthetized mirroring chemical structure or marketed on the grounds that their clinical effects were comparable to those showed by prototypes like chlorpromazine or imipramine. Modifications introduced in the chemical structure of products with a known psychotropic potency, searching for more potent analogous, generated a good deal of phenotiazinic or tricyclic me-toos. Clinicians’ appraisal of a neuroleptic effect in the prokinetic metoclopramide opened the way for the new group of benzamide antipsychotics, and the finding that some compounds shared a cataleptic effect in animal models resulted in the recognition of the new class of butyrophenone antipsychotics. But the arrival of biochemical hypotheses in the 1960s enabled investigators to search for molecules which fulfilled those posited mechanisms of action. Fluoxetine, synthetized in the mid-1970s, was a pioneer of that purposeful, targeted design, and also the first successful Serotonin Selective Reuptake Inhibitor (SSRI), as the group was to be labeled. With the identification of clozapine’s unique clinical and biochemical traits, with a low liability for extrapyramidal side effects and action on an array of receptors other than D1 and D2, the new clinical and but essentially marketing-friendly concept of atypical antipsychotic flourished and manufacturers attempted to find new compounds that mimicked clozapine. Atypicality is certainly a blurred concept, given that some older drugs share with atypicals a comparable receptorial profile [10], but have

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never been marketed on the grounds of those fashionable biochemical properties. On the other hand, amisulpride, a specific dopaminergic antagonist, has been put forward as atypically atypical [11]. Finally, it could be cynically asserted that atypicals are really the typical antipsychotics in as much as their market share is considered, even though they are significantly more expensive than old, first generation compounds. Other bandwagon too jump on has been the class of the so-called “mood stabilizers”, a term which, again, proves to be a practical marketing strategy rather than a truly scientifically-based concept. Any compound aiming for a share of the ever growing market of the pharmacological treatment for bipolar disease must show its best credentials to be considered a member of the class. However, only lithium seems to be effective for the four treatment issues of bipolar disorder, namely, acute mania, acute bipolar depression, maintenance therapy against mania and maintenance therapy against depression [12]. Instead, all other proposed compounds (notably, antipsychotics and anticonvulsants) fail to fulfill this four-fold requirement, a finding that has prompted Fountoulakis et al., [13] to assert that a class effect is the exception rather than the rule in the treatment of bipolar disorder. 3. MODERN PSYCHOPHARMACOLOGY: THE DISENCHANTMENT The introduction of drug therapy was enthusiastically hailed by the profession, even though the prevailing model for the treatment of psychiatric conditions, at least in the US, was Psychoanalysis. According to conventional wisdom (and also to Pharma ads), neuroleptics sparked the deinstitutionalization movement and promoted an atmosphere of therapeutic optimism that contributed to improve the quality of life of the mentally ill. As the use of drugs obviously refers to an organic site of action, the new discipline of Psychopharmacology highlighted a medical materialist viewpoint and paved the way for the definitive recognition of Psychiatry as a specialty like any other in modern Medicine. In fact, drug therapy in Psychiatry exerted an influence that can be tracked in developments such as DSM-III and its successors. Two major categories of drugs were delineated, that of antipsychotics (or neuroleptics) and that of antidepressants, which fitted the Kraepelinian model of two great well-defined major psychiatric illnesses. Moreover, as has been described, drugs also helped researchers to glimpse neurophysiological mechanisms which framed the basic tenets of the so-called Biological Psychiatry. Reliance on drug therapies for an increasing number of mental disorders led to an ever greater use of medications for the treatment of dubious conditions, thus exposing the intermingled problems of medicalization, disease mongering and overmedication. Widespread use of drugs provokes special

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concern in Pediatric Psychiatry, with the exponential increase of children diagnosed of Attention Deficit/Hyperactivity Disorder and an estimated 3.5% U.S. children receiving stimulant medication in 2008, with an overall annual growth rate of 3.4% [14]. However, more than half a century after the introduction of chlorpromazine there is a mounting criticism about drug-based psychiatric therapy and Medical Psychiatry. Widespread drug use raises serious concerns about iatrogenically induced epidemical dependence. This was the case some 30 year ago with benzodiazepines, a group which on the other hand was subjected to negative campaigning by competitors, especially SSRI, whose manufacturers highlighted classical anxiolytics’ addictive liability, thus raising awareness and concern amongst prescribers. In turn, antidepressants, especially SSRI, have been suspected to increase suicidal behavior and aggression during therapy [15], and have also been criticized because of poor results, with less than 60% of patients fully recovering and a great relapse rate after withdrawal, and, according to some researchers, an almost negligible effect size as compared to placebo [16]. Also, it has been recognized a specific clinical picture after halting antidepressants, or merely reducing dosage. Ingeniously termed discontinuation syndrome [17], the concept blames symptoms on the process of suppressing the drug rather than on a possible dependence to the compound itself. Atypical antipsychotics failed the expectation to achieve a neurologically-safe, patient and clinician-friendly remedy devoid of clozapine hematological toxicity, which makes complete blood counts mandatory, while at the same able to improve the long-term outcome of schizophrenia. Rigorous, well designed naturalistic followup studies such as CATIE [18] and CUtLASS [19] cast doubt on the effectiveness of atypicals and their purported superiority over first-generation compounds like perphenazine and sulpiride. And importantly atypicals have introduced new side effects, namely a metabolic and cardiovascular liability perhaps also associated to phenotiazines but that has become apparent with second-generation antipsychotics. Moreover, all antipsychotics are blamed of inducing brain shrinkage [20] and surprisingly clinical trials designed to gauge safety and effectiveness of new compounds are showing a decreasing differential potency as compared with placebo [21] something that has been attributed a poor quality design of trials. Also, doubt has been cast over the necessity for long term antipsychotic treatment after first episode schizophrenia, and drawing from models such as supersensitivity psychosis, it is being discussed whether antipsychotics could in fact worsen the outcome of the disease.

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Although a panoply of me-toos followed the path opened by clozapine or fluoxetine, it seems clear that not a truly novel psychotropic drug has emerged in the last 30 years, and while some improvements in safety and tolerability against older prototypes have been achieved, no product shows a greater antipsychotic effectiveness than laboriously monitored clozapine or a stronger antidepressant effect than the old and poorly tolerated tricyclics. New product scarcity in the last few years seems to be the sum of pharmaceutical companies giving up on Psychopharmacology, with a decreasing number of new compounds researched and patented, and the adjuvant failures in clinical trials described above. Ketamine seems to be the most exciting novelty. An anesthetic agent and drug of abuse, this compound has shown unusually powerful and rapid antidepressant effects, perhaps due to its blockade of NMDA receptor, which is not targeted by any available antidepressant. Disappointing as all those problems seem, more serious concern arises from the influence of the manufacturers on research. Some twenty years ago Evidence Based Medicine appeared as a reaction against a classical “expert-based medicine” grounded on unproven theories. It was also an opportunity to refute the evidence-lacking assertions by the pharmaceutical industry, who however soon managed to work things to its advantage. Beyond being a base for clinical practice, a great amount of evidence has been collected on the impact of sponsorship bias in comparative studies between compounds [22-24]. Even more discouragingly, dubious or openly unethical practices such as ghostwriting, publication bias or merely hiding inconvenient results are becoming recognized as a recurrent problem rather than an infrequent happenstance. Conflicts of interests are commonplace and after some scandals prominent researchers and academics have been found to have strong links to the industry, to such an extent that a renowned editorialist wondered, some years ago, if academic medicine is for sale [25]. Disturbingly, her reflection was actually triggered by a paper featuring a clinical trial involving an antidepressant. After such a gloomy portrait, what can be said of the particular field of Geriatric Psychopharmacology? Antipsychotics have been the treatment of choice not only for psychotic disorders such as schizophrenia, have also as the main therapy for the control of behavioral disorders in dementia o acute confusional states. Classical Thorazine adverts recommended the compound for “tyrant” elderly or cases of “senile agitation”, thus revealing a paradigmatic use of chlorpromazine on the grounds of its unspecific, sedative and large action effects. Parkinsonism and tardive dyskinesia appeared to be a common side effect in all geriatric patients treated with neuroleptics, especially in those suffering from dementing

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illnesses. Despite this recognition of toxicity, these products have been widely used in geriatric care, to the point that in the United States the Omnibus Budget Reconciliation Act of 1987 (OBRA-87) included provisions for regulating the use of psychotropic medication, particularly antipsychotics, in long-term-care facilities. More recently, neuroleptics have been suspected of hastening cognitive decline in dementing patients [26], and at the beginning of this century it was found that atypical antipsychotic therapy increased the risk of death from cerebrovascular conditions in patients with dementia. A comparable risk of death was later found with first-generation compounds, and presently both the FDA and the EMA warn of an increased risk of death for elderly patients suffering dementia-related psychosis treated with antipsychotics. Original tertiary-amine tricyclics (imipramine, amitriptyline) were considered potentially problematic in geriatric patients due to anticholinergicity, which increases the risk of developing mild cognitive impairment or acute confusional states and systemic untoward effects, as well. This led to a general view of secondary-amine compounds (their metabolites desipramine and nortriptyline, respectively) as first choice drugs, due to a lessen anticholinergic activity. Concern for the risks arising from inhibition of cholinergic activity favored also that SSRIs were saluted as the best choice, except for perhaps, paroxetine, the compound with a more marked anticholinergic activity in the group. As clinical experience grew, it became clear that old-age altered pharmacokinetics called for a careful prescription of benzodiazepines to avoid accumulation and subsequently prolonged sedation, impaired motor coordination, falls and confusional states. As benzodiazepines should be used with caution, the sedative treatment of behavioral disorders diverted to neuroleptics, a group with significant toxicity and not devoid of anticholinergicity and falls and accidents liability. In any case, there exists agreement that in the treatment of behavioral symptoms associated to dementia drug restriction is favored over non-pharmacological approaches. Given the side effects of psychotropics and the increased vulnerability of frail elderly patients, this reliance on drugs imposes an extra disability burden on those suffering of dementia with behavioral disturbances. A group of drugs especially relevant in Old Age Psychiatry is that of the compounds for the treatment of dementia associated to Alzheimer’s disease. The development of drugs to treat dementia has aligned with the pathophysiological hypotheses to explain the origin of the illness and the appearance and natural history of its symptoms. The old model that claimed that dementia was the

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outcome of a chronic brain blood flow deficit prompted the use of vasodilators, and global neurodegenerative theories spurred the use of compounds that purportedly increased neuron resistance to stress, modified the availability of the brain’s supply of neurochemicals, improved the brain’s oxygen supply, or stimulated nerve growth. All those compounds were labeled after the umbrella term of nootropics (derived from the Greek νους nous, or “mind”, and τρέπειν trepein, meaning “to bend/turn”). A range of vitamins, stimulants, nutraceuticals and food supplements, complementary medicine’s remedies, hormones, etc, allegedly are able to enhance learning and memory, as well as learned behaviors under conditions which are known to disrupt them, like hypoxia. Those products are also supposed to protect the brain from physical or chemical injury, and to enhance the tonic cortical/subcortical control mechanisms, while on the other hand exhibiting few side effects and extremely low toxicity, as they lack the pharmacology of typical psychotropic drugs (motor stimulation, sedation, etc.). Those characteristics are actually the criteria introduced by Giurgea [27], who coined the term of nootropics to designate this purported group of drugs. The finding of a deficit of cholinergic activity and degeneration in the nucleus basalis of Meynert in Alzheimer’s disease led to the development of products that enhanced central cholinergic transmission. Tetrahydroaminoacridine (tacrine), was the first compound in the new group of acetylcholinesterase inhibitors, which were able to increase the level and duration of acetylcholine by inhibiting the enzyme that hydrolyzes it [28]. Other products like donepezil and rivastigmine followed suit. An older product, galantamine, used for decades in Eastern Europe for the treatment of myasthenia, myopathy, and sensory and motor dysfunction associated with disorders of the central nervous system, was recycled as a drug for Alzheimer’s disease on the grounds of its cholinergic transmission enhancing properties by inhibiting acetylcholinesterase. However, the promise of a cure or at least a significant palliation of such a devastating illness as dementia has not been fulfilled. Actually, even though the first studies were conducted in moderate to severely affected Alzheimer’s patients, all those products have only been licensed for the treatment of mild to moderate dementia. Paradoxically, according to a recently published study [29], despite being licensed for the early stages of the illness, these compounds are not useful for the prophylaxis of dementia in mild cognitive impairment, a condition in which slight but noticeable and measurable decline in cognitive abilities can be detected and which definitely increases the risk of developing dementia. Another drug used in dementia is memantine, first synthetized in 1968 and later discovered to block NMDA receptors. Memantine found its market niche in the

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treatment of moderate-to-severe Alzheimer’s disease and in dementia with Lewy bodies, whereas there is little evidence of effect in mild Alzheimer’s disease, and as shown by Tricco et al., [29] it is not useful for mild cognitive disorder. As with rivastigmine, memantine seems to be more useful to control behavioral symptoms associated to dementia than cognitive symptoms. On the other hand, memantine has been proposed for the treatment of a vast array of psychiatric disorders (bipolar disorder, schizophrenia, catatonia, anxiety disorders, impulse control disorders, eating disorders, substance use disorders, and attention-deficit hyperactivity disorder) in a 21st century version of large action chlorpromazine [30]. The prescription for behavioral symptoms of those drugs conceived for the treatment of the cognitive dimension of dementia could be an expedient way to reduce the use of alternatives with a less favourable risk-benefit ratio, such as neuroleptics. With the introduction of the amyloid hypothesis, which postulates a central role for deposition of amyloid-beta (Aβ) protein in brain parenchyma in the pathogenesis of Alzheimer’s disease, strategies for treatment of the illness diverted to the inhibition or blockade of deposits. Anti-Aβ antibodies like bapineuzumab and solanezumab, have been tried with poor results till the date. However, this path can still lead to new developments concerning both the pathophysiology and the cure or palliation of Alzheimer [31]. 4. THE FUTURE As aforementioned, at the present moment the psychotropic pipeline is near to dry. Some relevant companies, as GlaxoSmithKline and AstraZeneca, have retreated from neuroscience research finding it economically unviable. Maybe such a conclusion has something to do with a failed promise of new, safer, more effective products based on the disease mechanisms inferred after the identification of the pharmacodynamics of the first psychotropics. However, identification of a mechanism of action should not lead to the conclusion that the pathogenesis of any given disease is just the opposite of what a drug remedying the condition does. It is impossible to be completely certain that the mechanisms identified are the ones that exert the therapeutic effect, and on the other hand, any condition can be palliated or have its symptoms reduced by mechanisms unconnected to its pathophysiology or pathogenesis, which can remain unknown. Antihypertensives can reduce blood pressure through ways related to physiological mechanisms, such as interference on the renin-angiotensinaldosterone system, but also by an action on artery walls unrelated to the endogenous regulation of blood pressure. In the case of psychotropics, although

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the dopamine or catecholamine hypotheses have doubtlessly some merit, jumping to the conclusion that disease mechanisms are just the identified psychodynamics of drugs the other way round can be hasty and ill-advised as far as there are not solid theories about the pathogenesis of mental disorders. In fact, as Moncrieff [32] points out, it remains to be distinguished if psychotropics do really heal psychiatric disorders or just alleviate some symptoms by inducing toxic states that mitigate them. If the future is to bring progress, therefore, a cautious, humble, and modest approach is needed that on the one hand recognizes what is known to help our patients without inflicting them untoward effects of our drugs and on the other hand admits that how much we are still ignorant of. ACKNOWLEDGEMENTS The author acknowledges the influence of David Healy's thorough and enjoyable writings on the History of Psychopharmacology, and of discussions with his partners in the Txori-Herri Medical Association, namely Pablo Malo and Jose Uriarte. CONFLICT OF INTEREST The author confirms that this chapter contents have no conflict of interest. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

Healy D. The creation of psychopharmacology. Cambridge, Massachussets: Harvard University Press, 2002. Hamon J, Paraire J, Velluz J. Remarques sur l’action du 4560 RP sur l’agitation maniaque. Ann Méd Psychol (Paris) 1952; 110: 331-5. Davies DL, Shepherd M. Reserpine in the treatment of anxious patients. Lancet 1955; 269: 117-20. Healy D. The antidepressant era. Harvard: Harvard University Press, 1997. King C, Voruganti LNP. What’s in a name? The evolution of the nomenclature of antipsychotic drugs. J Psychiatry Neurosci 2002; 27: 168-75. Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh); 1963; 20: 140-4. Chouinard G, Jones BD, Annable L. Neuroleptic-induced supersensitivity psychosis. Am J Psychiatry 1978; 135: 1409-10. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1966; 122: 509-22. Carlsson A, Corrodi H, Fuxe K, et al. Effects of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4,alpha-dimethyl-meta-tyramine. Eur J Pharmacol 1969; 5: 367-73. Glazer WM. Does loxapine have “atypical” properties? Clinical evidence. J Clin Psychiatry 1999; 60 Suppl 10: 42-6. Leucht S, Pitschel-Walz G, et al. Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry 2002; 159: 180-90.

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[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32]

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Sachs GS. Bipolar mood disorder: practical strategies for acute an maintenance phase treatment. J Clin Psychopharmacol 1996; 16(suppl 1): 32-47. Fountoulakis KN, Gonda X, Vieta E, et al. Class effect of pharmacotherapy in bipolar disorder: fact or misbelief? Ann Gen Psychiatry 2011; 10(1): 8. Zuvekas SH, Vitiello B. Stimulant medication use in children: a 12-year perspective. Am J Psychiatry 2012; 169: 160-6. Healy D. Let Them Eat Prozac: The Unhealthy Relationship Between the Pharmaceutical Industry and Depression. New York: New York University Press, 2004. Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial Severity and Antidepressant Benefits: A MetaAnalysis of Data Submitted to the Food and Drug Administration. PLoS Med 2008; 5(2): e45. Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry 1996; 67 Suppl 4: 27-30. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209-23. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079-87. Ho BC, Andreasen NC, Ziebell S, et al. Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia. Arch Gen Psychiatry 2011; 68: 128-37. Kemp AS, Schooler NR, Kalali AH, et al. What is causing the reduced drug-placebo difference in recent schizophrenia clinical trials and what can be done about it? Schizophr Bull 2010; 36: 504-9. Baker CB, Johnsrud MT, Crismon ML, et al. Quantitative analysis of sponsorship bias in economic studies of antidepressants. Br J Psychiatry 2003; 183: 498-506. Procyshyn RM, Chau A, Fortin P, et al. Prevalence and outcomes of pharmaceutical industrysponsored clinical trials involving clozapine, risperidone, or olanzapine. Can J Psychiatry 2004; 49: 601-6. Heres S, Davis J, Maino K, et al. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of secondgeneration antipsychotics. Am J Psychiatry 1006; 163: 185-94. Angell M. Is academic medicine for sale? N Engl J Med 2000; 342: 1516-1518. McShane R, Keene J, Gedling K, et al. Do neuroleptic drugs hasten cgnitive decline in dementia? Prospective study with necropsy follow up. BMJ 1997; 314: 266-270. Giurgea C. Vers une pharmacologie de l’activité intégrative du cerveau. Tentative du concept nootrope en psychopharmacologie. Actual Pharmacol (Paris) 1972; 25: 115-56. Summers WK, Majovski LV, Marsh GM, et al. Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N Engl J Med 1986; 315: 1241-5. Tricco AC, Soobiah C, Berliner S, et al. Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis. CMAJ 2013; 185: 1393-401. Sani G, Serra G, Kotzalidis GD, et al. The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence. CNS Drugs 2012; 26: 663-90. Karran E, Hardy J. Antiamyloid therapy for Alzheimer’s disease--are we on the right road? N Engl J Med 2014; 370: 377-8. Moncrieff J. The myth of the chemical cure. A critique of psychiatric drug treatment. Houndmills: Palgrave McMillan, 2008.

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CHAPTER 2

Evolution of Psychotropic Drug Use in Elderly Patients: Pharmaceuticals Emerging as Environmental Contaminants Unax Lertxundi1,* and Beatriz Corcostegui2 1

Pharmacy Service, Araba´s Mental Health Network, Vitoria-Gasteiz, Araba, Spain and Pharmacy Service, Bizkaia´s Mental Health Network, Bermeo, Bizkaia, Spain

2

Abstract: The use of drugs in the general population and especially in the elderly has dramatically increased over the last decades, with older people aged 65 consuming about four times as many drugs as the rest of the population. Psychotropic drugs prescription in particular is becoming a major public health issue as its use is steadily increasing. After their use, drugs are excreted in their original form or as metabolites and enter aquatic systems via different ways. Although there is some information about the environmental impact of certain drugs, knowledge about what happens with the vast majority of them is simply lacking.

Keywords: Drug Utilization, Drug Utilization Review, Antidepressant, Antipsychotic, Anxiolytic, Hypnotic, Benzodiazepine, Hip Fracture, Elderly, Disease Mongering, Drug Industry, Water Pollution, Pharmaceutical Database, Defined Daily Dose, Ecotoxicology, Water Pollutants, Drug-Related Side Effects and Adverse Reactions, Sewage/Analysis, Humans. 1. BACKGROUND Population demographics are changing worldwide, while life expectancy and the proportion of older persons quickly rising. Thus, it is reasonable to assume that the consumption of prescription drugs by older people will increase [1]. In fact, the use of drugs in the general population and especially in the elderly has dramatically increased over the last decades, with older people aged 65 consuming about four times as many drugs as the rest of the population [1]. In addition, most people older than 65 years suffer from chronic conditions that frequently require long-term medical treatment. Patients may receive a collection *Corresponding author Unax Lertxundi: Pharmacy Service, Araba´s Mental Health Network, C/Alava 43 01006 Vitoria-Gasteiz, Araba/Álava, Spain; Tel: 0034 945 00 65 33; Fax: 0034 945 00 65 87; E-mail: [email protected] Unax Lertxundi, Juan Medrano and Rafael Hernández (Eds.) All rights reserved-© 2015 Bentham Science Publishers

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of different drugs, many of which are of different classes increasing the risk of iatrogenic harm, especially in patients with multiple morbidities. In this sense, psychotropic drugs prescription is becoming a major public health issue as its use is increasing among the population. For example, drugs acting on the central nervous system (CNS) were the most used in a study carried out in Denmark [2], with over 80% of females and 60% of males consuming them. Again, The European Study of the Epidemiology of Mental Disorders (ESEMED) study [3] showed that for both genders psychotropic drug use increased in parallel with age; even more in the oldest age group (65+ years) 18.8% of subjects had used any psychotropic drugs in the last 12 months. Therefore, analyzing how psychotropic drug consumption is developing and specially the reasons why it’s happening is mandatory. In this chapter we will study the trend in the use of drugs in different countries considering the main psychotropic drug classes and focusing on the elderly population, which is the main consumer of psychotropic drugs. Nonetheless, the study of drug use is complicated. As stated by the ESEMED authors, “The precise knowledge of drug use patterns can be achieved through drug utilization studies (DUS). Quantitative DUS can be developed using direct or indirect methodologies. Direct methods which are based on the interview of representative samples drawn from the general population probably provide the most accurate estimate of psychotropic drug usage. Quantitative indirect methods used in pharmacoepidemiological research, are based on the monitoring of drug sales from retail pharmacies or on the analysis of insurance claims and medical chart reviews, and have many limitations, also, it is important to consider their heavy dependence on data sources and the methods used to gather data”. Drug-consumption data at the patient level is generally not publicly available in most countries of European Union (EU) and United States of America (USA). Historically, drug consumption databases were created with an administrative purpose, for example: to record drug use in the outpatient setting for refund. Back in 1969, The Word Health Organization (WHO) Drug Consumption Group was created, shifting the attention of drug consumption onto other healthcare research fields. One of the major problems of these kinds of studies, already recognized in 1960, is the standardization of raw data into comparable units. At a symposium of WHO in Oslo in 1969 entitled “The Consumption of Drugs”, it was agreed that an internationally accepted classification system for drug consumption studies was needed.

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Norwegian researchers developed a system known as the Anatomical Therapeutic Chemical (ATC) classification of drugs. In order to measure drug use, a technical unit of measurement called the Defined Daily Dose (DDD) was developed to be used in drug utilization. In 1996, WHO recognized a need to develop the use of ATC/DDD system as an international standard for drug utilization studies. The DDD is the assumed average maintenance dose for the main indication of a particular drug and it is normally expressed as the number of DDDs per 1000 inhabitants per day, which allows both comparisons between countries and regions and evaluation of trends over time. Problems in this system arise when a certain drug is used for more than one major indication or when drugs are prescribed in combination with other drugs for the same disease. Additionally, studying psychiatric drugs using the ATC/DDD methodology has others limitations. For example, some authors questioned the reliability of DDDs in the standardization of antipsychotic drugs, while others found no discrepancies between DDD methodology and classic chlorpromazine equivalents (CPZEs), a method to chart relative antipsychotic potencies of antipsychotic drugs. Nevertheless the ATC/DDD methodology is used by an increasing number of researchers worldwide. Sadly, it is surprisingly difficult to access to public patient linkage data and thus drug consumption in the elderly. Only a few countries in the world have this data freely available (consult appendix I for further information). 2. ANTIPSYCHOTIC DRUG UTILIZATION Antipsychotic drugs became the top selling drug class in the United States in 2008, surpassing lipid regulators and proton pump inhibitors, according to IMS data (a company that gathers and analyzes data on pharmaceuticals) [4]. This commercial success strongly suggests that atypical antipsychotics were being used widely off-label. Researchers speculate that some of the enthusiasm for atypical antipsychotics may have been driven by a perception that these drugs were more effective and had fewer neurologic adverse effects than their predecessors. Nevertheless, a growing body of evidence indicates these drugs are not more effective and are associated with serious risks of their own [5]. Dementia is a very common disease, which mainly affects older people. As stated by Harding and cols, “there are an estimated number of 25 million people with dementia worldwide who experience one or more of the behavioural and psychological symptoms of dementia (BPSD) which can include delusions,

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hallucinations, depression, anxiety, sleeplessness, wandering, agitation, and physical aggression”. Traditionally, these symptoms of dementia were treated with antipsychotic medications in spite of only modest evidence of their efficacy [6] and lack of regulatory approval for use in this indication. In fact, risperidone is the only drug labeled for BPSD and only in some countries. The reassessment of clinical trials data showed an increased risk of death with some second generation antipsychotics (SGAs) which prompted some countries to issue safety warnings. The first safety reports were published back in 2002 in Canada. It was not until April 2005 that the FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death. Three years later, in June 2008, the FDA extended this warning to conventional or “typical” antipsychotic medications. Despite there is some evidence that rates of prescribing have decreased in this population, the use for this indication remains common worldwide. 2.1. United States of America (USA) One study carried out in the USA found that before the warning was issued, physician prescribing of this class of medications was increasing 34% annually overall and rising 16% annually in patients with dementia [7]. Another study [8] that examined changes in atypical and typical antipsychotic use in outpatients with dementia from 1999 to 2007 in the national veteran affairs registries showed the following results: In 1999, 17.7% of patients with dementia were using atypical or conventional antipsychotics. Overall use began to decline during the no-warning period (rate: -0.12%). Following the black box warning, the decline continued (rate: -0.26%), with a significant difference between the early and black box warning periods. Use of atypical antipsychotics as a group increased during the no-warning period (rate: 0.23%), started to decline during the early-warning period (rate: -0.012%), and more sharply declined during the black box warning period (rate: -0.27%). In the black box warning period, there was a small but significant increase in anticonvulsant prescriptions (rate: 0.117%). The authors concluded that the use of atypical antipsychotics began to decline significantly in 2003, and the FDA warning was temporally associated with a significant acceleration in the decline.

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2.2. England A recent report for the British Government investigated the use of antipsychotic medication for people with dementia in the NHS in England and reported that antipsychotics were over-prescribed [9]. It was estimated that up to 180.000 people with dementia were treated with antipsychotic medication in England each year [10]. They quantified the risk of this drug as 1.620 additional cerebrovascular accidents per annum in people with dementia, and 1.800 deaths on the short term. In the longer-term up to 167 additional deaths among 1.000 people with dementia treated with antipsychotics over a two-year period may result. 2.3. Scotland The percentage of people with dementia and a prescribed antipsychotic was 15.9% in 2001 and was raised by an estimated 0.6% per quarter before a 2004 risk communication, and then it changed first to an absolute reduction in antipsychotic prescribing of 5.9% and later to a stable level of prescribing. Further, 2009 risk communication was disseminated in a limited circulation bulletin, and it only recommended avoiding initiation if possible so this could be the reason why there was no immediate associated impact, but a significant decline appeared in prescribing which could be due to a decline in initiation of new treatments, with the percentage of prescription of an antipsychotic falling from 18.4% in quarter 1 2009 to 13.5% in 2011. The authors concluded that although rates are falling, antipsychotic prescribing in dementia in Scotland remains unacceptably high. [11]. 2.4. Canada There was a modest impact of the warnings issued by Health Canadian Ontario [12]. The overall prescription rate of antipsychotic drugs among patients with dementia increased by 20%, from 1.512 per 100.000 elderly patients in September 2002, the month before the first warning, to 1.813 per 100.000 in February 2007, 20 months after the last warning. Before the first warning, growth in the use of atypical antipsychotics was responsible for an increasing rate of overall antipsychotic use. Each warning was associated with a small relative decrease in the predicted growth in the use of atypical antipsychotic drugs: a 5.0% decrease after the first warning, 4.9% after the second and 3.2% after the third. The authors of the study concluded that “although the warnings slowed the growth in the use of atypical antipsychotic drugs among patients with dementia, they did not reduce the overall prescription rate of these potentially dangerous drugs”.

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2.5. France The French agency also issued a warning in 2004 which was extended to all antipsychotics in 2008. Recently, a quasi-experimental study carried out from 2003 to 2011 that included subjects aged ≥65 with dementia and subjects aged ≥65 without dementia showed the following results: In patients with dementia (n=7169), there was a 40% reduction in antipsychotic use from 14.2% in 2003 to 10.2% in 2011. The reduction began before 2004 and was unaffected by the warnings. Use of first generation antipsychotics declined over the period, while use of SGAs increased and leveled off from 2007. In subjects without dementia (n=91, 942), rates of overall antipsychotic use decreased from 2.3% in 2003 to 1.8% in 2011 with no effect of the warnings. Meanwhile, use of SGAs continuously increased from 0.37% to 0.64%. Antipsychotic use decreased in the elderly between 2003 and 2011, especially in dementia. The timing of the decrease, however, did not coincide with safety warnings [13]. 2.6. Italy According to data on prescriptions from the Lombardy Region Drug Administrative Database, the prescription of atypical antipsychotics in patients exposed to cholinesterase inhibitors significantly declined from 21.0% in 2002 to 14.6% in 2008, while the prescribing prevalence of typicals slightly increased. After a first safety warning the prevalence of prescriptions for risperidone and olanzapine dropped significantly, and there was a significant increase for quetiapine. Haloperidol prescriptions increased, especially after a second warning. Despite regulatory warnings issued to discourage the use of antipsychotics, they are still frequently prescribed to patients taking cholinesterase inhibitors [14]. 2.7. Spain In the region of Valencia in Spain, a decrease in low strength pharmaceutical forms doses of olanzapine and risperidone used by pensioners was seen following the safety warnings [15]. 3. ANTIDEPRESSANT DRUG UTILIZATION The prevalence of antidepressant use has increased over time in many countries especially since the advent of selective serotonin reuptake inhibitors (SSRIs). Between 2000 and 2010 rates of use in Europe have continued to increase, with the highest DDD rates seen in Iceland, Denmark and Portugal [16]. This might be due to both the introduction of newer generation antidepressants and the

Evolution of Psychotropic Drug Use in Elderly Patients

Psychopharmacological Issues in Geriatrics 23

expansion of therapeutic indications. Antidepressants are approved not only for the treatment of mood disorders and actually other licensed uses are: anxiety disorders, sleep disorder, adjustment disorder, headache, back pain, neuropathic pain, fibromyalgia, dermatological disorders, functional gastrointestinal disorder, urogenital dysfunction, nocturnal enuresis, narcolepsy and tobacco cessation. But other factors might also be involved in this growth. Some authors consider that the current definition of depression is too loose and is causing widespread medicalization [17]. The Diagnostic and Statistical Manual of Mental Disorders (both DSM-IV and the recently released DSM-V) suggests defining two weeks of low mood as “clinical depression,” irrespective of circumstance. It even proposes that being low two weeks after bereavement should be considered depression. 3.1. The Case of Japan [18] In Japan, mild depression was rarely seen as a medical condition, and it was not common to think that such feelings should be counteracted with chemical substances. As direct-to-consumer advertising is prohibited in Japan, pharmaceutical companies initiated educational campaigns focusing on mild depression. In order to aid the drug’s acceptance by the Japanese public, they coined the catchphrase ‘kokoro no kaze’, which literally means ‘a cold of the soul’. The campaign accelerated when GlaxoSmithKline received approval for Paxil® (paroxetine). According to national data from the Ministry of Health and Welfare, the number of patients with a diagnosis of mood disorder increased from 441.000 in 1999 to 1.041.000 in 2003. Concordantly, antidepressant sales have increased six fold, from 14.5 billion ¥ back in 1998 to 87 billion ¥ in 2006. Thanks to marketing practices that equate depression with a cold, Japan has proven to be a fertile ground for selling antidepressants. 3.2. England Since 2006, prescriptions in England have increased by 17.3 million, a 59% of increment. Although it has been suggested that the increase of prescriptions could be due to longer duration of treatment, the prescription of antidepressants to even more people seems to be the most likely explanation [19]. 3.3. Spain Antidepressant consumption in 2005 in Castilla Leon, a region in Spain, increased 7-fold, from 6.9 DDD per 1000 inhabitants per day in 1992 to 47.3; the corresponding increase in cost was more than 10-fold. Moreover, the pattern of

24 Psychopharmacological Issues in Geriatrics

Lertxundi and Corcostegui

use has changed; there is an increase in the consumption of the new and more expensive antidepressants such as venlafaxine and escitalopram [20]. 3.4. Several European Countries A study carried out in 29 European countries between 1980 and 2009 showed the following results [16]: Overall, an increase of 40.33 units DDD/1000/day was found in the study period. A continuous growth in the use of antidepressants over time was seen, with an average growth per annum of 19.83% in DDD/1000/per day. The lowest rates of annual growth of just 3% were seen in the Netherlands and Switzerland followed by Bulgaria, France and Luxembourg (all 5%), with the highest growth rate of 59% seen in Finland followed by the Czech Republic (41%), Slovakia (40%) and Sweden (34%). The latest available five year data indicated that the use of antidepressants varied markedly from just 4.0 DDD/1000 per day in Romania, 5.6 in Latvia and 6 in Bulgaria, to as much as 68.5 in Denmark, 70.1 in Sweden and 95.2 in Iceland. There was an average DDD/1000/per day of 40 across all countries. 3.5. United States of America The latest study carried out in 6 waves of the cross-sectional National Health and Nutrition Examination Survey of the USA in has shown that the overall prevalence of antidepressant use increased from 6.5% in 1999-2000 to 10.4% in 2009-2010 [20]. 4. ANXIOLYTIC/HYPNOTIC DRUG UTILIZATION A recently published report which was part of the IMI PROTECT program, explored the suitability of IMS data (volume sales data of the Intercontinental Medical Statistics database.) for pharmacoepidemiological studies. More precisely it focused on the possible impact of the use of benzodiazepines on the rate of hip fracture in five large European countries (France, Germany, Italy, Spain, and the United Kingdom UK) and USA [21]. The literature review showed an increased risk of hip fractures in benzodiazepine users (RR = 1.4). The rate of benzodiazepine use showed considerable differences between countries, ranging from 4.7 % to 22.3 % of population ever in a 1-year period. This can be observed in the population attributable risks (PARs), so estimated attributions of benzodiazepines to the rate of hip fractures were 1.8 % (Germany); 2.0 % (UK); 5.2 % (Italy); 7.4 % (France); 8.0 % (USA); and 8.2 %

Evolution of Psychotropic Drug Use in Elderly Patients

Psychopharmacological Issues in Geriatrics 25

(Spain). In all countries, the PAR of SABs was higher than that of LABs, which suggests that a larger proportion of hip fractures may be associated with the use of SABs than the use of LABs. Table 1: Benzodiazepine use (DDD/1.000 persons/day) in five European countries and USA, calculated using IMS MIDAS drug sales data (2009) Country

Total

Short acting (SAB)

Long acting (LAB)

USA

82.9

75.9

6.96

Spain

85.5

67.9

17.6

France

76

64.1

11.9

Italy

52.4

42.4

10.0

UK

19.3

11.6

7.63

Germany

18

14.0

3.91

5. DISEASE MONGERING AS A CAUSE OF PSYCHOTROPIC DRUG OVERUSE IN THE ELDERLY Frequently used in an uncomplimentary sense, disease mongering connotes a widening of the diagnostic boundaries of illness. It is most often employed for activities of pharmaceutical companies, who conduct disease awareness campaigns on the pretext of educating the public about the prevention of illness or the promotion of health. Conceptual domains of diagnostic categories are strained to their own advantage under the cover of early detection and early treatment. Spurred by these disease awareness advertisement campaigns, patient´s concerns grow and require medical treatment. As a result, pharmacotherapy might be increasingly being applied to milder conditions, leading to potentially unnecessary medication, wasted resources, and an unneeded risk of adverse side effects. Among all fields of clinical medicine, psychiatry is perhaps one of the most vulnerable to the dangers of disease mongering. Some authors consider that mental illness is industry’s golden goose: incurable, common, long lasting, and involving multiple medications [17]. Moreover, Peter Goetzche, leader of Nordic Cochrane Centre, has directly linked pharmaceutical industry with corporate crime [22]. The Introduction to DSM V addresses some of these shortcomings by acknowledging that many psychiatric diagnoses give labels to phenomena that are dimensional, not categorical. The fact that symptoms are dimensional creates a zone of ambiguity and helps to explain disagreements about diagnosis. The psychiatric conditions most commonly targeted by the pharmaceutical industry include social anxiety disorder, attention deficit hyperactivity disorder, bipolar

26 Psychopharmacological Issues in Geriatrics

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disorder, and depression. Actually, the Center for Disease Control and Prevention reports, that at any time, 25% of US citizens have a psychiatric illness. 6. PHARMACEUTICALS EMERGING AS ENVIRONMENTAL CONTAMINANTS: SPECIAL FOCUS ON THOSE USED IN GEROPSYCHIATRY About 3.000 different substances are used in human medicine in the European Union (EU). After their use, they are excreted in their native form or as metabolites and enter aquatic systems via different ways. The main pathway from humans after ingestion is excretion and disposal via wastewater. For this reason, metropolitan wastewater is the principal route that transfers human drugs after normal use and disposal of unused medicines into the surroundings. Hospital wastewater, wastewater from manufacturers and landfill leachates may contain important concentrations of pharmaceuticals too. Drugs not rapidly degraded in the sewage treatment plant (STP) are being discharged in treated effluents resulting in the contamination of rivers, lakes, estuaries and rarely, groundwater and drinking water [24]. Drugs do not appear as isolated compounds in river water but as a mixture, and data on the responses of aquatic organisms to a mixture of pharmaceuticals are very limited. The current knowledge shows that residues of drugs at trace quantities are widespread in aquatic systems [25-28]. Although they are suggested to pose only a low risk for acute toxicity the situation may be different for chronic effects, where there is a considerable lack of information. The greatest concern is not necessarily a high production of a given pharmaceutical, but its environmental persistence and critical biological activity [24]. Enhanced sensitivity of analytical chemistry methods enabled effective detection of low-levels of pharmaceuticals in the environment, resulting in questions about the safety of surface waters used for drinking supplies [29]. In 2004 an unusually high death rate among three species of vulture in India and Pakistan was reported. It came as a surprise when the cause was discovered: residues of diclofenac present in the environment caused renal damage, leading to high adult and subadult mortality and resulting population loss [30]. Although some researches try to be reassuring [31], the truth is that the possible consequences on the environment and on human health of such contamination can turn out to be unpredictable.

Evolution of Psychotropic Drug Use in Elderly Patients

Psychopharmacological Issues in Geriatrics 27

For example, one of the most prevalent drug in the environment in the Western World is the antidepressant fluoxetine, a selective serotonin reuptake inhibitor. Usually detected in the range below 1 μg/L, fluoxetine and its active metabolite norfluoxetine are found to bioaccumulate in wild-caught fish, particularly in the brain. This has raised concerns over potential disruptive effects of neuroendocrine function in teleost fish [32]. In this sense, the results of one study suggested that sublethal exposure to fluoxetine decreased the ability of hybrid striped bass to capture prey and that serotonin can be used as a biomarker of exposure and effect [33]. The use of drugs in the general population and particularly in the elderly has dramatically increased in the last decades [2]. Although there is some information about the environmental impact of certain drugs, knowledge about what happens with the vast majority of them is simply lacking. ACKNOWLEDGEMENTS Declared none. CONFLICT OF INTEREST The authors confirm that this chapter contents have no conflict of interest. REFERENCES [1] [2] [3]

[4] [5] [6] [7] [8] [9] [10]

Gallagher P, Barry P, O'Mahony D. Inappropriate prescribing in the elderly. J Clin Pharm Ther. 2007;32:113-21. Barat I, Andreasen F, Damsgaard EM. The consumption of drugs by 75-year-old individuals living in their own homes. Eur J Clin Pharmacol. 2000 Sep;56(6-7):501-9. Alonso J, Angermeyer MC, Bernert S, et al ESEMeD/MHEDEA 2000 Investigators, European Study of the Epidemiology of Mental Disorders (ESEMeD) Project. Psychotropic drug utilization in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl 2004;(420):55-64. Kuehn BM. Questionable antipsychotic prescribing remains common, despite serious risks. JAMA 2010;303:1582-1584. Lertxundi U, Echaburu SD, Palacios RH. The use of antipsychotics in a medium-long stay psychiatric hospital from 1998 to 2010. Int J Psychiatry Clin Pract 2012 Jun;16(2):143-7. Harding R, Peel E. 'He was like a zombie': off-label prescription of antipsychotic drugs in dementia. Med Law Rev 2013 Mar;21(2):243-77. Dorsey ER, Rabbani A, Gallagher SA et al. Impact of FDA black box advisory on antipsychotic medication use. Arch Intern Med 2010 Jan 11;170:96-103. Kales HC, Zivin K, Kim HM, et al. Trends in antipsychotic use in dementia 1999-2007. Arch Gen Psychiatry 2011 Feb;68(2):190-7. Banerjee S, The use of antipsychotic medication for people with dementia: Time for action (Department of Health, London 2009). National Collaborating Centre for Mental Health, Dementia: a NICE-SCIE Guideline on supporting people with dementia and their carers in health and social care. National Clinical Practice Guideline no 42. (British Psychological Society, Leicester 2011). (NICE Dementia).

28 Psychopharmacological Issues in Geriatrics

[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]

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Guthrie B, Clark SA, Reynish EL, et al. Differential impact of two risk communications on antipsychotic prescribing to people with dementia in Scotland: segmented regression time series analysis 2001-2011. PLoS One 2013 Jul 17;8(7). Valiyeva E, Herrmann N, Rochon P. et al. Effect of regulatory warnings on antipsychotic prescription rates among elderly patients with dementia:a population based time-series analysis.CMAJ 2008.;179:438-446. Gallini A, Andrieu S, Donohue JM et al. Trends in use of antipsychotics in elderly patients with dementia: Impact of national safety warnings. Eur Neuropsychopharmacol. 2013 Sep 17. pii: S0924977X(13)00264-2. doi: 10.1016. Franchi C, Tettamanti M, Marengoni A, et al. Changes in trend of antipsychotics prescription in patients treated with cholinesterase inhibitors after warnings from Italian Medicines Agency. Results from the EPIFARM-Elderly Project. Eur Neuropsychopharmacol 2012 Aug;22(8):569-77. Sanfélix-Gimeno G, Cervera-Casino P, et al. Effectiveness of safety warnings in atypical antipsychotic drugs: an interrupted time-series analysis in Spain. Drug Saf 2009;32(11):1075-87. Gusmão R, Quintão S, McDaid D, et al. Antidepressant Utilization and Suicide in Europe: An Ecological Multi-National Study. PLoS One 2013 Jun 19;8(6). Spence D. Are antidepressants overprescribed? Yes. BMJ. 2013 Jan 22;346:f191. Arias LH, Lobato CT, et al. Trends in the consumption of antidepressants in Castilla y León (Spain). Association between suicide rates and antidepressant drug consumption. Pharmacoepidemiol Drug Saf 2010;19:895-900. Ihara H. A cold of the soul: a Japanese case of disease mongering in psychiatry. Int J Risk Saf Med 2012;24:115-20. Mojtabai R, Olfson M. National trends in long-term use of antidepressant medications: results from the US National Health and Nutrition Examination Survey. J Clin Psychiatry. 10.4088/JCP.13m08443. Khong TP, de Vries F, Goldenberg JS, Klungel OH, Robinson NJ, Ibáñez L, Petri H. Potential impact of benzodiazepine use on the rate of hip fractures in five large European countries and the United States. Calcif Tissue Int 2012 Jul;91(1):24-31. Gøtzsche PC. Big pharma often commits corporate crime, and this must be stopped. BMJ. 2012 Dec 14;345:e8462. Ferrer P, Ballarín E, Sabaté M et al, on behalf of the PROTECT project. Drug Consumption Databases in Europe. Barcelona, August 2011. 190 pages. (e-room link:https://eroombayer.de/eRoom/PH-GDC-PI-SID/IMI-PROTECT/0_d55d3). Fent K, Weston AA, Caminada D. Ecotoxicology of human pharmaceuticals. Aquat Toxicol. 2006 Feb 10;76(2):122-59. González S, López-Roldán R, Cortina JL. Presence and biological effects of emerging contaminants in Llobregat River basin: a review. Environ Pollut. 2012 Feb;161:83-92. doi: 10.1016/j.envpol.2011.10.002. Muñoz I, López-Doval JC, Ricart M, et al. Bridging levels of pharmaceuticals in river water with biological community structure in the Llobregat River basin (northeast Spain). Environ Toxicol Chem. 2009 Dec;28(12):2706-14. Schultz MM, Painter MM, Bartell SE, et al. Selective uptake and biological consequences of environmentally relevant antidepressant pharmaceutical exposures on male fathead minnows. Aquat Toxicol. 2011 Jul;104(1-2):38-47 Ternes, T.A. Occurrence of drugs in German sewage treatment plants and rivers. Water Res1998. 32: 3245-3260. Bercu JP, Parke NJ, Fiori J, et al. Human health risk assessments for three neuropharmaceutical compounds in surface waters. Regul Toxicol Pharmacol 2008 Apr;50(3): 420-7. Oaks JL, Gilbert M, Virani MZ, et al Diclofenac residues as the cause of vulture population decline in Pakistan. Nature 2004 Feb 12;427(6975):630-3. Cunningham VL, Binks SP, Olson MJ, et al. Regul Toxicol Pharmacol 2009 Feb;53(1):39-45. Mennigen JA, Stroud P, Zamora JM, et al. Pharmaceuticals as neuroendocrine disruptors: lessons learned from fish on Prozac. J Toxicol Environ Health B Crit Rev 2011;14(5-7):387-412. Gaworecki KM, Klaine SJ. Behavioral and biochemical responses of hybrid striped bass during and after fluoxetine exposure. Aquat Toxicol 2008 Jul 30;88(4):207-13.

Evolution of Psychotropic Drug Use in Elderly Patients

Psychopharmacological Issues in Geriatrics 29

Appendix Appendix I. NATIONAL DRUG CONSUMPTION DATABASES IN THE 11 COUNTRIES INCLUDED IN THE PROTECT STUDY EUROPE [23] Country

Organization

Denmark

Lægemiddelstyrelsen (Danish Medicines Agency)

Finland

Social Insurance Institution

France

Name

Accessibility

Linkage to other databases

Population Coverage (%)

Free. Further data application.

Yes (Health, demographic and socioeconomic)

100

http://www.kela.fi/in/in ternet/english.nsf

Application

Yes (Health, demographic and socioeconomic)

100

www.afssaps.fr

Application

Application.

Yes (Health, demographic and socioeconomic

87

http://wido.de/arzneive rordnungs-rep.html

Application.

Yes (Within the Statutory Health Insurance, to sociodemographic, hospital and outpatient data)

85

Application

No

100

Web

The Danish Registry http://medstat.dk/statist of Medicinal Products ics/#tabs-1 Statistics. Prescription reimbursement register

Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS) AFSSAPS database French Agency of Health Safety and Health Products

Caisse Nationale Extraction, d'Assurance Maladie des Travailleurs Salariés Recherches, Analyses http://www.ameli.fr/in pour un Suivi Médico(CNAMTS) dex.php Economique database National Insurance Fund (ERASME) for salaried employees. Wissenschaftliches Institut der AOK (WidO). The Research Institut of the Germany AOK. (AOK is the major German public health insurance company).

Italy

Netherlands

Norway

Agenzia Italiana del Farmaco. Osservatorio sull'impiego dei medicinali (OsMED) The Italian Medicines Agency. The Medicines Utilization Monitoring Centre.

OsMed database

http://www.agenziafar maco.it/it/content/osser vatoriosull% E2%80%99impiegodei-medicinali-osmed

Health Care Insurance Board

GIP Database

http://www.gipdataban k.nl/

Free online. Further data application

No

85

Foundation for Pharmaceutical Statistics (SFK)

Database of the Foundation for Pharmaceutical Statistics

http://www.sfk.nl

Application

No

92,5

Yes (Health, demographic and socioeconomic

100

No

100

No

100

Norwegian Free. Further data can Norwegian Institute of http://www.norpd.no/P Prescription Database be applied for Public Health revalens.aspx (NorPD). ([email protected]) Wholesaler-based drug statistics

Poland

Narodowy Fundusz National Health Fund Zdrowia (National Health database Fund)

Spain

Department of Pharmacy

www.fhi.no

Application ([email protected])

www.nfz.gov.pl

Application

www.msc.es/profesion Application to data

Lertxundi and Corcostegui

30 Psychopharmacological Issues in Geriatrics Country

Organization

Name

and Health Products (Ministry of Health, Social Policy and Equity).

The National Board of Health and Welfare

Sweden

Web

Accessibility

Linkage to other databases

Population Coverage (%)

Yes (Health, demographic and socioeconomic

100

No

100

No

100

No

100

No

100

ales/farmacia/organiza provider (Ministerio cion.htm de Sanidad. Paseo Prado, 18.28014 Madrid) Free online http://192.137.163.49/ sdb/lak/val.aspx (only in Swedish) Specific http://192.137.163.40/e data may be delivered Swedish Prescribed pcfs/index.asp?kod=en on requests for Drug Register gelska statistics or research. Approval from ethical committee is needed when data is used for research

Free online for OTC and total sales per county Further Apotek AB (The National information: www.apotekensservice Corporation of Swedish Apotek AB database application to data .se Pharmacies) provider statistik@apotekensser vice.se NHS Business Services Authority. Prescription Electronic Prescribinghttp://www.nhsbsa.nhs. Application to data Services. Electronic Database-England uk/PrescriptionService provider Prescribing Analysis and (ePACT) s/960.aspx Cost (ePACT) (Egland) Health & Social Care in Northern Ireland NHS National Services Scotland. Information Service Division (ISD) United Scotland. Scottish Kingdom Prescribing Analyses (SPA) NHS Wales Informatics Service (NWIS) Partneriaeth Cydwasanaethau. Gwasanaethau Rhagnodi 89 Shared Services Partnership. Prescribing Services

 

ePACT databaseNorth Ireland

Some data free online. http://www.hscbusines Further data must be s.hscni.net purchased

ePACT databaseScotland and HMUD www.isdscotland.org database

Application to data provider

Application to data www.wales.nhs.uk/siteprovider. ePACT databases3/home.cfm?orgid=42 Wales 8&redirect=yes Some data is available free online.

Psychopharmacological Issues in Geriatrics, 2015, 31-48

31

CHAPTER 3

Age-Related Pharmacokinetic/Pharmacodynamic Changes in Psychopharmacological Drugs Arantxa Isla Ruiz1,2,*, María Ángeles Solinís Aspiazu1,2 and Alicia RodríguezGascón1,2 1

Pharmacokinetics, Nanotechnology and Gene Therapy Group PharmaNanoGene, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain and 2Centro de Investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain Abstract: Demographic evolution will extensively increase the number of subjects aged 65 years and beyond in the upcoming years. This demographic trend becomes a relevant challenge for the professionals of health and a growing of medication demand, and also for deeper comprehension on how age affects the effect of drugs and their interactions. Changes in organ functions, homeostatic mechanisms and receptor responsiveness impair drug distribution, metabolism and excretion, and reduce the effectiveness of medicines. Good clinical trial data in this age group are often lacking, under-treatment is common, and increasingly fragility can make drug administration difficult. As a consequence, medication management is much more challenging in the elderly than in younger adult patients. It is well known that the pathophysiologic changes that occur in the transition from middle age to old age alter responsiveness to drugs, including psychotropic drugs. These Pharmacodynamic changes are especially important in the central nervous system (CNS), where an increasing of the sensitivity of the CNS to drug side-effects with age is observed. This chapter reviews extensively the age-related pharmacokinetic/pharmacodynamic changes in psychopharmacological drugs.

Keywords: Age, Antidemential agents, Antidepresssants, Antiepiletics, Antiparkinsonians, Antipsychotics, Anxiolytics, Clearance, Drug absorption, Drug distribution, Drug excretion, Drug metabolism, Frailty, Geriatric, Mood stabilizers, Pharmacodynamic, Pharmacokinetic, Psychotropics, Psycopharmacology, Volume of distribution. Demographic evolution will extensively increase the number of subjects aged 65 years and beyond in the upcoming years. In the near future, a significant increase of people aged more than 85 years will occur, even higher than in previous *Corresponding author Arantxa Isla Ruiz: Pharmacokinetics, Nanotechnology and Gene Therapy Group, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Paseo de la Universidad 7 01006 VitoriaGasteiz, Araba/Álava, Spain; Tel: 0034 945013469; E-mail: [email protected] Unax Lertxundi, Juan Medrano and Rafael Hernández (Eds.) All rights reserved-© 2015 Bentham Science Publishers

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decades [1]. On the other hand, by 2025, it is estimated that more than 20% of the European population will be 65 years of age or older [2]. This demographic trend becomes a relevant challenge for the professionals of health, a growing of medication demand, and also for deeper comprehension on how age affects the effect of drugs and their interactions. Aging has been described as a progressive alteration in the cellular, physiological and psychological properties of the human body, joint with a progressive decrease of cellular, molecular and physiological functionality of organs and tissues [2]. Medication management is much more challenging in the elderly than in younger patients. Changes in organ functions, homeostatic mechanisms and receptor responsiveness impair drug distribution, metabolism and excretion, and reduce the effectiveness of medicines [3, 4]. In parallel, aging is associated with increasing disease burden and needs and therefore increases the number of drugs for the treatment of different illnesses (polypharmacy) [5]. Consecutively, elderly people are particularly at risk of adverse drug reactions and drug-drug and drug-disease interactions. Good clinical trial data in this age group are often lacking, undertreatment is common, and increasingly fragility can make drug administration difficult. As an example to understand the complexity associated with drug prescription to elderly people, it has recently published that about one-third of the elderly Norwegian population is exposed to potentially inappropriate medications, and elderly females are at particular risk [6]. One in five community-dwelling elderly persons is prescribed psychotropic medications [7]. Additionally, between 20.9% and 44.3% of long-term-care residents are dispensed antipsychotics [8, 9]. Psychotropics are one of the leading agents causing preventable adverse drug events in long term-care facilities [10]. In spite of the difficulty for prescribing to elderly, there is limited geriatricsoriented clinical pharmacological information available to guide pharmacotherapy in late-life psychiatric disorders. The inclusion of a greater number of elderly persons in clinical trials, more intensive and standardized postmarketing studies in old patients and the vigorous application of clinical pharmacologic methodology (i.e., pharmacoepidemiology, population pharmacokinetic modeling, and pharmacogenetics) will be critical for improving safety and personalization of drug and dose selection for elderly people [11]. Pathophysiologic alterations occurring in the passing to middle age to old age are known to modify the response to drugs, repeated including psychotropic drugs. In this chapter, the pharmacokinetic and pharmacodynamic changes of psychoactive drugs with age are extensively reviewed.

Age-Related Pharmacokinetic/Pharmacodynamic Changes

Psychopharmacological Issues in Geriatrics 33

1. PHARMACOKINETIC CHANGES IN AGING Pharmacokinetics describes “what the body does to the drug” and studies the processes of absorption, distribution, metabolism and excretion (ADME). Old age is associated with alterations in cellular, subcellular, molecular and physiological functionality of an organ or a tissue, thus influencing the processes of absorption, distribution and elimination of drugs from the body. These changes in the pharmacokinetic parameters should be considered to prescribe an effective drug treatment and for the development of appropriate medicines for older people. In addition, two more issues make it challenging to understand pharmacokinetics in geriatric patients: i) Frailty and ii) The exclusion of older people from clinical research, and of under-recruitment to clinical trials. i)

The age of the patient is not the best variable for decision making when selecting medication for geriatric patients. The concept of frailty has to be understood and considered to optimize drug prescribing and dosing for older patients. Frailty, a term used as a marker of biologic age and physiologic reserve, is defined as a multidimensional syndrome characterized by the loss of physiologic reserves that gives rise to vulnerability to adverse events. It is more strongly associated than chronological age with altered responses to drug therapy [12, 13]. In this regard, some authors classify the elderly as “fit-elderly” and “frail-elderly”, which is independent from the numerical age and considers the elderly from the viewpoint of the physiological functions that can be maintained over a long age period or can decline very rapidly with an acute disease or hospitalization [4]. This concept has been considered unquestionable and has leaded European Medicines Agency (EMA) to perform a proposal for the development of a points to consider for baseline characterization of frailty status [14].

ii) Elderly patients are under-represented in clinical trials. However, considering that older people experience a higher incidence of disease-related morbidities, take more medicines, are subject to more multiple medication regimens, and account for more adverse drug related events than their younger counterparts [15], it is essential to increase their recruitment in order to demonstrate the safety and efficacy of pharmacological treatments [16]. The European Forum of Good Clinical Practice suggests that it is important to conduct more

34 Psychopharmacological Issues in Geriatrics

Ruiz et al.

research and clinical trials in this patient population for further knowledge in the understanding and management of their conditions and treatment; medicines used by the older people must be of high quality, appropriately researched and evaluated throughout their life cycles [15]. The major age-related changes that may affect psychopharmacological drug pharmacokinetics in elderly patients comparing with young adults include physiological changes or comorbidities, such as cardiovascular, metabolic, respiratory, osteoaarticular or nervous diseases that are extensively explained below. 1.1. Drug Administration As mentioned above, regulatory agencies consider that there are some issues that should be addressed in drug development in order to guarantee that they are suitable for old patients [17, 18]. Many of them are associated with drug administration and are briefly explained below. The oral route of drug administration is the most accepted and preferred route. The drugs administered orally are usually the best option. However, clinicians must consider some factors when prescribing medicines to older patients. For instance, if the patient has dysphagia, very common in elderly, the compliance of the treatment may be compromised, and consequently, the treatment may lose efficacy. Other problems are the weakness of the tongue, weak control of the muscles of the tongue in patients suffering stroke, surgery, and oesophagus and nervous system disorders [2]. Older patients commonly require lower doses than younger adults. The use of drug formulations adapted for dose requirements associated with age is a key point not only for children but also for geriatric patients. However there are not often commercially available oral dosage forms, hence available presentations must be manipulated, which may lead to dosing errors. For example breaking or splitting tablets is a common practice that could result in unpredictable dosing [19, 20] especially in patients with impaired motoric functions. In addition, as hand mobility and strength decreases gradually after 65 years and becomes apparent at an age of ≥75 years [2], some patients have difficulties to open pharmaceutical packaging designed to prevent children’s access. Finally, treatment compliance and adherence problems must be considered at this point. While these terms were initially used synonymously they have subtle

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Psychopharmacological Issues in Geriatrics 35

differences. The term compliance refers to “the extent to which a person’s behavior (in terms of taking medication, following diets, or executing lifestyle changes) coincides with medical or health advice”. Adherence, or patient-centred compliance, describes the extent to which patients take prescribed drugs. It implies a more active and collaborative involvement of patients working with health-care providers in managing their treatment [21]. Non-adherence involves not only failure to take prescribed treatments but also taking doses different to prescribed ones. Poor adherence to antipsychotics is a major problem in subjects with psychotic disorders in general. Between 25% and 80% of patients fail to take their drugs correctly at some point in their treatment [22]. Moreover, nonadherence in elderly people may stem from cognitive impairment or functional disability [23]. When managing elderly patients, practitioners should strive to understand and enhance compliance and adherence to prescribed therapies as an integral part of the therapy [4]. 1.2. Absorption Ageing may affect drug dissolution and absorption after oral administration. Changes in gastrointestinal physiology however do not have in general clinically significant impact on drug bioavailability. There is a decrease in saliva and gastric fluid production, which increases pH and may affect drug dissolution and absorption. Esophageal motility is diminished, gastric emptying is delayed and there is a decrease in peristalsis and colonic motility that slows transit time in the small and large bowel. In addition, aging is associated with villous atrophy that leads to a loss of gastrointestinal absorptive surface area, although the clinical significance of these changes is small due to the high absorptive capacity of human mucosa. Absorption of drugs by active transport may also be diminished in the elderly [2, 24, 25]. The bioavailability of some drugs (i.e., morphine, meperidine) that suffer first pass metabolism is increased, probably because liver mass, liver flow and metabolic capacity are reduced in the elderly. However, other high clearance drugs (verapamil, propafenone) do not show differences in bioavailability among young adults or old subjects [26]. Drug absorption can also be decreased if patients concomitantly take anticholinergic drugs, acid suppressive drugs or highfiber supplements. Age-related changes affecting drug absorption are rarely clinically relevant, but elderly people are at high risk for developing other problems that can affect

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absorption. Apart from age-related physiological changes some disease conditions cause gastrointestinal symptoms that can affect drug absorption after oral administration i.e., delayed gastric emptying occurs in both early and advanced Parkinson disease (PD) [27]. As described above, there are also other circumstances that may make it difficult for elderly patients to take their medicines orally, such as swallowing problems, poor nutrition, constipation or age-related anorexia [25]. Regarding other administration routes, the transdermal is a good approach for elderly people with some neurological disorders or chronic pain because it is simple, may reduce systemic adverse effects and provides sustained plasma concentrations [24]. Transdermal drug delivery systems have some advantages over oral route such as avoiding hepatic first-pass metabolism, ensuring a constant rate of drug administration or improving complicance [28], which makes them a good alternative route of administration. However, transdermal drug administration is still not well evaluated in the elderly. Transdermal absorption involves passive diffusion through the different layers of the skin. Diffusion may be affected by structural changes that occur with age. Age-related changes in hydration and lipidic structure result in an increased barrier function of the stratum corneum only for relatively hydrophilic compounds. However, no significant differences in absorption of drugs have been demonstrated between young and old individuals after transdemal administration. Therefore, the doseregimen modifications needed in elderly patients using transdermal drug delivery systems are not related to differences in absorption but to age-related cardiovascular, cerebral, hepatic and/or renal compromise, and to ensuing geriatric pharmacokinetic and pharmacodynamic changes [28]. 1.3. Distribution Body composition changes significantly with ageing, affecting drug pharmacokinetic profile. Body fat increases (20-40%), plasma volume decreases (8%) [25]. A reduction in the apparent volume of distribution of polar watersoluble drugs (e.g., lithium) is observed, which potentially can increase plasma drug concentration and toxicity. In contrast, as body fat acts as a reservoir, distribution volume of lipophilic drugs such as benzodiazepines, increases with aging, prolonging their elimination half life. There has been observed a relation among drug lipophilicity and the effect of age on the apparent volume of distribution [26].

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Psychopharmacological Issues in Geriatrics 37

Apart from changes in body composition, alteration in protein binding may affect drug distribution. There is a reduction in albumin plasma concentration whereas -1-acid glycoprotein tends to increase, although its clinical significance is overall minimal. Differences in protein binding may be clinically relevant only for drugs with small volume of distribution and narrow therapeutic index [24]. Moreover, relevant changes in drug exposure are expected only when drugs are highly extracted by the liver, are extensively bound to proteins and administered intravenously (such as alfentanil, amitriptyline, buprenorphine, butorphanol, chlorpromazine, cocaine, diphenhydramine, fentanyl, haloperidol, lidocaine, midazolam, propofol, remifentanil or sufentanil) or when are administered orally and are eliminated by nonhepatic high extraction ratio routes (Table 1) [29]. Table 1: Summary of situations when protein binding may be clinically relevant Administration Route Intravenous Oral

Clearance

High Extraction Ratio

Low Extraction Ratio

Hepatic clearance

Yes

No

Nonhepatic clearance

Yes

No

Hepatic clearance

No

No

Nonhepatic clearance

Yes

No

1.4. Metabolism Metabolism refers to the biotransformation processes through which the organism converts drugs into more polar molecules. Most metabolic reactions take place in the liver, thus age-related changes in this organ are the cause of many pharmacokinetic changes in elderly. Drug hepatic clearance depends on hepatic blood flow, and intrinsic clearance (enzyme activity and mass) and protein binding [24, 30]. Clearance of highly extracted molecules is predominantly determined by hepatic blood flow, while that of poorly extracted drugs is influenced by intrinsic clearance and in some cases by protein binding. Aging is associated with a gradual decrease in both liver mass and blood flow. Blood flow may approximately reduce by 40-45%, and liver mass by 30%. The clinical impact of this decrease is variable. Clearance of highly extraction psychotropics, such as tricyclic antidepressants, is reduced by the above mentioned blood-flow changes. There is also an age-related diminished capacity to metabolize some drugs, particularly those metabolized by Phase I reactions. Most of these reactions are mediated by cytochrome

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monoxygenase enzymes (CYP450 system). The activity of isozyme CYP2D6, responsible of the hydroxylation of many antidepressants (nortriptyline, desipramine, paroxetine, venlafaxine) and antipsychotics (perphenazine, thioridazine, and risperidone) [31] is not apparently affected by age, although significant interactions can occur with other pharmacological treatments. CYP2C19 isozyme activity, involved in the metabolism of diazepam, escitalopram, mephenytoin, and phenytoin or tertiary tricyclic antidepressants declines with age [31]. Isozyme CYP3A4 functioning also declines with age, affecting the metabolism of drug such as setraline, mirtazapine, alprazolam or triazolam. In some circumstances problems may be caused by the accumulation of drug’s active metabolites. For example, hydroxylated active metabolites of antidepressants may be responsible of clinically relevant side effects. The metabolite of imipramine, 2-OH desipramine, has been associated with prolonged QRS intervals. Desvenlafaxine, the major metabolite of venlafaxine, can impair heart’s conduction. The accumulation of paliperidone or 9-hydroxyrisperidone in patients with decreased renal or hepatic function may induce unexpected extrapyramidal side effects [31]. 1.5. Renal Elimination Ageing is associated with a loss in renal mass (25-30%) and a decrease in renal flow. However, decline in glomerular filtration rate (GFR) is considered the most important change that may affect drug pharmacokinetics in the elderly. Serum creatinine is not an adequate marker of renal function in old age because it often remains within reference range due to the simultaneous loss of muscle mass. Nowadays the most used indicator of renal function is the GFR. The most often used equation to estimate creatinine clearance, a useful measure for approximating the GFR, is the Cockcroft-Gault formula [32]:

Creatinine _ clearance 

(140  age( years)  weight(kg )  0.85 _ for _ females 72  serum _ creatinine(mg / dL)

Considering that Cockcroft-Gault equation underestimates GFR, MDRD (Modification of Diet in Renal Disease) equation can be used to assess the GFR in elderly. GFR  175  SerumCr 1.154  Age 0.203  0.742(if  female)  1.212(if  black )

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Psychopharmacological Issues in Geriatrics 39

Figure 1: Main pharmacokinetic changes in geriatric patients.

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40 Psychopharmacological Issues in Geriatrics

Renal tubular secretion also decreases in parallel with GFR with increasing age. Moreover, other clinical situations associated with elderly may cause further renal dysfunction. Such is the case of dehydratation, congestive heart failure or concurrent drug administration. As a consequence of all these changes in renal function, the clearance of drugs that are eliminated primarily in urine declines with age and dosage adjustments are needed. In Fig. 1 and Table 2 the main pharmacokinetic changes in geriatric patients, and in psychoactive drugs are presented. Table 2: Age-related pharmacokinetics changes in psychoactive drugs Drug

Absorption

Protein binding

Volume of Half Hepatic Clearance Renal impairment distribution life impairment

Dose in elderly

ANXIOLYTICS

Alprazolam

Chlordiazepoxide

Clorazepate

Diazepam

 Dosage Avoid in serious liver insufficiency (Child-Pugh C)

 Cautious dosage selection. Initiate therapy at the lower end of the usual range

=





Conflicting data reported







 Dosage

 Dosage Avoid in serious liver insufficiency (Child-Pugh C)

 Dosage









 Dosage

 Dosage Avoid in serious liver insufficiency (Child-Pugh C)

 Dosage

Conflicting data reported

Flurazepam



Lorazepam

Conflicting data reported

Oxazepam

Dosage adjustment not required for single injection; Caution with multiple doses

=















 Cautious dosage selection. Initiate therapy at the lower end of the usual range



Dosage adjustment not required for single injection; Caution with multiple doses



Dosage adjustment not required for single injection; Caution with multiple doses

 Cautious dosage selection. Initiate  Cautious therapy at the lower dosage end of the usual selection. range Initiate therapy at the lower end Avoid in serious of the usual liver range insufficiency(ChildPugh C) Avoid in serious liver insufficiency (Child-Pugh C)

 Dosage

Cautious use in Child-Pugh C

 Dosage

Cautious use in Child-Pugh C

 Cautious dosage selection. Initiate therapy at the lower end of the usual range

Age-Related Pharmacokinetic/Pharmacodynamic Changes

Psychopharmacological Issues in Geriatrics 41

Table 2: contd….

=

Temazepam

=

Conflicting data reported

Triazolam

 Cautious dosage selection. Initiate therapy at the lower end of the usual range

=





 Cautious dosage selection. Initiate therapy at the lower end of the usual range

 Cautious dosage selection. Initiate therapy at the lower end of the usual range Avoid in serious liver insufficiency (Child-Pugh C)

 Cautious dosage selection. Initiate therapy at the lower end of the usual range

ANTIDEPRESSSANTS Amitriptyline

 bioavailability

Conflicting data reported



Conflicting Conflicting data data reported reported

Citalopram



 Dose adjustment depending on clinical response

 Dose adjustment depending on clinical response

 Dose adjustment depending on clinical response





Avoid in CLCR>20mL/min

 Cautious dosage selection. Initiate therapy at the lower end of the usual range

 Dose reduction

Fluoxetine

No dosage  Cautious dosage adjustment selection. Initiate suggested in therapy at the lower mild/moderate renal end of the usual range insufficiency. Avoid in serious liver Dose reduction in insufficiency (Childsevere renal Pugh C) impairment

Fluvoxamine

 Cautious dosage selection. Initiate therapy with a low dose

 Cautious dosage selection. Initiate therapy with a low dose

 Cautious dosage selection. Initiate therapy with a low dose



Dose reduction

Dose reduction

Same initial dose than adults. Increase dose with caution



Cautious dosage selection. Dose reduction Monitor drug concentrations

Cautious dosage selection. Dose reduction Monitor drug concentrations

Cautious dosage selection. Dose reduction Monitor drug concentrations



Cautious dosage selection. Dose reduction

Cautious dosage selection. Dose reduction

Same initial dose than adults. Lower maximum dose



Not dose adjustment needed

Cautious dosage selection. Dose reduction

Cautious dosage selection. Risk of developing hyponatremia

Imipramine

=

No difference

Nortriptyline







= 

Mirtazapine

 



Conflicting data  reported

Paroxetine



Sertraline







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42 Psychopharmacological Issues in Geriatrics Table 2: contd….

Cautious dosage Same initial No dose adjustment selection. Monitor dose than adults. suggested. Cautious hepatic function Dose dosage selection in adjustment patients with severe Avoid in serious liver depending on insufficiency (Childrenal impairment clinical response Pugh C)



Trazodone

MOOD STABILIZERS Lithium





Lamotrigine

Conflicting data reported

Valproic acid

Monitor drug concentrations

Monitor drug concentrations

Monitor drug concentrations

Cautious dosage selection. Reduction in renal impairment

Cautious dosage selection. Dose reduction according to Child-Pugh score

No dose adjustment suggested

Dose reduction

Avoid in liver insufficiency

Dose reduction

ANTIPSYCHOTICS

Chlorpromazine

Haloperidol

Olanzapine





Conflicting data reported

=





Quetiapine

Risperidone



=





Cautious dosage selection. Dose reduction

Cautious dosage selection. Dose reduction

Dosages in the lower range. Dosage should be tailored to the individual, response carefully monitored, and dosage adjusted accordingly.



Cautious dosage selection. Dose reduction according to renal function

Cautious dosage selection. Dose reduction according to hepatic function

Cautious dosage selection. Reduce initial dose



Consider the administration of a lower initial dose

Consider the administration of a lower initial dose

Consider the administration of a lower initial dose



No dose adjustment suggested

Cautious dosage selection. Dose reduction

Cautious dosage selection. Reduce initial dose. 40-80% lower doses the younger patients



Consider the administration of a lower initial dose

Consider the administration of a lower initial dose

Cautious dosage selection. Reduce initial dose

No dosage adjustment suggested for mild/moderate hepatic impairment. No data for severe hepatic impairment.

No dosage adjustment suggested

COGNITIVE ENCHANCERS/ANTIDEMENTIAL AGENTS

Donepezil



=



No dosage adjustment suggested

Age-Related Pharmacokinetic/Pharmacodynamic Changes

Psychopharmacological Issues in Geriatrics 43

Table 2: contd….



Rivastigmine

No dosage adjustment suggested

No dosage adjustment suggested for mild/moderate hepatic impairment. No data for severe hepatic impairment.

No dosage adjustment suggested

Dose reduction according to creatinine clearance

No dosage adjustment suggested

Dose reduction

Cautious dosage selection

No dosage adjustment suggested in patients with normal renal fuction

ANTIEPILETICS 

Gabapentin

Reduction in renal impairment

Topiramate



Phenytoin



Monitoring free Monitoring free drug drug concentrations concentrations

Monitoring free drug concentrations

ANTIPARKINSONIANS

Levodopa

Ropirinole

 bioavailability



=









Cautious dosage selection Avoid in serious renal insufficiency

Cautious dosage selection Avoid in serious liver insufficiency

No dosage Cautious dosage adjustment suggested in selection in moderate mild/moderate renal hepatic impairment impairment Avoid in serious liver insufficiency Avoid in serious renal insufficiency

No dosage adjustment suggested in general. Individual dose adjustment

2. PHARMACODYNAMIC CHANGES IN AGING With aging, there is a progressive and natural loss of function of body tissues at the cellular level [1]. These pharmacodynamic changes are particularly important in the central nervous system (CNS). Movement disorders and forgetfulness are often a consequence of changes in the level of neurotransmitters rather than loss of neurons; moreover, mental confusion might be due to changes in cerebral blood flow, which also induce autonomic alterations that could result in bradycardia, augmented vasoconstriction in cold weather, vulnerability to hypothermia, and other problems with regulation of body temperature. The extent of the effect of a drug depends not only on its concentration at the site of action, but also on the proportion of receptors in the target tissue, on the capacity of the cells to react to occupied receptors (signal transduction), and on

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the counter-regulatory procedures which helps the preservation of the original functional equilibrium. Therefore, additionally to pharmacokinetics, pharmacodynamics of drugs is also a point for consideration. An increase in the response to a given plasma concentration would lead to a raise in drug sensitivity [33]. Alterations on drug pharmacodynamics due to age may involve the receptor or signal-transduction or changes in homeostatic mechanisms. Research has demonstrated that with aging, numerous CNS changes occur, including the neuronal loss and their replacement by proliferating glial cells, decreases in intracellular enzymes, and reductions in dendritic synapses [34]. Moreover, ageing causes a reduction in brain weight, grey matter and synapses [35] and altered brain phospholipid content [36]. Dopaminergic and cholinergic receptors and neurons are reduced [37]. Permeability of the blood-brain barrier to drugs increases with age and co-morbidity [38]. As a consequence, sensitivity of the CNS to drug side-effects, including headache, an impaired cognitive function, confusion, sedation and extrapyramidal changes, increases with age. A number of drugs may present an increased risk of CNS side-effects when prescribed to elderly people, including antimuscarinic drugs, opioids, benzodiazepines and general anaesthesia [3]. Conceptually, there are multiple receptors on neural cell membranes that are structurally specific to molecular portions of CNS neurotransmitters-or phychotropics (the “key-lock” metaphor) [39]. When activated, these various receptors, in combination, can alter membrane ionic permeability, the sum total of which at a point in time causes either cell excitation or inhibition. Drugs are thought to act by blocking or facilitating receptors, thus changing their usual function. Age-related physiological changes, as well as those caused by damage or disease, may also alter receptor function. Sensitivity may increase, decrease, or remain unchanged. This model of receptor selectivity to one neurotransmitter or drugs’s molecular specificity is, of course, an oversimplification. In vivo, effecting a change in one neurotransmitter pathway probably leads to changes in multiple others, given the interactions known among the various pathways. Also, at the receptor level, subsequent interactions in function may result from other synergistic or antagonistic cellular mechanisms: neural, chemical, or hormonal. The complexity of these dynamic interactions and the variability of the target organ capacity to respond make reliable prediction of outcomes with aging meaningless. Effective predictability in this area awaits future innovation and data. Meanwhile, it may be stated holistically that algebraic combinations of these actions can cause complex alterations at multiple levels (including molecular). These alterations are eventually manifested at the person level. With aging, they may also affect the body’s ability to maintain homeostasis [39].

Age-Related Pharmacokinetic/Pharmacodynamic Changes

Psychopharmacological Issues in Geriatrics 45

2.1. Receptor Properties In individual elderly, clinical significant drug responses due to pharmacodynamic changes vary but generally include (at least early in treatment) lithium efficacy at lower serum levels; an increased sensitivity to benzodiazepines, neuroleptics, dopamine agonists, and opioids; a decreased sensitivity at ß-adrenergic receptors (often to both agonists and blockers) and in -2 adrenergic responses. Older people usually have an increased sensitivity to the development of side effects, such as anaticholinergic side effects via altered acetylcholine receptor functions, and extrapyramidal symptoms via dopamine receptors in nigrostriatum. Paradoxical reactions also may occur (e.g., significant anxiety rather than calming with small doses of benzodiazepines), which may not be related directly to pharmacodynamic changes. In practice, receptor changes doubtlessly contribute to unpredictable or altered drug responses in older individuals, even at the usual low doses generally recommended. In theory, this could have benefits (e.g., prolonged pain relief with morphine at lower-than-expected doses), or be detrimental (e.g., less pain relief with morphine; altered sensitivity to the effects of ß-blockers; somnolence and postural instability with some psychotropics). Other factors, such as drug interactions, further confound the situation and no doubt alter the patient’s expected response. These multiple factors involved highlight once again the clinical need to always individualize drug doses (biotitrate) in older patients [39]. 2.2. Homeostasis The decreases in physiological function that occur with aging, plus chronic disease (including inflammation), gradually alter the effectiveness of the mechanisms responsible for maintaining homeostasis, particularly the rate of return to normal after a stress [39]. Thus, physiologic equilibrium remains but in a compensated and fragile state. Even minor alterations in this equilibrium can lead to multiple problems in various systems, including baroreceptor and chemoreceptor responses; autonomic nervous system dysfunction; circulatory control; impaired thermoregulation; visceral smooth muscle responses; laryngeal reflexes; hypoxic responses; immunosenescence; impaired postural and gait stability; glucose intolerance; and perhaps even mood disorders. There is a reduction in “physiologic reserve”, particularly in cerebral cortical function during severe stress, especially in those with existing cognitive dysfunction. Many commonly used drugs in older patients can change the existing equilibrium

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46 Psychopharmacological Issues in Geriatrics

resulting in sever compromise in functioning. Also, expected response to drugs can be negatively affected by this decline in homeostatic fidelity, leading to problematic side effects, for example, orthostasis and falls, delirium due to central nervous system and multiple peripheral anticholinergic changes, and hypothermia, all occurring at lower doses and blood levels than in younger patients [39]. In elderly, the brain is frequently a target for drugs, and compounds like psychotropics, anticonvulsivants and antihypertensives that act centrally, may difficult intellectual activities and motor coordination [33]. Table 3: Summary of drugs acting in the central nervous system affected by aging [1] Increased effects

side

Drug class

Drugs to be used with care

Drug-drug interactions

Opioids (higher blood levels in elderly)

Pentazocine, meperidine, dextropropoxyphene (in copraxamol)

Nausea, hypotension, CNS effects

Benzodiazapines

Small doses for the minimum possible period; short half-life drugs are best, e.g. lormetazepam

Phenothiazines

Small doses and regular reviews

Risk of tardive dyskinesia, extrapyramidal effects, anticholinergic effects (urinary retention, constipation); hypothermia in winter

With metoclopramide, extrapyramidal movements are seen

Anti-Parkinsonian drugs

Levodopa-samall doses; anticholinergic drugs have enhanced effects

Levodopa causes confusion, postural hypotension, psychosis; selegiline causes more agitation and confusion ; anticholinergic drugs cause constipation, dry mouth and urine retention

Levodopa with tricyclic antidepressants produce hypotension

Tricyclic antidepressants

With disopyramide and antihistaminics produce hypertension

ACKNOWLEDGEMENTS Declared none. CONFLICT OF INTEREST The authors confirm that this chapter contents have no conflict of interest.

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Noble RE. Drug therapy in the elderly. Metabolism 2003; 52: 27-30. Perrie Y, Badhan RK, Kirby DJ, et al. The impact of ageing on the barriers to drug delivery. J Control Release 2012; 161: 389-98. Lonsdale DO, Baker EH. Understanding and managing medication in elderly people. Best Pract Res Clin Obstet Gynaecol 2013; 27: 767-88. Ewing AB. Altered drug response in the elderly. In: Armour E, Cairns C , Eds. Medicines in the Elderly. London UK, Pharmaceutical Press, 2002: pp. 15-28. Stegemann S, Ecker F, Maio M, et al. Geriatric drug therapy: neglecting the inevitable majority. Ageing Res Rev 2010; 9: 384-98. Nyborg G, Straand J, Brekke M. Inappropriate prescribing for the elderly--a modern epidemic? Eur J Clin Pharmacol 2012; 68: 1085-94. Aparasu, R.R., Mort, J.R. & Brandt, H. Psychotropic prescription use by community-dwelling elderly in the United States. J Am Geriatr Soc 2003; 51,671-677. Rochon PA. Exploring the variation in Ontario nursing home prescribing rates for antipsychotics. Healthc Q 2007; 10(4): 20-2. Snowdon J, Day S, Baker W. Current use of psychotropic medication in nursing homes. Int Psychogeriatr. 2006; 18: 241-50. Gurwitz JH, Field TS, Avorn J, et al. Incidence and preventability of adverse drug events in nursing homes. Am J Med 2000 1; 109: 87-94. Pollock B, Forsyth C, Bies R. The critical role of clinical pharmacology in geriatric psychopharmacology. Clin Pharmacol Ther 2009; 85: 89-93. Hubbard RE, O'Mahony MS, Woodhouse KW. Woodhouse. Medication prescribing in frail older people. Eur J Clin Pharmacol 2013; 69: 319-326. Bagshaw SM, McDermid RC. The role of frailty in outcomes from critical illness. Curr Opin Crit Care. 2013; 19: 496-503. European Medicines Agency. Proposal for the development of a points to consider for baseline characterisation of frailty status. EMA/335158/2013. EFGCP Guidelines on Medical Research for and with Older People in Europe . http: //www.kcl.ac.uk/sspp/departments/sshm/news/EFGCP-GMWP-Research-Guidelines-Final-edited2013-05-27.pdf . Watts G. Why the exclusion of older people from clinical research must stop. BMJ 2012; 344: e3445. European Medicines Agency. EMA geriatric medicines strategy. EMA/CHMP/137793/2011 European Medicines Agency. Concept paper on the need for a reflection paper on quality aspects of medicines for older people. EMA/165974/2013. Cook TJ, Edwards S, Gyemah C, et al. Variability in tablet fragment weights when splitting unscored cyclobenzaprine 10 mg tablets, J Am Pharm Assoc 2003; 44: 584-586. van Riet-Nales DA, Doeve ME, Nicia AE, et al. The accuracy, precision and sustainability of different techniques for tablet subdivision: Breaking by hand and the use of tablet splitters or a kitchen knife. Int J Pharm 2014; 466: 44-51. Awofeso N. Anti-tuberculosis medication side-effects constitute major factor for poor adherence to tuberculosis treatment. Bull World Health Organ 2008; 86: B-D. Priebe S, Yeeles K, Bremner S, et al. Effectiveness of financial incentives to improve adherence to maintenance treatment with antipsychotics: cluster randomised controlled trial. BMJ 2013; 347: f5847. Gellad WF, Grenard JL, Marcum ZA. A Systematic Review of Barriers to Medication Adherence in the Elderly: Looking Beyond Cost and Regimen Complexity. Am J Geriatr Pharmacother 2011; 9: 11-23. Shi S, Mörike K, Klotz U. The clinical implications of ageing for rational drug therapy. Eur J Clin Pharmacol 2008; 64: 183-99. Dagan O. Lonsdale, Emma H. Baker. Understanding and managing medication in elderly people. Best Pract Res Clin Obstet Gynaecol. 2013; 27: 767-88. Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 2009; 41: 67-76.

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49

CHAPTER 4

Clinically Relevant Psychopharmacological Interactions in the Elderly Ainhoa Urrutia1, Javier Peral1* and Jesús Ángel Padierna2 1

Pharmacy Service, Galdakao-Usánsolo Hospital, Barrio Labeaga s/n, 48960 Galdakao, Bizkaia/Vizcaya, Spain and 2Psychiatry Service, Galdakao-Usansolo Hospital, Barrio Labeaga s/n, 48960 Galdakao, Bizkaia/Vizcaya, Spain Abstract: The elderly population suffers more drug-drug interactions (DDI), drugdisease interactions (DDE) and adverse drug reactions (ADR) than other age groups. The main risk factor is the high number of drugs administered. The use of psychotropic medications is very high in elderly individuals, especially in residents of nursing homes. A lot of the clinically relevant DDI involve a psychotropic drug. Besides, their medical care implies multiple professionals from different specialties and psychotropic drugs may interact with other prescribed medications used to treat concomitant medical illnesses. Moreover, the amount of time dedicated to their attention is usually insufficient. All these circumstances extremely complicate the possibility to detect DDI while prescribing. This is the reason why we consider electronic programs an indispensable help for this task. Anyway, physicians should have a basic knowledge of the main mechanisms implicated in DDI and of those DDI clinically relevant.

Keywords: Aged, Anticonvulsants, Antidepressive Agents, Antiparkinson agents, Antipsychotic Agents, Computer-assisted, drug Interactions, Drug therapy, Electronic prescribing, Food-Drug Interactions, frail elderly, Health Services for the aged, Herb-Drug Interactions, Inappropriate Prescribing, Medical Informatics, Medical Order Entry Systems, Mobile Applications, Mobile Apps, Neurotransmitter uptake inhibitors, Polypharmacy, Psychopharmacology. 1. INTRODUCTION Elderly population is constantly and rapidly increasing in numbers and percentage both in developed and developing countries. They are mentally and physically the most heterogeneous age group but they suffer drug-drug interactions (DDI), drugdisease interactions (DDE) and adverse drug reactions (ADR) more frequently than the rest of the population. This is due to changes in body composition, renal *Corresponding author Javier Peral: Pharmacy Service, Galdakao-Usansolo Hospital, Barrio Labeaga s/n, 48960 Galdakao, Bizkaia/Vizcaya, Spain; Tel: 0034 94 400 7000; E-mail: [email protected] Unax Lertxundi, Juan Medrano and Rafael Hernández (Eds.) All rights reserved-© 2015 Bentham Science Publishers

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and hepatic impairment, smaller homeostatic reserve, changes at receptor level, etc. but the most important risk factor for DDI, DDE and ADR appearance is the number of drugs prescribed. Comorbidities usually appear with the advanced age and they generally end up in polymedication (>5 drugs). The complete drug treatment prescribed to any patient is the responsibility of different prescribers from different specialties and frequently the knowledge of other physician’s prescriptions is not ideal, making it difficult to get a correct treatment. We must remember that in any patient treated with “n” drugs there will be n x (n-1)/2 number of different couples of medicines, in other words in a patient with 10 drugs we can find 45 different drug couples. Taking today’s working rhythms into account it seems complicated for the physician to make all these combinations mentally in an efficient way. Besides, interactions may occur between three or more drugs extremely complicating their prediction. On the other side, the appearance of new drugs with complex mechanisms of action complicates even more the physician’s work when prescribing to elders (example: new antineoplastic oral tyrosine kinase inhibitors). In this scenario, we consider indispensable medical data bases help in order to check a patient’s complete medication profile for interactions in just a few seconds. The particular professional setting with variable information technology (IT) use and/or prescription assistance will determine our ability to correctly prescribe. Once the potential DDI/DDE is detected by the computer it must be assessed and managed taking into account all the possible alternatives. Information technology help doesn’t take importance away from the knowledge of the most common and clinically relevant DDI/DDE in the medical practice. This is the reason why this chapter describes bibliographic and electronic sources of information about interactions first and then makes a brief review of the most common and clinically relevant DDI/DDE found while prescribing psychotropic drugs to elders. 2. BIBLIOGRAPHIC AND ELECTRONIC SOURCES OF INFORMATION ABOUT INTERACTIONS One of the biggest challenges while dealing with DDI is the clinical relevance of those DDI we detect. Too many alerts tend to fatigue the physician who will systematically override new DDI alerts in the future. Detection programs should focus on those clinically relevant by checking for the most severe DDI, personally assessing every DDI detected (usually the pharmacists) before alerting the prescriber, adding secondary filters (that is to say after detecting the couple: checking for the doses, route of administration, biochemical parameters, diagnose, etc.), etc.

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On the other hand there is no international uniformity in DDI severity rating. Some sources classify them numerically: 1, 2, 3, 4 and 5 [1]; others as: Contraindicated-Major-Moderate-Minor-Unknown interaction [2] and some others alphabetically: A, B, C, D and X [3]. Little agreement exists among commonly used drug interaction databases for DDIs regarding clinical relevance and importance [4]. This complete lack of standardization doesn’t help for the management and development of DDI knowledge. 2.1. Tertiary Sources We consider “Drug Interactions Analysis and Management” written by D. Hansten and John R. Horn [1] the best book specifically covering DDI aspects. It is published annually and can be found in usual commercial channels (around 80€). Each DDI description is divided into summary, risk factors, mechanism, clinical evaluation, related drugs, management options and references. This way of presenting the information has been a great help to inform and manage DDI detected by our electronic databases. We consider the essential source in case electronic databases about drugs are not available. The authors are an international reference in the field. It is only published in English. Another source widely used in our setting is: Stockley’s Drug Interactions which is translated from English to other languages such as Spanish in certain editions [5]. There is a pocket version, another one covering drug-herb interactions and an electronic version intended to be included in computerized prescribing and/or electronic dispensing of medication. Even if it is considered an international reference we find it less manageable in the daily clinical practice. Many books about drugs, such as the British National Formulary [6], include a chapter about DDI but usually the information provided is insufficient for the correct management of them. 2.2. Electronic Databases (DB) Many medicines and/or pharmacotherapy DB include a tool to check electronically the patient’s medication profile for DDI in a few seconds. Micromedex® [2] and UpToDate® (Lexicomp®) [3] are two examples with excellent results in the field. In Micromedex® the result of the analysis shows us a report which includes: time until the appearance of the DDI, severity, evidence, mechanism, clinical management, a summary of it and the references. Besides, the application will

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find interactions with food, ethanol, tobacco, pregnancy, breastfeeding or even with laboratory tests. There is an online pay version and a free App that if you or the organization you work for has an Internet-based subscription may install at no charge called “Free Micromedex Drug Reference”. If Internet-based subscription to Micromedex® is not available, a search for Micromedex Drug Essentials could be performed, which should be available for $2.99 per year. We consider Micromedex the ideal source of information in the case of not having a well-designed assistance about DDI in the electronic prescription program. UpToDate® offers a similar service through Lexi-Interact, from Lexicomp®. The application will find interactions between drug-drug, drug-herb, and herb-herb. The results will be shown as: summary, management, related drugs, discussion and references. Information displayed is less detailed than that obtained from Micromedex® but we think that it may fulfill most physicians’ needs in the case of not having any other source of information. The subscription to the online version doesn't include any access to mobile devices yet. Most of the medicines DB from each country include information about DDI/DDE but the reliability and utility is very changeable. In the case of our country (Spain) we consider (Bot-Plus) inferior than the previously mentioned DB. There are also countries where the handling of the DDI/DDE has experienced a prominent development with their own DB. We particularly like the “Thesaurus of Interactions medicamenteuses in France” and the KNMP-CIS (G-Standaard) in Holland. The French list can be freely accessed at the French Agency for medicinal products and sanitary products [7]. The Dutch drug database which includes DDI information is called the “G-Standaard” and it is monthly issued by Z-Index, an organization that is owned by the Royal Dutch Association for the Advancement of Pharmacy [8]. Nowadays, DDI checking at the prescribing moment is increasingly being included in electronic prescription programs both at ambulatory and hospital level. We think that this is the most efficient option and so we should approach this way of working in the future. 2.3. Other Mobile Applications The top 100 drug interactions is an App for pay (15€), that summarizes part of information given in the printed version of the book “Drug Interaction Analysis

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and Management” of Hansten. It includes a specific section about the probability scale of the DDI (DIPS) of the author, CYP450 inhibitors, inductors and substrate tables and transporters, genetic polymorphisms and others. In our own opinion it is too limited in order to design safetly the complete treatment for patient. Epocrates and RxDrugs are more generalist medicine Apps but they include interaction testers. Both are for free. 3. SOME CLINICALLY RELEVANT DRUG-DRUG OR DRUG-DISEASE INTERACTIONS [1, 9] In order to classify potential psychopharmacological DDI as clinically relevant we have selected: those classified as grades 1 and 2 by Hansten and Horn [1], those that our organization’s Pharmacy Service monitors (they have been selected through the years) and some suggested by a Psychiatrist (Dr. Padierna) from the same hospital. 3.1. Clinically Relevant DDI Implying Antipsychotics Aripiprazole-amiodarone: Amiodarone may markedly increase aripiprazole levels by inhibiting its metabolism. Monitor effects. Chlorpromazine-levodopa: Classic antipsychotics can reduce the effectiveness of antiparkinsonian drugs. If necessary, use atypical antipsychotics such as clozapine and quetiapine. Clozapine-erythromycin: Probably erythromycin inhibits the metabolism of clozapine, increasing plasmatic levels. Use preferably azithromycin. Clozapine-fluvoxamine: Fluvoxamine may increase clozapine concentrations while inhibiting its metabolism. Adjust clozapine dosage if necessary or use another SSRI such as fluoxetine, paroxetine or sertraline. Clozapine-tobacco: There had been severe events of intoxication by clozapine while giving up smoking. Monitor clozapine concentrations and reduce the dosage if necessary with the revocation of tobacco. Lithium-diuretics (furosemide, hydrochlorothiazide, indapamide and spironolactone): These diuretics can increase lithium levels; monitor concentrations and/or look after toxicity signs and symptoms.

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Lithium- non-steroidal anti-inflammatory drugs (NSAID): Most of the NSAID increase lithium levels; monitor concentrations and look after toxicity signs and/or symptoms. Neuroleptics in dementia with Lewy bodies: Do not use, (see chapter 4). Pimozide-clarythromycin/ketoconazole/voriconazole/verapamil/paroxetine/ritonavir /sertraline: Contraindicated in SPC. Avoid concomitant use with pimozide´s metabolism inhibitors such as antifungal azoles, protease inhibitors, macrolide antibiotics, SSRI (sertraline, paroxetine, citalopram and escitalopram). Combined administration could emerge on the elevation of pimozide’s blood concentration and increases the possibility of QT prolongation. Alternatives: terbinafine in case of antifungal azoles; azithromycin in case of macrolides; amlodipine or felodipine in case of verapamil. Ziprasidone-moxifloxacin: Contraindicated in SPC. Both prolong QT interval, increasing arrhythmia risk, such as “torsade de pointes” (TdP). Alternatives: levofloxacin, ciprofloxacin and ofloxacin. Quetiapine, risperidone, haloperidol and olanzapine seems to have minor effect. If the combination is inevitable, look after arrhythmias and prolongation of the QT interval. Ziprasidone-pimozide/quinidine/sotalol: Concomitant treatment with drugs that can prolong QT interval is contraindicated in the SPC. There is an additive effect and increased risk of ventricular arrhythmias. 3.2. Clinically Relevant DDI Implying Antiepileptics Carbamazepine-danazol: Danazol increases carbamazepine levels by inhibiting its metabolism, producing toxicity in some patients. Avoid danazol if possible. Carbamazepine-diltiazem/verapamil: Diltiazem and verapamil increase carbamazepine concentrations. Monitor the possible toxicity of carbamazepine. Carbamazepine-felodipine: Carbamazepine is an enzymatic inducer whose presence may reduce substantially felodipine and other calcium channel blocker’s levels. If the combination is inevitable, look after reduced response to calcium antagonist, and if it is necessary, increase the dosage. Phenytoin-irinotecan: Phenytoin increases the metabolism of irinotecan, reducing plasmatic levels. It may be necessary to increase the dosage of irinotecan. Monitor possible inefficiency of irinotecan.

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Phenytoin-methadone: Phenytoin can reduce methadone levels, causing withdrawal syndrome. If the combination is inevitable, consider adjustment of methadone dosage at the initialization, dosage change or end of phenytoin treatment. Sodium valproate-lamotrigine: Combined therapy may increase the risk of toxic epidermal necrolysis. Be alert for any evidence of rash and discontinue lamotrigine in that case. 3.3. Clinically Relevant DDI Implying Amine Reuptake Inhibitors Citalopram/fluoxetine/paroxetine/venlafaxine-methylene blue: Summary of products characteristics (SPC) of citalopram/clomipramine/fluoxetine/venlafaxine contraindicate the combined use with MAOI. Methylene blue is a strong inhibitor of MAO-A, and a weak inhibitor of MAO-B, therefore, its administration together with these drugs can cause serotoninergic syndrome. Stop taking these drugs 2 weeks before the administration of the methylene blue. In those patients who take fluoxetine, wait 5 weeks before administrating methylene blue. Duloxetine-cyclobenzaprine: There are notified cases of serotoninergic syndrome because of the concomitant use. Avoid, if possible, all the antidepressants which inhibit serotonin reuptake, or look after serotoninergic toxicity symptoms. Duloxetine-fluvoxamine/paroxetine: Combined use is contraindicated in the SPC. Both fluvoxamine and paroxetine inhibit the metabolism of duloxetine, increasing plasmatic levels. If it is necessary to combine duloxetine with another SSRI, use less strong enzyme inhibitors (citalopram, escitalopram, venlafaxine). If using this combination is considered inevitable, monitor the effect of duloxetine, especially at the beginning or ending of the treatment with fluvoxamine, and consider dosage changes if necessary. Duloxetine/fluoxetine/venlafaxine-tranylcypromine: There are documented severe or mortal reactions of serotoninergic syndrome by combining MAOI and amine reuptake inhibitors. Contraindicated use in summary of product characteristics (SPC). Wait at least 2 weeks since the ending of the MAOI treatment before initiating duloxetine/fluoxetine/venlafaxine; wait 5 days to initiate MAOI since the ending of the treatment with duloxetine, and 5 weeks to start MAOI treatment since stopping fluoxetine treatment. Fluoxetine/paroxetine-tamoxifen: Fluoxetine/paroxetine inhibits the metabolism of tamoxifen, so there is no active metabolite production responsible of their

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activity, the effectiveness of the tamoxifen is reduced. Venlafaxine and mirtazapine don't interact. Fluoxetine-rasagiline/selegiline: This combination theoretically increases the risk of serotoninergic syndrome. Wait at least 5 weeks between the interruption of the administration of fluoxetine and starting treatment with rasagiline, and at least 14 days between the interruption of rasagiline and starting fluoxetine. Look after serotoninergic syndrome signs/symptoms. Fluvoxamine-theophylline: Even though the causality is not completely established, it seems that fluvoxamine inhibits the metabolism of theophylline, increasing levels and causing toxicity. Citalopram, fluoxetine, paroxetine and sertraline seem less interacting drugs. Fluvoxamine-tizanidine: Fluvoxamine increases substantially tizanidine levels, causing hypotension and CNS depression. Contraindicated in the SPC. Citalopram, escitalopram, fluoxetine, paroxetine, sertraline, mirtazapine, trazodone and venlafaxine, theoretically interact to a lesser extent. Fluvoxamine-rasagaline: Contraindicated combination in the SPC. Fluvoxamine inhibits rasagiline's metabolism, increasing plasmatic levels. Besides, they both possess a serotoninergic additive effect. Mirtazapine-clonidine: There is one case report of severe hypertensive reaction while adding mirtazapine to the clonidine treatment. Clonidine is an antagonist of alfa-2 receptors, whereas mirtazapine inhibits these receptors. Tricyclic antidepressants and trazodone also interact. Preferably use mianserin, it does not interact. Mirtazapine-rasagiline: Additive serotoninergic effect. Avoid concomitant use because of the risk of serotoninergic syndrome. Wait 2 weeks after completing rasagiline treatment to initiate mirtazapine. SSRI-tramadol: Additive serotoninergic effects. Monitor toxicity signs and symptoms, and consider using another analgesic. 3.4. Clinically Relevant DDI Implying Tricyclic Antidepressants Clomipramine-methylene blue: Summary of products characteristics (SPC) of clomipramine contraindicate the combined use with MAOI. Methylene blue is a strong inhibitor of MAO-A, and a weak inhibitor of MAO-B, therefore, its

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administration together with these drugs can cause serotoninergic syndrome. Stop taking these drugs 2 weeks before the administration of the methylene blue. 3.5. Clinically Relevant DDI Implying MAOI Moclobemide-dextromethorphan: Dextromethorphan seems to block reuptake of serotonin, and it shouldn't be used together with non-selective MAOI, or together with MAOI-A such moclobemide because of the risk of serotoninergic syndrome. Rasagiline/selegiline-clomipramine: Additive serotoninergic effect, increased risk of serotoninergic syndrome. It is expected the same effect with selegiline. Clomipramine SPC: contraindicated concomitant administration with MAOI. If the combination is indispensable, monitor for serotoninergic syndrome signs. Rasagiline-cyclobenzaprine: Concomitant use is contraindicated in the SPC. Rasagiline/selegiline-dextromethorphan/propoxyphene: Rasagiline can act as a non-selective MAOI (also selegiline, especially in high doses). Possible serotoninergic additive effect, increased risk of serotoninergic syndrome. It is not expected to interact with codeine, although there is not adequate supporting information. Wait 2 weeks since stopping rasagiline to initiate treatment with dextromethorphan. Rasagiline/selegiline-meperidine: Meperidine-rasagiline use contraindicated in SPC. Serotoninergic additive effects. Wait at least 2 weeks since the end of the treatment with rasagiline to initiate meperidine. Meperidine-selegiline: a single case report, but no established causality. Caution required. Rasagiline-methadone: Avoid combination, because of the possible serotoninergic additive effect. Wait 2 weeks since rasagiline treatment has ended to start methadone. Rasagiline-pseudoephedrine: Non-selective MAOI increase noradrenaline concentration. Sympathomimetic agent's addition may cause severe hypertensive crisis. Wait 2 weeks since stopping rasagiline to initiate treatment with indirect sympathomimetic agents. Caution patients that some flu medicines may contain sympathomimetic agents such as ephedrine or pseudoephedrine. Rasagiline-tramadol: Possible additive serotoninergic effect, increased risk of serotoninergic syndrome. It is expected the same effect with selegiline. Wait 2 weeks since stopping rasagiline to initiate treatment with tramadol.

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Rasagiline-tranylcypromine: Contraindicated in SPC, possible additive effects. It is expected the same effect with selegiline. Tranylcypromine-Linezolid: Contraindicated administration with other MAOI in SPC. Additive effects. Wait 2 weeks after completing MAOI treatment to initiate linezolid. 3.6. Clinically Relevant DDI Implying Anti-Dementia Drugs Donepezil-digoxin: Concomitant use can induce bradycardia; the same may occur with other anticholinesterase drugs such as galantamine and rivastigmine. If there is not alternative, look after a possible bradycardia, hypotension and syncope. 3.7. Clinically Relevant DDI Implying Drugs used in Alcohol Dependence Disulfiram-isoniazid: Combined use of these drugs can cause adverse effects on the central nervous system. Monitor the appearance of symptoms such behavioral changes, mood changes or ataxia. Disulfiram-lopinavir/ritonavir: Oral solution of Kaletra® contains a considerable quantity of alcohol. Disulfiram inhibits alcohol metabolism, accumulating accordingly acetaldehyde, and causing intolerance. All the solutions containing alcohol are contraindicated in those patients who are in treatment with disulfiram. Use capsule formulations if possible. Disulfiram-warfarin: Disulfiram inhibits the metabolism of warfarin, increasing its levels and bleeding risk. If the association is required, monitor the anticoagulant effect. 3.8. Clinically Relevant DDI Implying Anti-Migraine Drugs Eletriptan-erythromycin: Combined administration increases eletriptan’s plasmatic levels. Use azithromycin. For those patients who require erythromycin, consider to use triptans that primarily are metabolized by MAO (rizatriptan, sumatriptan). Ergotamine/dihydroergotamine-sumatriptan: Contraindicated use in SPC, because of the risk of excessive vasoconstriction and coronary vasospasm. Do not give triptans until 24 hours after administering ergotic alkaloids. Ergotamine-voriconazole: Voriconazole inhibits the metabolism of ergotamine, increasing the toxicity risk. Alternative: terbinafine. If the combination is inevitable, look after excessive vasoconstriction.

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Rizatriptan/moclobemide: Moclobemide increases rizatriptan’s level and in its active metabolite. Alternative: Naratriptan. If the combination is inevitable, monitor for excessive vasoconstriction. 4. SOME CLINICALLY INTERACTIONS

RELEVANT

PHARMACODYNAMIC

Pharmacodynamic interactions happen when two drugs act over the same receptor, either over the same metabolic pathway. The interaction may have an additive or a synergic effect, boosting the therapeutic effect, or even increasing toxicity risk. Another possibility is to produce antagonism. Most common adverse effects due to pharmacodynamic interactions between antipsychotics drugs are extrapyramidal effects, metabolic disorders, cognitive deficits or delirium. Additionally, most frequently involved neurotransmitters are: dopamine, serotonin, acetylcholine and histamine. Some relevant pharmacodynamic interactions of antipsychotics with other groups are: 4.1. Additive Sedative Effect If the administration of antipsychotics is combined with CNS depressant drugs: anti-depressants, benzodiazepines, alcohol, etc. [1]. 4.2. Additive Anticholinergic Effect (See Chapter 5) If antipsychotics are given in conjunction with anti-depressives, antiparkinsonians or antihistamines. In the elderly population, anticholinergic effect of some drugs increase the risk to suffer adverse effects at a peripheral level, such as constipation, urinary retention, tachycardia or blurry vision; and also at a central level, such as cognitive disorders, and memory and attention problems. Lots of drugs that are used in psychiatry, have high anticholinergic properties, consequently, this group of patients may have a high risk to suffer anticholinergic adverse effects. Several scales have been developed in order to predict the risk to suffer anticholinergic adverse effects: The Anticholinergic Drug Scale (ADS), The Anticholinergic Risk Scale (ARS), Anticholinergic Cognitive Burden Scale (ACB) [10-12]. 4.3. QT interval Prolongation Increased risk if there is concomitant use of drugs that prolong the QT interval. Most frequent involved drugs are antiarrhythmics (amiodarone, dronedarone, flecainide, procainamide, sotalol), antidepressants (citalopram and escitalopram),

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antipsychotics (chlorpromazine, haloperidol, pimozide), antibiotics (azithromycin, clarithromycin, erythromycin and moxifloxacin) and others such as alfuzosin, chloroquine, domperidone, cisapride, ondansetron, methadone etc. Some predisposing factors to develop these kind of arrhythmias are: electrolytic disorders (hypokalemia, hypomagnesaemia, hypocalcaemia), renal or hepatic deficiency, female sex, elderly population, pre-existing cardiovascular disease, basal prolonged QT interval or family history of prolonged QT interval, hyperthyroidism/hypothyroidism, bradycardia and recent cardioversion of atrial fibrillation to sinus rhythm [13-17]. 4.4. Increased Risk of Serotoninergic Syndrome When MAOI are being administered (including antiparkinsonians such as rasagaline and selegiline), together with another serotoninergic antidepressants (SSRI, venlafaxine, duloxetine), an additive effect is produced, and serotoninergic syndrome risk is increased, characterized by CNS toxicity signs such us excitement, rigidity, hyperthermia, autonomic system hyperactivity, coma or death [18]. 4.5. Increased Risk of Bleeding Concurrent use of SSRI and oral anticoagulants, drugs that involve platelet function and other drugs that can increase risk of bleeding (atypical antipsychotics, most of tricyclic antidepressants, AAS, NSAID and coxibs). Special caution should be taken in elderly patients with previous history of bleeding or with factors predisposing to bleeding [18-21]. 4.6. Central Acting Antidopaminergics in Parkinson’s Disease (PD) Psychosis treatment in PD represents a clinical dilemma since the use of antipsychotics may worsen motor function. For further information see chapter 4. On the other hand, nausea and vomiting are common adverse effects of levodopa and the dopaminergic agonists that are used in order to treat Parkinson´s Disease. Metoclopramide crosses the blood-brain barrier, producing central blocking of dopamine receptors and deteriorating motor function of Parkinson’s disease patients. One alternative to treat nausea and vomiting (or just as prokinetic) in these patients is domperidone, an antidopaminergic with peripheral action, which barely crosses blood-brain barrier. One adverse effect of domperidone that must be taken into account is the risk of the appearance of serious ventricular arrhythmias/sudden cardiac death. The risk is increased in people over the age of

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60, in those with high doses of the drug and in those who take simultaneously other drugs which can prolong the QT interval [22, 23]. 5. SOME CLINICALLY RELEVANT FOOD-DRUG INTERACTIONS Food-drug interactions are not as easily detected as drug-drug interactions; however, their potential frequency is much higher, in that food is the substance that is more associated with administration of medication [24-26]. Drugs that usually interact with food in a clinically relevant manner are drugs with narrow therapeutic margin, those with high gradient dosage-effect curve, in the way that small changes in the dosage causes high changes in effectiveness, and those drugs in order to be effective should maintain sustained plasma concentration [26, 27]. Most important food-drug interactions are described below: 5.1. Monoamine Oxidase Inhibitors (Including Antiparkinsonians such Rasagiline or Selegiline) with Foods Rich in Tyramine (“Pate”, Herring, Highly Cured Cheeses, Salami, Beer, Wine, etc.): MAOI block the oxidative deamination of biogenic amines such as adrenaline and noradrenaline (catecholamines), serotonin and dopamine, but also inhibit the metabolism of amines ingested with food like tyramine and histamine. As consequence of the interaction, pressor amines concentration increases due to the direct action causing hypertensive crisis that could be serious. Antibacterial oxazolidindiones (linezolid) or isoniazid also interact with these foods, also by MAO's inhibition [1]. 5.2. Anxiolytics, Sedatives, Hypnotics or Certain Antihistamines (of Sedative Effect) with Alcoholic Drinks Additive effect on CNS. Another kind of alcohol-drug interaction is produced in consequence of the blockade of the ethyl alcohol metabolism because of the aldehyde dehydrogenase enzyme, with the empowerment of its toxic effects, known as ANTABUS like or disulfiram. It is a serious interaction, causing sweating, face and neck blush, nausea, vomiting, stomach pain and cephalea. In these cases, serious falling of blood pressure may happen and also heart rhythm disturbances that can cause death [1].

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5.3. Anxiolytics and Caffeine Caffeine neutralizes sedative effects of anxiolytics. 5.4. Fluoxetine and Paroxetine Interact with Food Rich in Tryptophan Supplements Due to the increase of serotonin levels. Serotoninergic syndromes have been notified while the combined administration of SSRI with tryptophan, therefore, combined use should be done with caution [1, 18]. 5.5. Chronic Ingestion of Certain Drugs could Derive in Reduction of Food Intake Drugs with high anticholinergic potential can cause mouth dryness or metallic flavour, causing a reduction in food intake [10-12]. 6. DRUG-HERB INTERACTIONS Drug-herb interactions have not been studied in depth but they are often part of medication regimens (usually without prescription) and clinical implications of herbal medicine-drug interactions depend on a variety of factors, such as the coadministered drugs, the patient characteristics, the origin of the herbal medicines, the composition of their constituents and the applied dosage regimens. We just mention those interactions more probable and clinically relevant in psychogeriatric field [28, 29]. St John's wort (Hypericum perforatum) is frequently used to treat depression; it induces both a hepatic enzymes and p-glycoprotein. As a result it has generated a lot of different medicinal herb-drug interactions with clinically relevant adverse outcomes. Serotoninergic syndrome cases have been described in patients treated with SSRI and St John's wort. This plant can reduce bioavailability and/or plasma levels of drugs such as: digoxin, theophylline, cyclosporine, phenytoin, maraviroc, imatinib, irinotecan, ixabepilone, nevirapine and tacrolimus. Concomitant use with rasagiline is contraindicated because of additive serotoninergic effects [1]. Ginkgo Biloba may increase bleeding risk associated to warfarin or aspirin. It seems that ginkgo inhibits platelet aggregation. The benefit of ginkgo is questionable and the potential adverse outcome of the interaction is dangerous.

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Berberine (Goldenseal) may increase cyclosporine concentrations, increasing toxicity. Monitor for altered immunosuppressant response. Pausintystalia johimbe (Yohimbe) cointains yohimbine, which may increase blood pressure when combined with tricyclic antidepressants such as clomipramine. Atomoxetine may interact in the same way. Anthraquinone containing plants, including senna (Cassia Senna) and sacred bark (Rhamus pueshiana) may recude the absortion of certain drugs [30]. ACKNOWLEDGEMENTS Declared none. CONFLICT OF INTEREST The authors confirm that this chapter contents have no conflict of interest. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]

Hansten P, Horn J. Drug interaction analysis and management. St Louis: Wolters Kluwer Health; 2013. Micromedex Healthcare Series. DRUGDEX System. Greenwood Village, CO: Truven Health Analytics, 2013. Available at: http://www.thomsonhc.com/. Accessed [8/5/2014]. UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Accessed [8/5/2014]. Abarca J, Malone DC, Armstrong EP, et al. Concordance of severity ratings provided in four drug interaction compendia. J Am Pharm Assoc 2004 Mar-Apr;44(2):136-41. Baxter K, editor. Stockley, interacciones farmacológicas. 2nd edition. London: Pharmaceutical press; 2006. Translation: Pharma editores SL, Barcelona. BMJ Group and The Royal Pharmaceutical Society of Great Britain. British National Formulary. 62nd edition. Basingstoke: Pharmaceutical Press; 2011. French Agency for medicinal products and sanitary products. Available at: http://ansm.sante.fr/, Accessed [20/5/2014]. Royal Dutch Association for the Advancement of Pharmacy. Available at http://knmp.nl/. Accessed [20/5/2014]. Drug labels and summary of product characteristic, Available at http://www.aemps.gob.es/cima/ fichasTecnicas.do?metodo=detalleForm. Accessed [15/04/2014] Lertxundi U, Domingo-Echaburu S, Hernandez R, et al. Expert-based drug lists to measure anticholinergic burden: similar names, different results. Psychogeriatrics 2013 Mar;13(1):17-24. Rudolph JL, Salow MJ, Angelini MC, et al. The anticholinergic risk scale and anticholinergic adverse effects in older persons.Arch Intern Med 2008 Mar 10;168(5):508-13. Durán CE, Azermai M, Vander Stichele RH. Systematic review of anticholinergic risk scales in older adults. Eur J Clin Pharmacol 2013 Jul;69(7):1485-96. Van Noord C, Eijgesheim M, Stricker BH. Drug-and non-drug-associated QT interval prolongation. Br J Clin Pharmacol 2010;70:1623. Roden DM. Drug-Induced Prolongation of the QT Interval. N Engl J Med 2004;350:1013-22. Shah RR. Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter? Br J Clin Pharmacol 2012;75:347-358. Jayasinghe R, Kovoor P. Drugs and the QTc interval Aust Prescr.2002;25:63-5.

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Isbister GK, Page CB. Drug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice. Br J Clin Pharmacol 2012;76:48-57. Mandrioli R, Mercolini L, Saracino MA, Raggi MA. Selective serotonin reuptake inhibitors (SSRIs): therapeutic drug monitoring and pharmacological interactions. Curr Med Chem 2012;19(12):1846-63. Mort JR, Aparasu RR, Baer RK. Interaction between selective serotonin reuptake inhibitors and nonsteroidal antiinflammatory drugs: review of the literature. Pharmacotherapy 2006 Sep;26(9):130713. Vidal X, Ibáñez L, Vendrell L, Conforti A, Laporte JR; Risk of upper gastrointestinal bleeding and the degree of serotonin reuptake inhibition by antidepressants: a case-control study. Drug Saf 2008;31(2):159-68. de Abajo FJ, García-Rodríguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal antiinflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008 Jul;65(7):795803. Lertxundi U, Domingo-Echaburu S, Soraluce A, García M, Ruiz-Osante B, Aguirre C. Domperidone in Parkinson's disease: a perilous arrhythmogenic or the gold standard? Curr Drug Saf 2013 Feb;8(1):63-8. Domingo-Echaburu S, Lertxundi U, Gonzalo-Olazabal E, Peral-Aguirregoitia J, Peña-Bandres I. Inappropriate Antidopaminergic Drug Use in Parkinson's Disease Inpatients. Curr Drug Ther 2012 Sept; 7(3):164-169. Boullata JI. Drug and nutrition interactions: not just food for thought. J Clin Pharm Ther 2013 Aug;38(4):269-71. Wallace AW, Amsden GW. Is it really OK to take this with food? Old interactions with a new twist. J Clin Pharmacol 2002;42:437-43. Akamine D, Filho MK, Peres CM. Drug-nutrient interactions in elderly people. Curr Opin Clin Nutr Metab Care 2007 May;10(3):304-10. Schmidt LE, Dalhoff K. Food-drug interactions. Drugs 2002;62(10):1481-502. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs 2009;69(13):1777-98. Singh D, Gupta R, Saraf SA Herbs-Are they Safe Enough? An Overview. Crit Rev Food Sci Nutr2012;52(10):876-98. Windrum P, Hull DR, Morris TC. Herb-drug interactions. Lancet 2000; Mar 18;355(9208):1019-20.

Psychopharmacological Issues in Geriatrics, 2015, 65-109

65

CHAPTER 5

Potentially Inappropriate Medication in Elderly Rafael Hernández1,*, Ane Gómez de Segura2, Juan Medrano3, Beatriz Corcóstegui4 and Unax Lertxundi2 1

Internal Medicine, Araba´s Mental Health Network, Vitoria-Gasteiz, Araba/Álava, Spain; Pharmacy Service Araba´s Mental Health Network, Vitoria-Gasteiz, Araba/Álava, Spain; 3 Ezkerraldea - Enkarterri Mental Health Community Services, Bizkaia´s Mental Health Network, Portugalete, Bizkaia, Spain and 4Pharmacy Service, Araba´s Mental Health Network, VitoriaGasteiz, Araba, Spain 2

Abstract: The number of elderly people is rapidly growing all over the world. The use of drugs in this age group is risky due to physiological changes associated to the aging process and the potential interactions. Polypharmacy and potentially inappropriate medication is a common finding in the elderly and it is considered a public health issue related to morbidity, mortality and health care resource use. Avoiding the use of inappropriate and high risk drugs is an important, simple and effective strategy to reduce the problems associated with medication in the elderly. A compromise between the principles of evidence-based medicine and good gerontological practice is required. Different strategies have been developed to help reduce potentially inappropriate prescribing. Regular and systematic review of treatment, patient education, collaboration with the pharmacist, the use of electronic aids and tools like Beers or STOPP-START criteria are strategies to help reduce potentially inappropriate prescribing of our elders.

Keywords: Adverse drug reaction, Anticholinergic risk, Appropriate prescribing, Beers criteria, Drugs, Drug prescription, Drug withdrawl, Elderly, Electronic prescribing, Electronic aids, Explicit criteria, Geriatric, Implicit criteria, Inappropriate medication, Inappropriate prescribing, Medicine Appropriateness Index, Pharmacology, Polypharmacy, Potentially inappropriate medication, STOPP-START criteria. 1. INTRODUCTION Elderly people are an important and growing part of the world population. It is a heterogeneous group in which, both the coexistence of pathologies and the exposure to a large number of drugs that increase the risk of adverse drug reactions, are usual. The use of drugs in this age group is risky due to physiological changes associated to the aging process and the potential interactions, both between drugs and diseases, and between the many drugs often co-prescribed [1, 2]. *Corresponding author Rafael Hernández: Internal Medicine, Araba´s Mental Health Network, C/Alava 43 01006 Vitoria-Gasteiz, Araba/Álava, Spain; Tel: 0034 945 00 65 69; Fax: 0034 945 00 65 87; E-mail: [email protected] Unax Lertxundi, Juan Medrano and Rafael Hernández (Eds.) All rights reserved-© 2015 Bentham Science Publishers

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The European Ad-HOC (Aged in Home Care) project revealed a prevalence of polypharmacy (defined as 9 or more drugs) of 22% in adults over 65 receiving home care in Europe [3]. In the U.S., 60% of the elderly receive 5 or more drugs and about 20% receive 10 or more drugs [4]. The estimated incidence of avoidable adverse drug effects in the outpatient setting is of 5.6 cases per 1,000 people and month [5, 6]. The probability of suffering an adverse drug reaction is three times higher in patients older than 60 years than in patients under 30 [7, 8]. More than 35% of the elderly living in the community suffer from adverse drug reactions every year, and this percentage is even higher in nursing homes [9]. Approximately 1 out of every 3 community-dwelling elderly people treated with at least 5 medications will experience an adverse drug reaction in the next 12 months. Three of those reations will be severe and will be involved in up to 17% of hospital admissions [10]. In some publications, this figure is even higher, exceeding 30% of hospital admissions of older people [9]. Among emergency department in the elderly population, the potential for an adverse drug interactions rises with the number of drugs administered, from 13% for those receiving 2 medications, 38% for those receiving 4 and up to 82 % for those receiving 7 or more drugs [11]. In hospitalized patients, the complications derived from the use of drugs are the leading cause of adverse events [12, 13]. The risk of severe adverse reactions in a hospital setting increases by more than 50% in patients treated with 5-7 drugs as compared with those who receive less than 5 drugs, and is 4 times higher in those on 8 or more drugs [14]. Polypharmacy and its relationship to adverse events has been identified as the main drug safety issue by the Healthy People 2000 report [15]. As well, Polypharmacy and the use of inappropriate medication have been identified as the main causes of non-rational prescribing in the elderly [1, 2]. Inappropriate prescribing in the elderly is considered a public health issue and is related to morbidity, mortality and health care resource use [9, 16]. The impact of the use of inappropriate drugs and medication errors in the elderly on the national economy is noticeable [17]. In an american study, the estimated total health expenditure, generated by potentially inappropriate medication use in community-dwelling elderly was $7,200 million in the period 2000-2001 [18]. In another study conducted in Ireland, it accounted for 9% of total drug expenditure in 2007 [19].

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Psychopharmacological Issues in Geriatrics 67

More than half of all hospital admissions due to adverse drug reactions are potentially avoidable [20, 21]. In a systematic review, four groups of drugs (antiplatelet agents, diuretics, non-steroidal anti-inflammatory drugs and anticoagulants) accounted for more than half of the groups associated with preventable drug-associated hospital admissions. Any intervention focused on these groups of drugs could significantly reduce the number of preventable hospitalizations related to drugs [22]. Many of those adverse drug side effects (one quarter of those reactions involving communitydwelling patients and 30% to 55% of those causing hospitalization) could be prevented by avoiding the use of inappropriate drugs [21, 23, 24]. 2. CONCEPT A drug prescription is a written order that includes detailed instructions of how a medicine should be given, to whom, in what formulation, at what dose, by what route, when, how often and for how long. It starts an experiment in which the prescriber discusses the treatment with the patient, monitors and investigates the effects of the prescribed drug, in order to devise a dosage regimen that maximizes benefits and minimizes risks [25]. The administration of a drug can achieve the expected benefits, but can also produce deleterious health effects such as worsening of a pre-existing disease, interaction with other medications resulting in untoward effects, toxicity due to accumulation or production of adverse effects mimicking symptoms of other diseases or geriatric syndromes. An appropriate prescribing should maximize efficacy and safety, minimize costs and respect patient preferences [26]. A medication is deemed appropriate if there is clear evidence supporting its use for a specific indication, is well tolerated in most patients, takes into account life expectancy and is cost-effective [16]. A prescription is considered inappropriate if it entails a greater risk than benefit, especially if there are safer alternatives; if dosage or treatment duration is inappropriate, if it involves drugs with significant drug-drug or drug-disease interactions; and the omission of any potentially beneficial drug [9]. Inappropriate drug prescription is defined as any prescription that poses a significant risk of a drug adverse event when there is evidence of an equal or more effective alternative [24, 27]. However, in the elderly, prescribing decisions are often made in the absence of clear evidence supported by good-quality research, because elderly patients with multiple comorbidities and high levels of complexity are often excluded from

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these studies. The average age of clinical trial participants is much lower than that of the actual users of drugs [28]. Thus, the gap between rational and irrational drug use in Geriatrics is narrow, and decisions are often complicated by a lack of research and evidence [29]. 3. MAGNITUDE OF THE PROBLEM A number of studies have documented that potentially inappropriate medication is a common finding in outpatient care, nursing homes and emergency departments. Information on prescription of potentially inappropriate medication in acute hospitals is limited, even though adults aged 65 or older represent more than 35% of annual hospital admissions [30]. Data vary depending on geographical area, health care setting, and the tool used for assessment. In a systematic literature review including 19 studies, 14 of which used the Beers criteria, the mean inappropriate prescribing was 20.5% (2.9%-38.5%). Approximately one out of every five prescriptions in older people in primary care is inappropriate [31]. In a review of studies, most of them conducted in USA using the Beers criteria, the reported prevalence of potentially inappropriate medication in community-dwelling elderly was 11.5 to 62.5% [32]. Epidemiological studies in USA and Canada, using the Beers criteria, have documented a wide use of potentially inappropriate medications in communitydwelling elderly, with prevalences ranging between 14% and 37% [33-35]. In Europe, the use of potentially inappropriate medication in frail communitydwelling elderly seems to be common, with substantial variations depending on the geographical setting and the criteria employed (average 19.8% from 5.8 to 41.1%). Those differences probably reflect distinct clinical practices, socioeconomic inequalities and different legislations [3]. Overall prevalence of potentially inappropriate medication is reported to be 51.3%, ranging from 34.7% to 77.3%, according to the STOPP criteria, and 30.4% ranging from 22.7% to 43.3% using the Beers criteria. With regard to inappropriate drug prescribing by omission, the global prevalence of potentially inappropriate medication was reportedly 59.4%, using the START criteria, ranging from 51.3% to 72.7% [36]. As several studies have shown, the prevalence of potentially inappropriate medication in elderly people is even higher in nursing homes than in the community, reaching more than 50% of all prescriptions [37-40]. There are few studies about the prevalence of potentially inappropriate medication in hospitalized elders. These studies have shown a prevalence ranging between 14 and 34% [41-43].

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Psychopharmacological Issues in Geriatrics 69

Patients on five or more drugs are 3 times more likely to receive inappropriate drugs that those on less than 5 drugs [11]. In addition to polypharmacy, other factors have been associated with higher prevalence of potentially inappropriate medication, such as age, female gender and comorbidities [32], as well as the presence of psychiatric comorbidity and cognitive impairment [44-46]. The high consumption of psychotropic, sedatives and hypnotics drugs in nursing homes is of particular concern, and it is likely conditioned by a greater complexity, the clinical presentation and the presence of depression and dementia [47]. The use of potentially inappropriate antipsychotics is more prevalent in elderly in nursing homes than those living in community [48]. Although there is some evidence that supporting short-term use of antipsychotics in patients with dementia, evidence of long-term use in these patients is limited. The prevalence of use of antipsychotics in people with dementia in specialized care units is high and inadequate long-term use is common [49]. Prescription of antipsychotics in people with dementia has been associated with 1,800 additional deaths in the UK [50]. It is not surprising that inappropriate prescribing is common in adults aged 65 or older, as they have a higher prevalence of chronic disease, disability and dependence than younger adults and are the highest per capita consumers of medicines [30]. Therefore, a rational prescription is always essential to minimize risks to the patient, but it is especially important in the elderly, as they are exposed to higher burden of disease and are more heavily medicated. Some reviews have suggested that between 25% and 95% of adverse events could be prevented by reducing inappropriate prescribing [51]. In the last years, different strategies have been developed to help reduce potentially inappropriate prescribing, including the use of different scales or assessment tools of potentially inappropriate medication, electronic aids for prescribing, review by pharmacists or patient education. 4. TOOLS FOR ASSESSING INAPPROPRIATE PRESCRIBING Even though some doubts have arisen about the true relationship between the evaluation of potentially inappropriate medication and its correlation with health outcomes [27], avoiding the use of inappropriate drugs and high risk drugs is an important, simple and effective strategy to reduce the problems associated with medication and adverse drug reactions in the elderly [52]. There are two approaches to identify potentially inappropriate medication: tools with implicit criteria, and tools with explicit criteria.

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Implicit tools ponder the wide patient complexity and the best scientific evidence available in order to make individual judgments. Therefore, these tools require expert judgment, are more laborious and are, theoretically, more affected by subjectivity. On the other hand, explicit methods or tools are based on specific criteria of drugs, diseases and other indicators developed by experts. They have a greater interobserver reliability, are generally faster to use, require less clinical experience, are cheaper to implement and its use allows for a greater equity. However, patient circumstances are not considered. The focus is on potentially inappropriate medication globally, although in some individual circumstances, that medication might be the best option. Some authors argue that explicit tools may incorrectly spot some drugs as non-suitable, and may not identify real cases of inappropriate prescribing. In addition, explicit criteria need periodic updates and for the sake of validity they must be adapted to the standards and medications available in each country [30, 53-55]. In a recent review, 46 different tools to evaluate the use of potentially inappropriate medication were identified. Of them, 28 (61%) used explicit criteria, whereas 10 (22%) relied on implicit criteria and 8 (17%) combined both criteria. Only 6 (14%) of them evaluated prescribing omissions as a cause of inappropriate prescribing. Merely 36 (78%) of them studied the elderly population and 10 (22%) did not specify the population targeted. Four of them (8.5%) were designed to detect inappropriate medication in hospitalized population, 9 (19.5%) were devised for outpatients and 6 (13%) for long-stay centers, while most 27 (59%), did not specify the setting. Nineteen (41%) tools were designed by a consensusbased method, while the rest were based either on the criteria of unique expert panels 13 (28%) or in a review of the literature 11 (24%). In 3 of the studies (7%) the method used for its development was not specified [26]. An ideal tool should include all aspects of drug prescription suitability (effectiveness, safety, cost-effectiveness and patient preferences), should be developed using evidence-based methods, should demonstrate a significative correlation between the degree of non-suitability and clinical outcomes, and should be applicable not only for research, but also in daily clinical practice. None of the available tools fulfills all these requirements. Furthermore, for most of these tools it is not possible to find studies that demonstrate any correlation with clinical results [26]. 4.1. Tools Based on Implicit Criteria The instruments using implicit criteria are based on clinical judgment, compilation of patient information and updated scientific evidence to assess the

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Psychopharmacological Issues in Geriatrics 71

suitability of the prescription. Implicit criteria focus on the person, are universal and do not need to be updated, but require high professional competence. Reliability can suffer from disagreement between physicians assessing suitability. Furthermore, the application of these criteria is an individualized, time-consuming approach, and therefore more expensive. For these reasons, implicit criteria are less used than explicit ones [55]. Different implicit criteria tools have been developed to assess the prescription suitability, either alone or in combination with explicit criteria (Table 1).

•

•

Owens Steps to achieve optimal Pharmacotherapy (USA, 1994) Five questions: 1) Diagnosis: Is pharmacological intervention necessary? 2) Drug appropriateness? 3) Dose appropriateness? Pharmacokinetic and pharmacodynamic parameters; 4) Reassess: Is medication still needed? 5) Drug-induced disease.

Lit

ns

El

•

•

Hamdy Criteria for Medication Profile Review in Extended Care (USA, 1995) The criteria were developed with the aim of reducing Lit polypharmacy in patients in long-term care. Five open questions assess the appropriateness of patients’ medication focusing on patients taking 10 or more medications.

L

ns

Robertson’s Flow Charts to prevent, identify and resolve Drug Therapy Problems (USA, 1996) Robertson’s Flow Charts were developed to help pharmacy students to focus on drug therapy issues during clinical clerkship rotations. Ten flow charts encourage a uniform approach to preventing, identifying, and correcting drug therapy problems.

H

ns

Development

•

•

Only implicit approach

ns

•

•

•

•

•

•

•

•

•

o

•

•

•

o

•

Alternative Therapies

El

•

Non-Adherence

ns

•

Cost Effectiveness

Union’s Tool to assess the Appropriateness of Physicians’ Geriatric Drue Prescribing (USA, 1992) Evaluation of each drug in the patient’s regimen in seven categories of potential drug-therapy problems: 1) Drug allergy, 2) Drug dosage, 3) Drug schedule, 4) Appropriateness of drug therapy, 5) Drug-drug interactions, 6) Therapeutic duplication Ex and 7) Prescribing omission. For all categories, a score is given: 0=no problem, l=clinically significant but not life-threatening, 2=potentially life threatening or potentially leading to serious injury or hospitalization; 9=not enough clinical information to make an assessment.

•

Underprescribing

•

Overprescribing

•

Drug-Food Interactions

•

Drug-Drug Interactions

Duplication

•

Drug-Disease

Duration of Therapy

ns

Drug Choice

ns

Patient Group

MAI-Medication Appropriateness Index (USA, 1992) Ten questions used to assess medication appropriateness, which Ex are answered using a three-point Likert scale.

Tools

Health Care Setting

Dosage

Table 1: Tools with implicit approach

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72 Psychopharmacological Issues in Geriatrics Table 1: contd…. PMDRP-Pharmacist’s Management of Drug-Related Problems (Canada, 1997) Developed by pharmacists to facilitate learning and the better provision of pharmaceutical care. It requires the pharmacists to Ex collect patients’ clinical and medical data and serves as a comprehensive documentation system guiding the pharmacists through the whole pharmaceutical care process.

ns

ns

•

•

Cantrill Indicators of Appropriateness of long term prescribing (UK, 1998) Nine indicators of prescribing appropriateness for assessing the Dp entire drug regimen of patients on long term medication in general practice.

L

ns

•

•

Barenholtz Levy self-administered Medication-Risk Questionnaire (USA, 2003) Ten-item, self-administered questionnaire for use by elderly patients to identify who is at increased risk of potentially experiencing a medication-related problem.

ns

El

•

Lit

•

•

•

•

•

•

•

•

•

•

•

•

•

•

Mixed approach (implicit/explicit) The Geriatric Medication Algorithm (USA, 1994) Designed to educate physicians in reducing inappropriate prescribing, divided into four steps: 1) Obtaining a complete medication list from patient and orthostatic blood pressure; 2) Evaluating each drug regarding indication, high risk medications and dosage; 3) Evaluating the entire drug regimen regarding drug-drug interactions and simplification of drug regimen; 4) Evaluating adherence. Some explicit lists of high risk drugs and drugs requiring dosage reduction in the elderly are also provided.

Ex

ns

El

•

•

Kaiser Permanente Model (USA, 1995) Consists of a pathway for determining high risk patients, then guides the pharmacist with a list through Rx-validation and dispensing, and offers drug grids in order to improve appropriate interventions.

Lit

A

ns

•

•

Oborne’s Prescribing Indicators (UK, 1997) A list of 14 prescribing indicators based on the drug charts of 1686 patients. The indicators were presented in the form of algorithms guiding the user through the process of detecting inappropriate prescribing. A version of Prescribing Indicators thought for use in nursing homes is available.

Ex

H

El

•

Brown Model for Improving Medication Use In Home Health Care Patients (USA, 1998) A list of 15 potential medication problems occurring in patients receiving home health care. A structured procedure is Ex described, where home health nurses, in consultation with a drug utilization review coordinator (e.g. clinical pharmacist), present problems and potential solutions to the patient’s physician.

A

El

Medication Management Outcomes Monitor (USA, 2006) The criteria focus on reducing inappropriate prescribing (including medication from Beers Criteria 1991), decreasing polypharmacy, avoiding adverse events and maintaining the functional status of older adults. Those four major outcomes serve as an outline and are divided into several specific subgroups, each containing bibliographical references or guidelines on how to assess or intervene. These guidelines are to be used by registered nurses, nurse practitioners, and pharmacists.

ns

El

Lit

•

•

•

•

•

o

o

o

•

•

•

o

•

•

•

•

o

o

o

•

•

•

Potentially Inappropriate Medication in Elderly

Psychopharmacological Issues in Geriatrics 73

Table 1: contd…. Indicators for Quality Use of Medicines (Australia, 2007) The New South Wales Advisory Group Quality Indicators were developed for the monitoring of aspects of care in Australian Ex hospitals. Not all of the 30 mentioned indicators consider aspects of prescribing. Each indicator is clearly described and usage information is provided.

H

ns

o

o

Australian Prescribing Indicators (Australia, 2008) A list of 41 indicators is presented based on the medications most frequently prescribed to Australians and the most frequent RD ns medical conditions in the elderly. An additional list provides criteria usage information containing necessary medical information for each criterion.

El

•

o

TIMER-Tool to Improve Medications In the Elderly via Review (USA, 2009) Developed to help pharmacists and pharmacy students identify Ex drug-related problems during patient medication reviews. TIMER addresses four main categories: 1} Cost-effectiveness, 2) Adherence, 3) Medication safety, with methods to assess ADEs and drug-drug interactions 4) Attaining therapeutic goals

ns

El

•

POM-Prescribing Optimization Method for Improving Prescribing in Elderly Patients (Netherlands, 2009) POM assists physicians to optimize polypharmacy prescribing Lit in the elderly population. This method is based on six open questions, whereby each question is presented with an overview of the most frequent and clinically relevant problems, together with explicit suggestions to improve prescribing.

ns

El

•

•

ARMOR- A Tool to Evaluate Polypharmacy In Elderly Persons (USA, 2009) ARMOR is a stepwise approach for the assessment of a geriatric patient who is: (1) receiving nine or more medications; (2) seen for initial assessment; (3) seen for falls and/or changes ns in behavior; and/or (4) admitted for rehabilitation. The tool consists of five steps: Assess (medication), Review (e.g. interactions), Minimize (nonessential drugs). Optimize (e.g. Duplication, Dose adjustment) and Reassess (e.g. blood pressure).

ns

El

•

•

o

•

•

o

•

o

•

•

•

•

•

o

o

•

•

•

•

•

•

o

•

• = Aspect totally covered by the criteria, o =Aspect partially covered by the criteria. Abbreviations: RD RAND method; Dp Delphi method; NGT Nominal Group Technique; Ex Expert panel; Lit based on literature research; El Elderly; L Patients in long-term care; H Hospitalized patients; A Ambulatory patients; ns not specified. Source: Kaufmann CP, Tremp R, Hersberger KE, Lampert ML. Inappropriate prescribing: a systematic overview of published assessment tools. Eur J Clin Pharmacol. 2013. DOI:10.1007/s00228-013-1575-1778.

The most widely used implicit measure is the Medicine Appropriateness Index (MAI). Originally devised by Hanlon et al., the MAI has been translated into several languages and has been used in different countries and at a range of health care levels. Interestingly, the MAI gauges multiple components of a right prescription and can be applied in all healthcare settings, with a good and interobserver reliability. It includes 10 criteria to assess various aspects of prescribing (indication, effectiveness, dosage, correct directions, practice instructions, drug interactions, drug-disease interactions, duplication of class, duration and cost) that must be evaluated for each drug included in the patient therapeutic regimen. The MAI was initially designed with a three-point Likert scale for each criterion (1: appropriate; 2: marginally appropriate, 3: inappropriate). A drug is considered inappropriate if one

Hernández et al.

74 Psychopharmacological Issues in Geriatrics

or more items received a score of 3 [56]. A rating system was later developed to allow to generate a weighted score that serves as a summary of the appropriateness of prescriptions ranging from 0 to 18 (0 = no inappropriate element; 18= all criteria are inappropriate) [57]. Although it has been emphasized that implicit measures of inappropriate prescribing overcome explicit measures in predicting adverse drug reactions, a recent study found that only one version with a modified MAI score (Table 2), but not the standard score, was able to significantly predict the risk of adverse drug reactions [46]. Table 2: Medication appropriateness index criteria and scoring weights Standard Weight

Modified Weighta

Are there significant drug-drug interactions?

2

2

Are there significant drug-disease interactions?

2

2

Is there an indication for the drug?

3

1

Is the drug effective for the indication?

3

1

Is there unnecessary duplication with other drugs?

1

1

Criteria

Is the duration of therapy acceptable?

1

1

Is the dosage correct?

2

0

Are the directions correct?

2

0

Are the directions practical?

1

0

Is this drug the less expensive alternative compared with others of equal utility?

1

0

a A weight of zero indicates that the criterion was not used in the modified scoring. Source: Levy HB, Marcus E-L, Christen C. Beyond the Beers Criteria: A Comparative Overview of Explicit Criteria. Annals of Pharmacotherapy. 2010 Dec 7; 44(12):1968-75.

In addition to be laborious and time consuming, the MAI does not allow to assess non-suitability due to prescribing omission. Some critical reviews question the interobserver reliability and suggest that some instructions and / or additional examples could improve the validity and reliability of this instrument [58, 59]. While it seems reasonable to encourage the use of instruments that approach the different dimensions of the suitability of drugs for patients, in practice, there are often limitations hindering its application and utility. 4.2. Tools Based on Explicit Criteria In healthcare settings where high levels of evidence are hard to find, techniques based on consensus are the methods used to develop an evidence base. The

Potentially Inappropriate Medication in Elderly

Psychopharmacological Issues in Geriatrics 75

combination of expert opinion and evidence from the literature has been established as a good choice to develop valid tools [26]. This fact, associated with the recognition that a small number of drugs are responsible for the majority of adverse drug events in older adults, [60] has favored the development of lists of drugs (explicit criteria) considered potentially inappropriate in the elderly. These criteria have a high reproducibility and can be easily applied to large samples of people. However it must be remarked that as individual characteristics and needs are not addressed, incorrect individual assessments can occur [55]. Although there is a large number of explicit criteria tools (Table 3), the most widely used are the Beers criteria and the STOPP/START criteria.

o

Alternative Therapies

Non-Adherence

Cost effectiveness

Underprescribing

Overprescribing

Drug-Food Interactions

o

Drug-Drug interactions

o

Drug-Disease Interactions

•

Duplication

Duration of Therapy

Patient Group El

Dosage

ns

Drug Choice

Beers Criteria (USA, 1991) The Beers Criteria, originally developed for nursing home residents, consist of 19 medications or medications classes to avoid generally in the elderly and 11 criteria describing doses, frequencies, or durations that should not be exceeded. Update 1997: 28 medications or medication classes to avoid generally in the elderly and 15 diseases and conditions and medications to be Dp avoided in these conditions. Update 2003: 48 medications or medication classes to avoid generally in the elderly and 20 diseases and conditions and medications to be avoided in these conditions. Update 2012: 34 medications or medication classes to avoid in the elderly and 14 diseases and conditions and medications to be avoided in these conditions, and 5 medications to be used with caution in older adults.

Health care Setting

Tools

Development Method

Table 3: Explicit tools to assess inappropriate prescribing

o

Hernández et al.

76 Psychopharmacological Issues in Geriatrics Table 3: contd…. McLeod Criteria (Canada, 1997) Includes 38 inappropriate prescribing practices to avoid in elderly, focused on four main topics: 1) Drugs to treat cardiovascular diseases, 2) Nonsteroidal anti-inflammatory drugs and other analgesics, 3) Psychotropic drugs, and 4) Miscellaneous drugs. For each practice, the risk to the patient is specified and an alternative therapy is suggested. ACOVE Qls-Assessing Care of Vulnerable Elders Quality Indicators (USA, 1999) A set of Qls to measure the medical care provided to vulnerable, older persons, created in 1999 and twice updated in 2001 (ACOVE-2) and 2006 (ACOVE-3) All ACOVE Qls are presented in the following format: IF-THEN(BECAUSE). Not all Qls measure aspects of inappropriate prescribing but some consider inappropriate prescribing. ACOVE-3 (2006) covers 26 clinical conditions and includes 392 quality indicators. IPET-Improving Prescribing in the Elderly Tool (Canada, 2000) The IPET resulted as a shortened version of the McLeod Criteria and consists of 14 criteria representing potentially inappropriate prescription. Commonly encountered drug-disease Interactions and medication classes are discussed, mostly focusing on cardiovascular and psychotropic drugs. Than Criteria (USA, 2001) Includes 33 potentially inappropriate medications divided into the categories: 1) Drugs to avoid 2) Drugs, appropriate in rare circumstances and 3) Drugs with some indications but often misused. Sloane List of Inappropriate Prescribed Medicines (USA, 2002) The Sloane List was developed for identifying inappropriately prescribed medications in older patients in residential care/assisted living facilities. The Beers Criteria served as its basis. Inappropriate medication is presented together with the usual indication, a rationale for being classified as “inappropriate”, and possible appropriate alternatives.

Dp

ns

El

•

RD ns

El

•

Lit

ns

El

•

Dp

A

El

•

Lit

L

El

•

o

o

o

o

o

•

o

o

o

•

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Table 3: contd…. Malones List of Drug-Drug Interactions (USA, 2004) A list of 25 potential harmful drugdrug interactions with clinical importance, designed for use in community pharmacies, implemented in a computerized alert system. Rancourt Criteria (Canada, 2004) Consists of a list of 111 potentially inappropriate prescriptions categorized as 1) Potentially inappropriate medication, 2) Potentially inappropriate dosage 3) Potentially inappropriate duration and 4) Potentially inappropriate drug-drug interaction. Lechevallier Criteria (France, 2005) The French adaption of Beers Criteria 1997 includes 24 inappropriate prescriptions. Drugs mentioned in Beers criteria but not available in France were excluded, drugs available in France belonging to medication classes considered inappropriate in Beers Criteria were included. CMS-List of unnecessary Medications Used In Residents of Long-Term Care Facilities (USA, 2006) The Centre of Medicare and Medicaid Services (CMS) list of medications which have the potential to cause clinically significant adverse consequences, that may have limited indications, require specific monitoring, and which warrant careful considerations of relative risk and benefit for use in older adults. All medications are grouped into a total of 24 medication classes/pathophysiological domains. Important information about dosage, adverse consequences, indications, interactions, monitoring and duration of therapy are added. In an additional table drugs with anticholinergic properties that should be avoided in elderly are listed. Beside the medication list, users will find a lot of additional tips about how to improve medications management. Lindblad’s List of Clinically Important Drug-Disease Interactions (USA, 2006) A consensus list of 28 clinically important drug-disease interactions ordered by disease.

Dp

A

ns

•

Dp

L

El

•

Ex

A

El

•

Lit

L

El

•

Dp

A

El

•

•

o

o

•

o

o

o

o

•

o

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78 Psychopharmacological Issues in Geriatrics Table 3: contd…. KPC- Kaiser Permanente Colorado Criteria (USA, 2007) The criteria consist of 11 potentially inappropriate medications for use in elderly and suggestions for alternative therapies. The criteria are incorporated in an electronic pharmacy information management system. Alerts are generated if a drug, included in the Kaiser Permanente Colorado Criteria, should be dispensed. For each medication, a specific intervention guideline and patient counseling script is defined. Beers-Liste (Germany, 2007) German adaption of Beers Criteria 2003. Structure and content are similar to the original Beers Criteria, but have been adapted for the German Market. Laroche Criteria (France, 2007) Designed for use in the French health care system, including 34 medications to be avoided in elderly. Each drug has a declaration for its inappropriateness and safer therapeutic alternatives were recommended for most of the criteria. START-Screening Tool to Alert doctors to the Right Treatment (Ireland, 2007) A list of 22 prescribing indicators to identify prescribing omissions in older adults. The prescribing indicators are arranged according to the physiological system and present information about disease status for which a drug should be prescribed. Combining this tool with STOPP (see directly below) is possible. STOPP-Screening Tool of Older Person’s Prescriptions (Ireland, 2008) 65 criteria focusing on prevalent problems associated with commonly prescribed medication, arranged according to physiological systems. Each criterion is accompanied by a short explanation concerning the inappropriateness of its use. Winit-Watjana Criteria (Thailand, 2008) The list consists of 77 high-risk drugs divided into drugs to be avoided; drugs rarely appropriate; and drugs with some indications for older patients. A practice statement for each drug gives additional information about the inappropriateness.

Ex

A

El

•

•

Dp

ns

El

•

o

Dp

ns

El

•

o

Dp

ns

El

•

Dp

ns

El

•

Dp

ns

El

•

o

•

o

o

o

o

•

o

o

o

o

o

o

o

o

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Table 3: contd…. NCQA Criteria-High Risk Medications (DAE-A) and potentially harmful Drug-Disease Interactions (DDE) in the Elderly (USA, 2008) The DAE-A and the DDE lists are part of the Health Care Effectiveness Data Information Set (HEDIS), a tool to measure performance on important dimensions of care and a service developed by the National Committee for Quality Assurance (NCQA). The DAE-A list includes 17 medication classes which should be avoided in the elderly, the DDE list shows medication categories affecting the condition of the elderly in a negative way. As a part of HEDIS, the DAE-A and DDE lists are available as interactive, web-based reporting software and receive regular updates. NORGEP-Norwegian General Practice Criteria (Norway, 2009) A list of 21 drugs and drug dosages, as well as 15 drug combinations to be avoided in the elderly in general practice. Each criterion is specified by a comment. Matsumura Alert System for Inappropriate Prescriptions (Japan, 2009) A clinical decision support system combined with a computerized physician order entry system to aid physicians in prescribing medication appropriately. The system focuses on renal disease, liver disease and diabetes mellitus and generates alerts in case of inappropriate dosage or contraindication. The alert system is patient-specific, changes in therapy parameters and clinical laboratory data were automatically updated. FORTA- Fit for the aged criteria (Germany, 2009) A positive list which grades medications into four groups (A-D) concerning their evidence for use in the elderly. Category A: indispensable, with obvious benefit, B: proven efficacy but limited effects, C: questionable efficacy or safety, should be used carefully; D: no evidence, should be avoided in the elderly. Until now, the FORTA criteria are not yet fully tested in a clinical setting and an overview of recommended drugs is not yet available.

Dp

ns

El

•

o

Dp

A

El

•

o

Lit

ns

ns

•

o

ns

ns

El

•

•

•

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80 Psychopharmacological Issues in Geriatrics Table 3: contd…. Terrell Computerized Decision Support System to reduce potentially inappropriate prescribing (USA, 2009) This system was developed for the emergency department and serves as an alert system whem using one of nine high-use potentially inappropriate medications. Safer substitute therapies are proposed The PRISCUS List (Germany, 2010) Consists of 83 potentially inappropriate medications in a total of 18 medication classes and is designed for use in the German health care system. For each inappropriate medication, the criteria include main concerns, possible therapeutic alternatives and precautions to be taken when these medications are used. The freely available online version additionally focuses on drug-disease interactions. Maio Criteria (Italy, 2010) The Italian adaption of Beers Criteria 2003. The criteria contain 23 potentially inappropriate drugs and divide them into three categories: 1) Drugs to always be avoided, 2) Drugs rarely appropriate, and 3) Drugs with some indications but often misused. Unangemessene Arzneistnofe für geriatrische Patienten (DE, 2010) German adaption of Laroche Criteria. Structure and content are similar to the original Laroche Criteria, but have been adapted to the German market, and new recommendations were added. American Medical Directors Association-Top 10 Particularly Dangerous Drug Interactions (USA, cited 2011) An online list of America’s top 10 dangerous drug interactions for patients in long-term care. For each interaction, information about impact, mechanism of interactions, alternatives to patient management, monitoring, precautions and references were provided. The list is based on considerations of drug-drug interactions with clinical significance and a potential to cause harm, the frequency with which these interactions occur and the frequency with which these drugs are prescribed in nursing homes.

Ex

H

El

•

Dp

ns

El

•

o

El

•

o

El

•

o

ns

•

NGT

Lit

Ex

A

ns

L

•

•

•

o

o

o

o

•

•

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Psychopharmacological Issues in Geriatrics 81

Table 3: contd…. New Mexico Criteria (USA, 2012) The New Mexico Prescription Improvement Coalition (NMPIC) created a list of 72 drugs, based on the Beers criteria and the Zahn criteria, to Ex ns El • o • be used with caution in the elderly. The list uses a color-coded scheme to identify different severity levels and lists concerns and alternative suggestions for each drug. Austrian Criteria (Austria, 2012) A list of 73 drugs to avoid in older patients because of an unfavorable benefit/risk profile and/or unproven Dp ns El • o effectiveness. A justification for the inappropriateness of a specific drug or drug class is given and for some of the drugs safer alternatives are proposed. • = Aspect totally covered by the criteria, o =Aspect partially covered by the criteria; Abbreviations: RD RAND method; Dp: Delphi method; NGT: Nominal Group Technique; Ex: Expert panel; Lit based on literature research; El Elderly; L Patients in long-term care; H Hospitalized patients; A Ambulatory patients; ns not specified. Source: Kaufmann CP, Tremp R, Hersberger KE, Lampert ML. Inappropriate prescribing: a systematic overview of published assessment tools. Eur J Clin Pharmacol. 2013. DOI:10.1007/s00228-013-1575-1778.

4.2.1. Beers Criteria In 1991, Mark Howard Beers, an American geriatrician, developed a list of 30 drugs that he argued should be avoided in elderly people living in nursing homes, in what are deemed to be the first explicit criteria for potentially inappropriate medication in elderly and were later known as the Beers criteria [61]. Although these criteria did not initially included diagnosis, subsequent revisions added a second table with drugs inappropriate in the presence of certain diseases. Beers criteria were successively modified to extend its use to community-dwelling elderly and were reviewed in 1997 and 2003. The 2003 update included 48 drugs, or groups of drugs, to be avoided in people over 65 because of ineffectiveness or posing an unnecessary risk when acceptable alternatives were available, and also 20 drugs that should not be used in older persons in the presence of certain diseases [24, 62]. Beers criteria have predominated in the international geriatric literature and are the most cited resource for the identification of potentially inappropriate medications in the elderly [52, 63]. Beers criteria have shown a prevalence of potentially inappropriate medication ranging between 14 and 37% in the community-dwelling elderly and over 50% in elderly people in nursing homes [34, 35, 38, 64]. A number of studies have shown a correlation between the Beers criteria and an increase of adverse drug reactions, risk of falls and probability of hospitalization and death [65-68].

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However, the use of lists of drugs in different settings for which they have been designed can lead to inaccuracies and lack of usefulness. Thus, despite its popularity, its usefulness, has been controversial, especially, in Europe. Up to 50% of the drugs in the Beers list were not included in the drug formularies of most European countries. In addition, a growing number of cases of inappropriate prescribing were not included in the Beers criteria and some of the drugs deemed inappropriate would not be an absolute contraindication according to the British National Formulary. Finally, the Beers criteria forgot other inappropriate prescribing patterns, such as drug interactions, therapeutic duplicity or inappropriate prescription by drug omission [16, 69]. For this reason, some countries have developed their own tools, often developed on the basis of Beers criteria [70-77]. Recently, in 2012, the Beers criteria have been updated (Appendix 1: Tables 1-5) with the collaboration of the Americam Geriatric Society (AGS) [52]. The support of the AGS has made this list more dynamic and relevant to practice in the real world of medicine [78]. The Beers criteria of 2012 differ from previous editions in several aspects. Drugs that are no longer available have been removed, and new drugs introduced since 2003 have been added. Furthermore, the research on drugs included in earlier versions is updated and new information is provided on appropriate medication prescribing for an extended list of common geriatric conditions. For the updating, the interdisciplinary panel has followed an evidencebased approach. Thus, the new criteria include the grading of quality of evidence supporting the recommendations by the panel and the strength of these recommendations [79]. The recent 2012 update of Beers criteria was performed including three basic areas: potentially inappropriate medication in elderly regardless of diagnosis (34 medications or classes of medications), potentially inappropriate medication considering the interaction between drug and disease/syndrome (14 diseases and conditions), and drugs that should be used with caution in the elderly (5 medications or groups of medications) [52]. It has been highlighted that the new 2012 Beers criteria have probably a greater applicability and usefulness in European countries that the earlier versions. Some European studies have shown that the new 2012 criteria include up to 80% of those medicines available in national formularies such as Belgium’s [80]. It is expected that with the support of the AGS, these criteria will continue to develop over time. It has been suggested that future updates should include,

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among other possible improvements, drug interactions and the development of a list of drugs and non-pharmacological resources that could be used as therapeutic alternatives [78]. Nonetheless, the Beers criteria do not allow to assess other aspects of inappropriate use of drugs such as overdose (excess dose, excess treatment duration, or use of unnecessary drugs) and infradose (omission, underdosing or lack of adherence to treatment). These disadvantages, along with others, have led to the development of other explicit tools [81]. 4.2.2. STOPP-START Criteria STOPP (Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions) and START (Screening Tool to Alert doctors to the Right Treatment) criteria were published in 2007 and 2008 respectively. Created in Ireland and with their clinical development assumed by the European Union Geriatric Medicine Society (EUGMS), these criteria emerge as a European response to the problems of the tools previously available and thus they adapt better to the European availability of drugs and prescription habits (Appendix 2: Tables 1 and 2) [81]. These criteria attempt to detect the most common and important cases of inappropriate prescribing, grouped by physiological systems. They are easy to use, can be applied in about 5 minutes and each criterion is accompanied by a brief explanation that justify why a non-suitability judgement is proposed [69]. The STOPP criteria include 65 criteria grouped in 7 physiological systems and three other groups including falls, use of analgesics and duplication of class. The START criteria help identify prescribing omissions in the elderly and, like the STOPP criteria, are grouped in physiological systems. This is the most innovative aspect of these criteria and represents a forgotten aspect in the evaluation of potentially inappropriate prescribing of drugs, such as errors of omission of those treatments probably beneficial for elderly patients [16] and, unlike Beers criteria, have been validated for hospitalized patients [82]. Some experiences with this tool in Spain, conducted in geriatric hospital, primary care and nursing homes, have shown potentially inappropriate prescribing in 54%, 36% and 50% of patients, respectively, whereas the prescribing omission rate as 54%, 28% and 46%, respectively [83]. The STOPP-START criteria have shown a good interobserver reliability with a kappa index of 0.93 and 0.85, respectively [84], and have been validated in several European languages [16, 85, 86].

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Several studies have shown that the prevalence of inappropriate prescribing is higher with STOPP-START criteria than with Beers criteria [69]. Also STOPPSTART criteria have been found to correlate with an increased risk of adverse drug reactions, hospitalization and mortality [82, 87, 88]. Prospective studies show that STOPP criteria detect preventable adverse drug effects causing or contributing to acute hospitalization in elderly people 2.5 times more often than the 2003 Beers criteria [87]. 4.2.3. A Reflection on the Use of Explicit Criteria and the Heterogeneity of the Elderly Population The existence of a single, universal set of explicit criteria would be the ideal situation, but this is unlikely and unfeasible. International differences in drug availability, preferences due to economic issues and regional practice patterns would probably remain an obstacle [53, 89]. Beyond the Beers criteria, the STOPP-START criteria have elicited the largest body of literature since their development. Although the 2012 AGS Beers criteria are considered to overlap with the STOPP-START criteria, and many drugs are included in both, the later cover some areas unapproached by the 2012 Beers criteria. As some authors have proposed, a complementary use of both criteria could guide physicians in making decisions for a safe use of drugs in the elderly [78]. However, the notion of pharmacological accuracy of explicit criteria does not always agree with what might be called the individual suitability, which represents the viewpoints of patients, prescribers and pharmacology. The assessment of the suitability of a prescription should therefore surpass the use of measures based solely on the drug [27]. Explicit criteria should not replace professional judgment or dictate the requirements of an individual patient. This would be against the principles of geriatrics, which require an adaptation to the needs of each particular patient, and a careful consideration of personal circumstances and desires [79]. Individual needs should always be contemplated, especially in the elderly, where there is considerable physiological heterogeneity and where the ratio between risk and benefit of a drug varies significantly depending on the clinical situation of the person [55]. Neither Beers nor STOPP/START recognize the heterogeneity of the elderly and therefore, cannot be applicable in all circumstances [79]. This is especially important in situations of advanced disease and at the end of life, where treatment

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objectives are different and neither of these tools deliberate when it should be appropriate to withdraw or withhold medication which would be appropriate in other circumstances [90]. The principles of appropriate prescribing should consider life expectancy, the objectives of care and the potential benefits of treatment in these circumstances [91]. In the scope of the end of life, with so much uncertainty and lack of evidence, the efforts of Holmes et al., to propose a consensus list of drugs with different levels of prescribing suitability for patients with late-stage dementia are to be emphasized [92]. In this sense, it has been proposed that the STOPP-START criteria should include a section contemplating the needs of patients with palliative care objectives, as other aspects relevant in elderly care, such as falls are already covered [90]. 5. ANTICHOLINERGIC RISK: OTHER ASSESSMENT TOOLS Anticholinergic toxicity is a common problem in older people and is associated with multiple side effects, both at peripheral system (dry mouth, constipation, and visual disturbances) and at the central nervous system level (confusion, delirium, and cognitive impairment). Often, toxicity is not the result of the effect of a single drug but the product of the cumulative anticholinergic burden of multiple drugs and their metabolites [93]. There are more than 600 substances with a known anticholinergic activity [94]. Most of the drugs considered potentially inappropriate in the elderly are anticholinergics [95]. The updated 2012 Beers criteria include a list of those drugs with strong anticholinergic effect [52]. Several studies have shown a high anticholinergic burden in elderly patients, with a tendency to increase in recent years [96], especially in the psychogeriatric care. Apparently, psychiatric patients are especially at risk as a result of the anticholinergic activity of drugs frequently used in psychiatry [45, 95]. Although the measurement of serum anticolinergic activity has been considered the gold standard, this laboratory test is expensive and not available for most clinicians. Moreover, although this measure, has been well correlated with peripheral anticholinergic activity, it has shown a low correlation to the central anticholinergic effects [97]. For these reasons, different quantitative scales have been developed to estimate the total anticholinergic load by adding up the score assigned to each drug a patient receives. Two recent publications have reviewed the different scales of anticholinergic risk available today [95, 98].

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One of these scales, the Drug Burden Index (DBI), assigns a score based on the principles of dose-response relationship and the cumulative effect, and allows to quantify the total exposure of a person to drugs with anticholinergic and sedative effects [99]. In prevalence studies, exposure to drugs included in the DBI ranged from 29 to 70%. A higher score on the DBI has been associated with an increased risk of functional impairment, frailty, falls and hospitalization in elderly of USA, Australia and Europe [100-107]. In a study with another scale, the Anticholinergic Risk Scale (ARS), high scores were negatively associated with various components of the Barthel Index and positively with hospital mortality in the presence of hyponatremia in older patients [108]. However, these scales have shown little concordance between them. The drugs included vary across the scales and the score assigned to each drug differs between them. In addition, the distinct availability of drugs in the different countries hampers a systematic application and, as with all lists of drugs, these scales require periodic updating [95, 98, 109]. In an attempt to reconcile 7 revised scales, Duran et al., proposed a list of 100 drugs with clinically relevant anticholinergic properties, classifying them into high power (47 drugs) and low power (53 drugs). However, none of the current scales consider dosage, which is decisive for the calculation of the total anticholinergic load [110]. Besides the anticholinergic load resulting from the sum of the intrinsic anticholinergic potency of each drug, it would yet be necessary a calculation according to dosage and route of administration, which necessarily calls for further research in order to develop validated, useful scales including all these elements [98]. 6. ELECTRONIC PRESCRIBING Several reviews have shown that computer-based support interventions for treatment decisions can be effective to improve prescribing practices in the elderly [111-115]. Many technological applications are currently available in health care. These can be classified basically into 3 groups: those that allow data storage, management and retrieval, those that facilitate remote care and those that support clinical decision which include the use of electronic prescribing (e-prescribing) and decision systems with computerized support. The impact of the first two categories is assumed to be potentially beneficial as they facilitate the integration of patient information and favor the access to health resources although its real effect is unknown [116, 117].

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With regard to the third category of electronic aids, a recent review on the usefulness of e-prescribing and decision systems with computerized support, provided an overview of the current evidence of the utility of these electronic resources to reduce inappropriate prescribing in the elderly. In total, 14 studies (6 in ambulatory care, 4 in hospitals and 4 in nursing homes) were identified. Overall, there is evidence that they have the potential to reduce inappropriate prescribing and polypharmacy in the elderly. Eleven out of the 14 identified studies reported positive results in reducing the rates of inappropriate prescribing and polypharmacy. However, the magnitude of the effect varied according to the study design and setting. There was a significant heterogeneity in the studies in terms of study design, intervention design, adjustment of patients and outcome measures. Few studies in this review examined the effect of the interventions on patient outcomes, such as hospitalizations, morbidity and mortality, which limits any interpretation of the usefulness of this type of intervention and the knowledge about its impact on clinical outcomes [115]. More rigorous research is needed, with a greater emphasis on the effect of interventions on health outcomes centered in the patient. 7. OTHER MEASURES To reduce the likelihood of clinically significant adverse results, a rational drug withdrawal may be the appropriate clinical decision and may result in significant clinical benefits in some older people on medicines with an associated risk [118, 119]. Polypharmacy is an indicator of high-risk prescribing. The prescription of 8 or more drugs is one of the most predictive risk factor. It is a useful starting, easily verifiable point to identify patients at high risk of adverse outcomes [120]. The review of a patient’s medications regularly is a key element to reduce polypharmacy and inappropriate prescribing [51]. Such a simple procedure as the “brown bag” method, consisting in asking patients to take to the next appointmentall their medications (both prescription and overthe-counter) in a brown bag, can be highly effective. This type of intervention was useful to discontinue at least one drug in 20% of patients or a change of treatment in 29% of patients [121]. The high prevalence of prescribing errors in older derives, from geriatric specific aspects, but also other factors, including care fragmentation, contribute to prescribing errors in all age groups [29]. The greater the number of doctors who

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prescribe medication to an elderly patient, the greater the risk of polypharmacy and inappropriate prescribing. A single primary care physician and a single dispensing pharmacy may be protective factors [122]. It has been demonstrated that pharmacists can help improve prescribing and are an aid to reduce resource use and pharmaceutical expenditure, thus contributing to better outcomes in many chronic diseases, such as cardiovascular disease, diabetes and psychiatric illness [123-125]. In addition, some studies have shown that interdisciplinary teams including nurse and pharmacist are associated with a reduction in the use of potentially inappropriate medication [126]. A systematic review that identified and summarized the effect of interventions to reduce potentially inappropriate use of medication in nursing homes found 20 studies evaluating different types of interventions: 10 educational, 7 medication reviews by pharmacists, 1 intervention by geriatric care teams, 1 early psychiatric intervention and 1 of activity programs for residents. Although the overall quality of all the studies included was low, this survey suggested that educational interventions and medication review by a pharmacist, under certain circumstances, can reduce the consumption of potentially inappropriate medication in nursing homes [127]. 8. RECOMMENDATIONS OF PRESCRIPTION IN ELDERLY A number of basic principles should guide rational prescribing in the elderly. First, frequently drugs are not the only therapeutic option, therefore nonpharmacological alternatives should be considered whenever possible. It is basic to make strategic prescribing practices such as postponing a non urgent drug treatment, avoiding unwarranted change of drug, a cautious use of less experienced drugs, or starting treatment with a single new drug. A constant vigilance of adverse effects of medicines through patient education is mandatory to anticipate the effects, keeping an eye on those drugs with a greater risk. Caution and skepticism must be taken when prescribing new drugs, and impartial information should be sought, delaying use till there is enough experience in routine clinical practice, rather than the initial pre-marketing clinical trials. It is essential to conciliate the treatment with the patient’s drug regimen. Accordingly the possibility of nonadherence should be considered, treatments that previously proved to be ineffective should not be prescribed, and those drugs presently unnecessary should be discontinued. Patient reluctancy must be respected but unjustified concessions should be avoided. Finally, the long-term effects of any medication must never be forgotten [128].

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To achieve these objectives of rationalization, avoiding at the same time the use of inappropriate medication and conditioned iatrogenia, different models of prescription have been proposed. We consider that the pattern proposed by Scott et al., contains all the key elements to consider in order to make a rational and appropriate prescribing in the elderly. This prescription framework comprises 10 sequential steps: 1) verify all current medications, 2) identify patients with high risk or who experience adverse drug reactions, 3) assess the estimated life expectancy in patients at high risk, 4) define the general goals of care in the context of life expectancy 5) define and confirm the actual indications of ongoing treatment, 6) determine the time to the benefit of prescribed medications, 7) estimate the magnitude of the comparison between the benefit and the risk of each drug, 8) review the relative utility of different drugs, 9) identify drugs that can be removed and 10) apply and supervise a plan of minimization of drugs with continuous reassessment of use of medications and patient adherence by a single responsible physician [120]. 9. A FINAL REFLECTION The number of elderly people is rapidly growing all over the world. In this age group, chronic and degenerative diseases are highly prevalent. Doctors consume an increasing proportion of their time in the treatment of elderly patients, and thus the knowledge of pharmacokinetic and pharmacodynamic characteristics of the elderly and geriatric prescribing have become essential in everyday clinical practice [129]. Drug prescribing is a complex process in which the usual approach tends to concentrate on the starting of new drugs, the change of the therapeutic regimen or its continuation. However, a cautious approach to prescribing should not forget the end of treatment, either because it should not have been initiated, because continued use can cause damage, or because it is no longer effective [130]. A framework for minimizing the use of drugs must face the therapeutic urge to prescribe more drugs based on clinical guidelines for specific diseases that overlook the risk of drug-drug and drug-disease interactions in elderly patients with multiple comorbidities [131, 132]. Furthermore, there are studies showing that the total benefit of multiple drugs tends to be lower than the sum of the envisaged benefits of any individual drug [133]. However, these facts should not overshadow another important aspect of inappropriate prescribing, often forgotten, which is underprescribing, especially relevant in the elderly [26].

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Inappropriate prescribing in the elderly is becoming an important health problem associated with considerable morbidity and resource use. A compromise between the principles of evidence-based medicine and good gerontological practice is required. In this sense, tools like Beers or STOPP/START criteria, and different strategies of regular and systematic review of treatment, patient education, collaboration with pharmacist and the use of electronic aids are the key pillars on which rest the solution to this health problem of our elders [51]. Future research endeavors are needed to implement and validate different strategies that contribute to good prescribing practices in the elderly to improve at the same time health outcomes in this important and significant part of the population [27]. ACKNOWLEDGEMENTS Declared none. CONFLICT OF INTEREST The authors confirm that this chapter contents have no conflict of interest. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Gallagher P, Barry P, O’Mahony D. Inappropriate prescribing in the elderly. J Clin Pharm Ther 2007; 32: 113-121. Jano E, Aparasu R R. Health care outcome sassociated with beers’criteria: a systematic review. Ann Pharmacother 2007; 41: 438-447. Fialová D, Topinková E, Gambassi G, et al. AdHOC Project Research Group. Potentially inappropriate medication use among elderly home care patients in Europe. JAMA 2005; 293: 13481358 Slone Epidemiology Center. Patterns of medication use in the United States, 2006: a report from the Slone survey. Available at: http: //www.bu.edu/slone/SloneSurvey/AnnualRpt/SloneSurveyWeb Report2006.pdf. Accesed [2/06/2014] Thomsen LA, Winterstein AG, Søndergaard B, et al. Systematic review of the incidence and characteristics of preventable adverse drug events in ambulatory care. Ann Pharmacother 2007; 41: 1411-1426. Beijer HJM, de Blaey CJ. Hospitalisations caused by adverse drug reactions (ADRs): a meta-analysis of observational studies. Pharm World Sci 2002; 24: 46-54. Franklin BD, Bhandari S. Potentially inappropriate medication in elderly patients with chronic renal disease is it a problem?. Postgrad Med J 2013; 89: 247-250. Breton G, Froissart M, Janus N, et al. Inappropriate drug use and mortality in community-dwelling elderly with impaired kidney function—the Three-City population-based study. Nephrol Dial Transplant 2011; 26: 2852-2859. Hamilton HJ, Gallagher PF, O’Mahony D. Inappropriate prescribing and adverse drug events in older people. BMC Geriatrics 2009; doi: 10.1186/1471-2318-9-5 Hanlon JT, Schmader KE, Koronkowski MJ, et al. Adverse drug events in high risk older outpatients. J Am Geriatr Soc 1997; 45: 945-948.

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Appendix Appendix 1: Beers´s criteria Table 1: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Organ System/ Therapeutic Category/Drug(s)

Rationale

Recommendation

Quality of evidence

Strength of recommendation

Anticholinergics (excludes TCAs) First-generation antihistamines (as single agent or as part of combination products)  Brompheniramine (R06AB01/ R06AB51)  Carbinoxamine (R06AA08)  Chlorpheniramine (Chlorphenamine) (R06AB04)  Clemastine (R06AA04/ R06AA54)  Cyproheptadine (R06AX02)  Dexbrompheniramine (R06AB06/ R06AB56)  Dexchlorpheniramine (R06AB02/ R06AB52)  Diphenhydramine (oral) (R06AA02/ R06AA52)  Doxylamine (R06AA09/ R06AA59)  Hydroxyzine (N05BB01/ N05BB51)  Promethazine (R06AD02/ R06AD52)  Triprolidine (R06AX07)

Highly anticholinergic; clearance reduced with advanced age, and tolerance develops when used as hypnotic; increased risk of confusion, dry mouth, constipation, and other anticholinergic effects/toxicity. Use of diphenhydramine in special situations such as acute treatment of severe allergic reaction may be appropriate.

Antiparkinson agents Benztropine (oral) (Benzatropine) (N04AC01)  Trihexyphenidyl (N04AA01)

Not recommended for prevention of extrapyramidal symptoms with antipsychotics; more effective agents available for treatment of Parkinson disease.



     

Antispasmodics Highly anticholinergic, uncertain effectiveness. Belladonna alkaloids (A03BA/ A03BB/ A06AB30) Clidinium -chlordiazepoxide (A03CA02) Dicyclomine (Dicycloverine) (A03AA07) Hyoscyamine (A03BA03/ A03CB31) Propantheline (A03AB05/ A03CA34) Scopolamine (A03BB01/ A03DB04/ A03BB03/A03CB01 /A04AD01/ N05CM05 A04AD51)

Avoid

Hydroxyzine and promethazine: high; All others: moderate

Strong

Moderate

Strong

Avoid except in Moderate short-term palliative care to decrease oral secretions.

Strong

Avoid

Antithrombotics Dipyridamole (B01AC07), oral short-acting* May cause orthostatic hypotension; more effective (does not apply to the extended- release alternatives available; IV form acceptable for use in combination with aspirin) cardiac stress testing. Ticlopidine* (B01AC05)

Avoid

Moderate

Strong

Avoid

Moderate

Strong

Potential for pulmonary toxicity; safer alternatives Avoid for long- Moderate available; lack of efficacy in patients with CrCI 25 mg/day (C03DA01)

In heart failure, the risk of hyperkalemia is higher in older adults especially if taking >25 mg/day or taking concomitant NSAID, angiotensin converting- enzyme inhibitor, angiotensin receptor blocker, or potassium supplement.

Avoid in patients Moderate with heart failure or with a CrCI 90 days) (e.g. delirium, falls, fractures); minimal improvement in sleep latency and duration.

Strong

Ergot mesylates* (C04AE01) Isoxsuprine* (C04AA01)

Lack of efficacy.

Avoid

Strong

Potential for cardiac problems and contraindicated in men with prostate cancer.

Avoid unless Moderate indicated for moderate to severe hypogonadism.

Weak

Desiccated thyroid (thyroid gland preparations) Concerns about cardiac effects; safer alternatives (H03AA05) available.

Avoid

Strong

Estrogens with or without progestins (G03C, G03F)

Evidence of carcinogenic potential (breast and endometrium); lack of cardioprotective effect and cognitive protection in older women. Evidence that vaginal estrogens for treatment of vaginal dryness is safe and effective in women with breast cancer, especially at dosages of estradiol 75 or taking oral  Aspirin >325 mg/day (acetylsalicylic acid) (N02BA01, M01BA03, N02BA51, or parenteral corticosteroids, anticoagulants, or antiplatelet agents. Use of proton pump inhibitor or N02BA71) misoprostol reduces but does not eliminate risk. Upper  Diclofenac (M01AB05, M02AA15, Gl ulcers, gross bleeding, or perforation caused by M01AB55) NSAIDs occur in approximately 1% of patients treated  Diflunisal (N02BA11) for 3- 6 months, and in about 2%-4% of patients treated  Etodolac (M01AB08) for 1 year. These trends continue with longer duration of use.  Fenoprofen (M01AE04)  Ibuprofen (M01AE01, M02AA13, M01AE51)  Ketoprofen (M01AE03, M02AA10, M01AE53)  Meclofenamate (meclofenamic acid) (M01AG04, M02AA18)  Mefenamic acid (M01AG01)  Meloxicam (M01AC06, M01AC56)  Nabumetone (M01AX01)  Naproxen (M01AE02, M02AA12, M01AE52, M01AE56)  Oxaprozin (M01AE12)  Piroxicam (M01AC01, M02AA07)  Sulindac (M01AB02)  Tolmetin (M01AB03, M02AA21)

Avoid chronic use Moderate unless other alternatives are not effective and patient can take gastroprotective agent (protonpump inhibitor or misoprostol)

Strong

Indomethacin (M01AB01, M02AA23, M01AB51) Ketorolac, includes parenteral (M01AB15)

Increases risk of Gl bleeding/peptic ulcer disease in high- Avoid risk groups (See above Non-COX selective NSAIDs) Of all the NSAIDs, indomethacin has most adverse effects.

Indomethacin: Moderate Ketorolac: high;

Strong

Pentazocine* (N02AD01)

Opioid analgesic that causes CNS adverse effects, Avoid including confusion and hallucinations, more commonly than other narcotic drugs; is also a mixed agonist and antagonist; safer alternatives available.

Low

Strong

Skeletal muscle relaxants  Carisoprodol (M03BA02, M03BA52, M03BA72)  Chlorzoxazone (M03BB03, M03BB53, M03BB73)  Cyclobenzaprine (M03BX08)  Metaxalone (ATC none)  Methocarbamol (M03BA03, M03BA53, M03BA73)  Orphenadrine (N04AB02, M03BC01, M03BC51)

Most muscle relaxants poorly tolerated by older adults, because of anticholinergic adverse effects, sedation, increased risk of fractures; effectiveness at dosages tolerated by older adults is questionable.

Moderate

Strong

Avoid

* Infrequently used drugs Abbreviations: ACEI, angiotensin converting-enzyme inhibitors; ARB, angiotensin receptor blockers; CNS, central nervous system; COX, cyclooxygenase; CrCI, creatinine clearance; Gl, gastrointestinal; NSAIDs, nonsteroidal antiinflammatory drugs; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TCAs, tricyclic antidepressants. Source: The American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc 2012;60:616-31.

Table 2: 2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults Due to Drug-Disease or Drug-Syndrome Interactions That May Exacerbate the Disease or Syndrome. Disease or Syndrome

Drug(s)

Rationale

Recommendation

Quality of Evidence

Strength of Recommendation

Cardiovascular Heart failure

NSAIDs (M01A) and COX-2 inhibitors (M01AH) Nondihydropyridine CCBs (avoid only for systolic heart failure)  Diltiazem (C08DB01)  Verapamil (C09BB10, C08DA01, C08DA51) Pioglitazone (A10BG03),

Potential to promote fluid retention and/or exacerbate heart failure.

Avoid

NSAIDs: moderate; Strong CCBs: moderate; Thiazolidinediones (glitazones): high; Cilostazol: low; Dronedarone: moderate

Potentially Inappropriate Medication in Elderly

Psychopharmacological Issues in Geriatrics 101

Rosiglitazone (A10BG02) Cilostazol (B01AC23) Dronedarone (C01BD07) Syncope

Acetylcholinesterase inhibitors (AChEls) (N07AA) Peripheral alpha blockers  Doxazosin (C02CA04)  Prazosin (C02CA01, C02LE01)  Terazosin (G04CA03) Tertiary TCAs Chlorpromazine (N05AA01), thioridazine (N05AC02), and olanzapine (N05AH03)

Increases risk of orthostatic hypotension Avoid or bradycardia.

Alpha blockers: high TCAs, AChEIs, and antipsychotics: moderate

AChEls and TCAs: strong Alpha blockers and antipsychotics: weak

Central Nervous System Chronic seizures Bupropion (N06AX12) Lowers seizure threshold; may be or epilepsy acceptable in patients with wellChlorpromazine (N05AA01) controlled seizures in whom alternative Clozapine (N05AH02) agents have not been effective. Maprotiline (N06AA21) Olanzapine (N05AH03) Thioridazine (N05AC02) Thiothixene (Tiotixene) (N05AF04) Tramadol (N02AX02, N02AX52) Delirium

Avoid

Moderate

Strong

Avoid

Moderate

Strong

All TCAs (N06AA) Anticholinergics (see Table 4.5 for full list) Benzodiazepines (N05BA) Chlorpromazine (N05AA01) Corticosteroids H2-receptor antagonist (A02BA) Meperidine (Pethidine) (N02AB02, N02AG03, N02AB52, N02AB72) Sedative hypnotics (N05C) Thioridazine (N05AC02)

Avoid in older adults with or at high risk of delirium because of inducing or worsening delirium in older adults; if discontinuing drugs used chronically, taper to avoid withdrawal symptoms.

Dementia and cognitive impairment

Anticholinergics (see Table 4.5 for full list) Benzodiazepines (N05BA) H2-receptor antagonists (A02BA) Zolpidem (N05CF02) Antipsychotics (N05A), chronic and as-needed use

Avoid due to adverse CNS effects. Avoid Avoid antipsychotics for behavioral problems of dementia unless nonpharmacological options have failed and patient is a threat to themselves or others. Antipsychotics are associated with an increased risk of cerebrovascular accident (stroke) and mortality in persons with dementia.

High

Strong

History of falls or fractures

Anticonvulsants (N03A) Antipsychotics (N05A) Benzodiazepines (N05BA) Nonbenzodiazepine hypnotics  Eszopiclone (N05CF04)  Zaleplon (N05CF03)  Zolpidem (N05CF02) TCAs (N06AA) and SSRIs (N06AB)

Ability to produce ataxia, impaired psychomotor function, syncope, and additional falls; shorter-acting benzodiazepines are not safer than longacting ones.

High

Strong

Avoid

Moderate

Strong

Avoid

Moderate

Strong

Insomnia

Parkinson´s disease

Oral decongestants  Pseudoephedrine (R01BA02, R01BA52)  Phenylephrine (R01AA04,R01AB01, R01BA03, R01BA53) Stimulants  Amphetamine (N06BA01)  Methylphenidate (N06BA04)  Pemoline (N06BA05) Theobromines  Theophylline (R03DA04, R03DB04, R03DA54, R03DA74)  Caffeine (N06BC01) All antipsychotics (N05A) (see Table 3.4 for full list, except for quetiapine (N05AH04) and clozapine (N05AH02))

CNS stimulant effects

Dopamine receptor antagonists with potential to worsen parkinsonian symptoms. Quetiapine and clozapine appear to be less likely to precipitate

Avoid unless safer alternatives are not available; avoid anticonvulsants except for seizure disorders

Hernández et al.

102 Psychopharmacological Issues in Geriatrics Antiemetics worsening of Parkinson´s disease.  Metoclopramide (A03FA01)  Prochlorperazine (N05AB04)  Promethazine (R06AD02, R06AD52) Gastrointestinal Chronic constipation

Oral antimuscarinics for urinary Ability to worsen constipation; agents Avoid unless no incontinence for urinary incontinence: antimuscarinics other alternatives overall differ in incidence of  Darifenacin (G04BD10) constipation; response variable; consider  Fesoterodine (G04BD11) alternative agent if constipation  Oxybutynin (oral) (G04BD04) develops.  Solifenacin (G04BD08)  Tolterodine (G04BD07)  Trospium (G04BD09) Nondihydropyridine CCB  Diltiazem (C08DB01)  Verapamil (C09BB10, C08DA01, C08DA51) First-generation antihistamines as single agent or part of combination products  Brompheniramine (various) (R06AB01, R06AB51)  Carbinoxamine (R06AA08)  Chlorpheniramine (Chlorphenamine)’ (R06AB04, R06AB54)  Clemastine (various) (R06AA04, R06AA54)  Cyproheptadine (R06AX02)  Dexbrompheniramine (R06AB06, R06AB56)  Dexchlorpheniramine (various) (R06AB02, R06AB52)  Diphenhydramine (R06AA02, R06AA52)  Doxylamine (R06AA09, R06AA59)  Hydroxyzine (N05BB01, N05BB51)  Promethazine (R06AD02, R06AD52)  Triprolidine (R06AX07) Anticholinergics/antispasmodics (see Table 4.5 for full list of drugs with strong anticholinergic properties)  Antipsychotics (N05A)  Belladonna alkaloids (A03BA/ A03BB/ A06AB30)  Clidinium-chlordiazepoxide (A03CA02)  Dicyclomine (Dicycloverine) (A03AA07)  Hyoscyamine (A03BA03, A03CB31)  Propantheline (A03AB05, A03CA34)  Scopolamine (A03BB01/ A03DB04/ A03BB03/A03CB01 /A04AD01/ N05CM05 A04AD51)  Tertiary TCAs (amitriptyline (N06AA09, N06CA01), clomipramine (N06AA04), doxepin (N06AA12), imipramine (N06AA02), and trimipramine(N06AA06))

History of gastric Aspirin (>325 mg/day) or duodenal ulcers (acetylsalicylic acid) (N02BA01, M01BA03, N02BA51, N02BA71)

May exacerbate existing ulcers or cause Avoid unless other new/additional ulcers. alternatives are not effective and patient

For urinary incontinence: high All others: Moderate/low

Moderate

Weak

Strong

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Psychopharmacological Issues in Geriatrics 103

Non-COX-2 selective NSAIDs

can take gastroprotective agent (proton- pump inhibitor or misoprostol)

Kidney/Urinary Tract Chronic kidney NSAIDs (M01A) disease Stages IV Triamterene (alone or and V in combination) (C03DB02)

May increase risk of kidney injury.

Avoid

NSAIDs: moderate NSAIDs: strong Triamterene: low Triamterene: weak

Urinary Estrogen oral and transdermal incontinence (all (excludes intravaginal estrogen) types) in women

Aggravation of incontinence.

Avoid in women

High

Strong

Avoid in men

Moderate

Inhaled agents: strong All others: weak

Avoid in women

Moderate

Strong

Lower urinary tract symptoms, benign prostatic hyperplasia

Inhaled anticholinergic agents Strongly anticholinergic drugs, except antimuscarinics for urinary incontinence (see Table 4.5 for complete list).

Stress or mixed urinary incontinence

Alpha-blockers  Doxazosin (C02CA04)  Prazosin (C02CA01, C02LE01)  Terazosin (G04CA03)

May decrease urinary flow and cause urinary retention.

Aggravation of incontinence.

Abbreviations: CCBs, calcium channel blockers; AChEls, acetylcholinesterase inhibitors; CNS, central nervous system; COX, cyclooxygenase; NSAIDs, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants. Source: The American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc 2012;60:616-31.

Table 3: 2012 AGS Beers Criteria for Potentially Inappropriate Medications to Be Used with Caution in Older Adults Quality of Evidence

Strength of Recommendation

Low

Weak

Dabigatran (B01AE07) Increased risk of bleeding compared with warfarin in Use with caution in adults≥75 years old adults ≥75 years old; lack of evidence for efficacy and or if CrCI 150 mg/day (increased bleeding risk, no evidence for increased efficacy). Aspirin with no history of coronary, cerebral or peripheral vascular symptoms or occlusive event (not indicated). Aspirin to treat dizziness not clearly attributable to cerebrovascular disease (not indicated). Warfarin for first, uncomplicated deep venous thrombosis for longer than 6 months duration (no proven added benefit). Warfarin for first uncomplicated pulmonary embolus for longer than 12 months duration (no proven benefit). Aspirin, clopidogrel, dipyridamole or warfarin with concurrent bleeding disorder (high risk of bleeding).

B. Central nervous system and psychotropic drugs 1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11.

Tricyclic antidepressants (TCAs) with dementia (risk of worsening cognitive impairment). TCAs with glaucoma (likely to exacerbate glaucoma). TCAs with cardiac conductive abnormalities (pro-arrhythmic effects). TCAs with constipation (likely to worsen constipation). TCAs with an opiate or calcium channel blocker (risk of severe constipation). TCA’s with prostatism or prior history of urinary retention (risk of urinary retention). Long-term (i.e. > 1 month), long-acting benzodiazepines, e.g. chlordiazepoxide, flurazepam, nitrazepam, chlorazepate and benzodiazepines with long-acting metabolites, e.g. diazepam (risk of prolonged sedation, confusion, impaired balance, falls). Long-term (i.e. > 1 month) neuroleptics as long-term hypnotics (risk of confusion, hypotension, extrapyramidal side effects, falls). Long-term neuroleptics (> 1 month) in those with parkinsonism (likely to worsen extrapyramidal symptoms). Phenothiazines in patients with epilepsy (may lower seizure threshold). Anticholinergics to treat extrapyramidal side effects of neuroleptic medications (risk of anticholinergic

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Psychopharmacological Issues in Geriatrics 107

toxicity). 12. Selective serotonin re-uptake inhibitors (SSRIs) with a history of clinically significant hyponatremia (non-iatrogenic hyponatremia 1 week) of first-generation antihistamines, i.e. diphenhydramine, chlorpheniramine, cyclizine, promethazine (risk of sedation and anti-cholinergic side effects). C. Gastrointestinal system 1.

2. 3. 4. 5.

Diphenoxylate, loperamide or codeine phosphate for treatment of diarrhea of unknown cause (risk of delayed diagnosis, may exacerbate constipation with overflow diarrhea, may precipitate toxic megacolon in inflammatory bowel disease, may delay recovery in unrecognized gastroenteritis). Diphenoxylate, loperamide or codeine phosphate for treatment of severe infective gastroenteritis, i.e. bloody diarrhea, high fever or severe systemic toxicity (risk of exacerbation or protraction of infection). Prochlorperazine or metoclopramide with parkinsonism (risk of exacerbating parkinsonism). PPI for peptic ulcer disease at full therapeutic dosage for > 8 weeks (dose reduction or earlier discontinuation indicated). Anticholinergic antispasmodic drugs with chronic constipation (risk of exacerbation of constipation).

D. Respiratory system

Theophylline as monotherapy for COPD (safer, more effective alternative; risk of adverse effects due to narrow therapeutic index). 2. Systemic corticosteroids instead of inhaled corticosteroids for maintenance therapy in moderate-to- severe COPD (unnecessary exposure to long-term side effects of systemic steroids). 3. Nebulized ipratropium with glaucoma (may exacerbate glaucoma). 1.

E. Musculoskeletal system 1.

2. 3. 4. 5. 6. 7. 8.

Non-steroidal anti-inflammatory drug (NSAID) with history of peptic ulcer disease or gastrointestinal bleeding, unless with concurrent histamine H2 -receptor antagonist, PPI or misoprostol (risk of peptic ulcer relapse). NSAID with moderate-to-severe hypertension (risk of exacerbation of hypertension). NSAID with heart failure (risk of exacerbation of heart failure). Long-term use of NSAID (> 3 months) for symptom relief of mild osteoarthritis (simple analgesics preferable and usually as effective for pain relief). Warfarin and NSAID together (risk of gastrointestinal bleeding). NSAID with chronic renal failure* (risk of deterioration in renal function). Long-term corticosteroids (> 3 months) as monotherapy for rheumatoid arthrtltls or osterarthritis (risk of major systemic corticosteroid side-effects). Long-term NSAID or colchicine for chronic treatment of gout where there Is no contraindication to allopurinol (allopurinol first-choice prophylactic drug in gout).

F. Urogenital system 1. 2. 3. 4. 5. 6.

Bladder antimuscarinic drugs with dementia (risk of increased confusion, agitation). Antimuscarinic drugs with chronic glaucoma (risk of acute exacerbation of glaucoma). Antimuscarinic drugs with chronic constipation (risk of exacerbation of constipation). Antimuscarinic drugs with chronic prostatism (risk of urinary retention). Alpha blockersin males with frequent incontinence, i.e. one or more episodes of incontinence daily (risk of urinary frequency and worsening of incontinence) Alpha blockers with long-term urinary catheter in situ, i.e. more than 2 months (drug not indicated).

G. Endocrine system 1.

Glibenclamide or chlorpropamide with type 2 diabetes mellitus (risk of prolonged hypoglycemia).

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Beta blockers in those with diabetes mellitus and frequent hypoglycemic episodes i.e. > 1 episode per month (risk of masking hypoglycemic symptoms). 3. Estrogens with a history of breast cancer or venous thromboembolism (increased risk of recurrence). 4. Estrogens without progestogen in patients with intact uterus (risk of endometrial cancer).

2.

H. Drugs that adversely affect fallers

5.

Benzodiazepines (sedative, may cause reduced sensorium, impair balance). Neuroleptic drugs (may cause gait dyspraxia, parkinsonism). First-generation antihistamines (sedative, may impair sensorium). Vasodilator drugs with persistent postural hypotension, i.e., recurrent > 20 mmHg drop in systolic blood pressure (risk of syncope, falls). Long-term opiates in those with recurrent falls (risk of drowsiness, postural hypotension, vertigo).

I.

Analgesic drugs

1.

Use of long-term powerful opiates, e.g. morphine or fentanyl as first-line therapy for mild-to-moderate pain (World Health Organization analgesic ladder not observed). Regular opiates for more than 2 weeks in those with chronic constipation without concurrent use of laxatives (risk of severe constipation). Long-term opiates in those with dementia unless indicated for palliative care or management of moderate/severe chronic pain syndrome (risk of exacerbation of cognitive impairment).

1. 2. 3. 4.

2. 3. J.

Duplicate drug classes

Any duplicate drug class prescription, e.g. 2 concurrent opiates, NSAIDs, SSRIs, loop diuretics, ACE inhibitors (optimization of monotherapy within a single drug class should be observed prior to considering a new class of drug). * Serum creatinine > 150 μmol/l, or estimated GFR < 50 ml/min Source: Gallagher P, Ryan C, Byrne S, Kennedy J, O’Mahony D. STOPP (Screening Tool of Older Person’s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment).Consensus validation. Int J Clin Pharmacol Ther. 2008;46:72-83.



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Psychopharmacological Issues in Geriatrics 109

Table 2: START: Screening Tool to Alert doctors to Right, i.e. appropriate, indicated Treatments. A. Cardiovascular system 1. Warfarin in the presence of chronic atrial fibrillation. 2. Aspirin in the presence of chronic atrial fibrillation, where warfarin is contraindicated, but not aspirin. 3. Aspirin or clopidogrel with a documented history of atherosclerotic coronary, cerebral or peripheral

vascular disease in patients with sinus rhythm. 4. Antihypertensive therapy where systolic blood pressure consistently > 160 mmHg. 5. Statin therapy with a documented history of coronary, cerebral or peripheral vascular disease, where the

patient’s functional status remains independent for activities of daily living and life expectancy is greater than 5 years. 6. Angiotensin converting enzyme (ACE) inhibitor with chronic heart failure. 7. ACE inhibitor following acute myocardial infarction 8. Beta blocker with chronic stable angina B. Respiratory system 1. Regular inhaled beta2-agonist or anticholinergic agent for mild-to-moderate asthma or COPD. 2. Regular inhaled corticosteroid for moderate/severe asthma or COPD, where predicted FEVi < 50%. 3. Home continuous oxygen with documented chronic type 1 respiratory failure (p02 < 8.0 kPa, pC02 < 6.5

kPa) or type 2 respiratory failure (p02< 8.0 kPa, pC02 > 6.5 kPa).

C. Central nervous system

1. L-DOPA in idiopathic Parkinson’s disease with definite functional impairment and resultant disability. 2. Antidepressant drug in the presence of moderate/severe depressive symptoms lasting at least three months. D. Gastrointestinal system 1. Proton pump inhibitor with severe gastroesophageal acid reflux disease or peptic stricture requiring

dilation. 2. Fiber supplement for chronic, symptomatic diverticular disease with constipation. E. Musculoskeletal system 1. Disease-modifying antirheumatic drug (DMARD) with active moderate/severe rheumatoid disease lasting

> 12 weeks. 2. Bisphosphonates in patients taking maintenance corticosteroid therapy. 3. Calcium and vitamin D supplement in patients with known osteoporosis (previous fragility fracture,

acquired dorsal kyphosis). F. Endocrine system

1. Metformin with type 2 diabetes ± metabolic syndrome (in the absence of renal impairment*). 2. ACE inhibitor or angiotensin receptor blocker in diabetes with nephropathy, i.e. overt urinalysis proteinuria or microalbuminuria (> 30 mg/24 hours) ± serum biochemical renal impairment*. 3. Antiplatelet therapy in diabetes mellitus with coexisting major cardiovascular risk factors (hypertension, hypercholesterolemia, smoking history). 4. Statin therapy in diabetes mellitus if coexisting major cardiovascular risk factors present. * Serum creatinine > 150 μmol/l, or estimated GFR < 50 ml/min Source: Gallagher P, Ryan C, Byrne S, Kennedy J, O’Mahony D. STOPP (Screening Tool of Older Person’s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation. Int J Clin Pharmacol Ther. 2008;46:72-83.

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CHAPTER 6

Pharmacovigilance in Geropsychiatry Carmelo Aguirre* and Montserrat García Basque Pharmacovigilance Unit, Galdakao-Usánsolo Hospital, Bizkaia/Vizcaya, Spain Abstract: The overall consensus is that elderly psychiatric patients are more prone to develop adverse drug reactions than younger patients as a consequence of psychopharmacological medication. Elderly persons with psychiatric disorders frequently suffer from somatic diseases and may receive polypharmacy more than younger patients. Thus, they may tend to develop adverse drug reactions more frequently. In addition, medications are brought to market with limited experience regarding their adverse effects, given the small number of people who have taken them during pre-marketing clinical tests. This is particularly true with elderly patients. As a result of this conditioning factor, in particular during the years leading up to the appearance of a new medication, health professionals (basically the physician) should pay special attention to: both a) Identifying the adverse effects of medications.and b) Reporting them in order to always maintain a favourable risk-benefit balance.

Keywords: Adverse drug reactions, Antipsychotics, Case reports, Case-control study, Clinical Trial, Cohort Study, Drug authorization, Elderly, Geropsychiatry, Health Databases, Intensive monitoring studies, Metaanalysis, Pharmacogenetics, Pharmacovigilance, Post marketing studies, Prescription event-monitoring, Psychopharmacology, Risk management, Spontaneous, Yellow card. 1. INTRODUCTION Pharmacovigilance is defined as the public-health activity aimed at identifying and quantifying the risk associated with the use of medicines, emphasising two facts - first, its existence and to a certain extent inevitability, deriving in many cases from the drug’s action mechanism (type A reactions); and second, the lack of knowledge of its amount. Medications are brought to market with limited experience regarding their adverse effects, given the small number of people who have taken them during pre-marketing clinical tests, based on the results of which the competent health authorities (European Medicines Agency, Food and Drug Administration) consider the risk-benefit balance to be positive and expressly *Corresponding author Carmelo Aguirre: Basque Country Pharmacovigilance Unit, Galdakao-Usansolo Hospital, Barrio Labeaga s/n, 48960 Galdakao, Bizkaia/Vizcaya, Spain; Tel: 0034 94 40 07 070; E-mail: [email protected]

Unax Lertxundi, Juan Medrano and Rafael Hernández (Eds.) All rights reserved-© 2015 Bentham Science Publishers

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authorise their sale. As a result of this conditioning factor, in particular during the years leading up to the appearance of a new medication, health professionals (basically the physician) should pay special attention to: a) Identifying the adverse effects of medications. b) Reporting them in order to always maintain a favourable risk-benefit balance. This concept is dynamic, as shown by the case of sertindole, which was removed from the market in the European Union in February 2000 due to its association with heart arrhythmia and sudden-death cases, but was authorised once again in June 2002, albeit with usage restrictions [1]. This chapter describes the various types of studies used in Pharmacovigilance, followed by an analysis of the detected risks and their management. Considered overall, the so-called yellow card method has been shown to be the most effective and cheapest in identifying risks (signals). For example, a study that analysed the drugs removed from the Spanish market from 1990 to 1999 concluded that the decision to withdraw the product was taken in 82% of cases based on reporting of individual cases, and that almost half of all cases were type B reactions (unrelated to the action mechanism) [2]. Some decisions by drugs regulating agencies have affected the medications used in psychiatry in recent years, including tetrazepamserious skin reactions-marketing authorization suspension (May 2013) [3], or zolpidem-risk of impaired driving (March 2014) [4]. 2. HOW TO ASSESS THE RELATIONSHIP BETWEEN ADVERSE REACTIONS AND DRUGS 2.1. Case Reports and Case Series Publishing individual case, or sometimes broader or narrower series of cases, is a very common procedure in medicine to share observations in medical practice with the rest of the scientific community. In general, most biomedical journals have included, and include, the description of adverse effects associated with medications in their sections, in the form of letters to the editor, clinical notes, or others. This type of reporting is known as “voluntary unsystemised reporting of adverse reactions” to distinguish it from the “systemised reporting by forms” introduced for the first time by a state, the United Kingdom, in 1964, with the introduction of the yellow card programme (first attempt to systemise the

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Psychopharmacological Issues in Geriatrics 113

voluntary reporting of adverse reactions associated with medications; see the section on Spontaneous Reporting: Yellow Card). The validity of the unsystemised reporting method is backed by noteworthy examples like thalidomide-phocomelia [5] or clozapine-agranulocytosis [6], where reporting of cases provided prompt alert. However, this form of reporting is erratic and anarchic, and therefore poses significant problems. These can include: a) The tendency to publish cases where the causal link of the drug reaction is elucidated; thus, for instance, the first case linking captopril to coughing was turned down by the medical journal where it was sent for publication. b) The lack of enough information to define the drug/adverse reaction causal link [7]. c) The delay between diagnosis and publication of the case [8]. d) The publication, in many cases, in the original language of the place where the case occurred, hampering its dissemination. Therefore, although the value of publishing clinical observations of the undesired effects of drugs is limited in terms of generating signals in pharmacovigilance [9], for it to be of any true value the medical journal publishers must follow the established guidelines for assuring the quality of the information [10] and the authors, in addition to following the guidelines, must feel that they have a responsibility for reporting the individual cases that come to their knowledge to the regulating authorities, which by no means is incompatible with publishing cases in magazines [8]. Many Marketing Authorisation Holders (MAHs) regularly revise cases of adverse reactions to the products they market published in biomedical journals by professionals, and mine any unreported effects, when the minimum information is available, reporting them to the drugs regulating agencies. 2.2. Spontaneous Reporting: Yellow Card In general, the systemised spontaneous reporting of suspected adverse reactions by health care professionals (“yellow card”) is deemed to be the most efficient method for identifying previously unknown drug risks. The purpose of this system is to: a) Facilitate reporting by professionals by providing a simple form containing all significant informational aspects;

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114 Psychopharmacological Issues in Geriatrics

b) Collect and validate this information; c) Record it in a common database that makes it possible to generate “signals”. The confidentiality of both patient and reporter is assured throughout the entire process. The benefits of spontaneous reporting include its simplicity and its universal nature, as it potentially encompasses the entire population, all adverse reactions and all drugs from the very moment they are marketed. Its main drawback is underreporting. Thus, for instance, in Great Britain, the number of doctors who report does not exceed 10%, and in some studies it was shown that only 4% of medication-related hospital admission cases were spontaneously reported to the relevant pharmacovigilance centre [11]. As a result, by definition, the number of registered cases of a drug-adverse reaction link accounts for but a small part of the actual number. The system prioritises the reporting of suspected serious adverse reactions and those involving medications subjected to additional follow-up (identified with an inverted black triangle in the EU-▼) without disregarding those that do not meet these conditions. It is also important to note that health professionals are only asked to report any suspicions that a drug may be involved in the onset of any clinical condition. The pharmacovigilance centre is in charge of assessing the degree of the causal link. As indicated in the introduction, it is important to stress that inspite of the limitations of the yellow card system, its contribution has been essential in identifying many risks that led to decisions to recall or withdraw a medication, while other pharmacovigilance methods with stronger associations in epidemiological terms did not contribute as decisively to such decisions. Table 1 describes some of these in chronological order. Table 1: Some risks identified by spontaneous reporting that led to the recall or withdrawal of drugs from the market in the European Union DRUG

PROBLEM

Year

Ebrotidine

Hepatotoxicity

1998*

Cerivastatin

Rhabdomyolisis

2002

Veralipride

Depression, dyskinesia

2007

Nefazodone

Hepatotoxicty

2003

Carisoprodol

Abuse and dependence

2007

*Only in Spain.

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Psychopharmacological Issues in Geriatrics 115

2.3. Cohort Studies A cohort study is an observational study where patients are selected according to their exposure to a drug (exposed and not exposed); each of these populations with differing exposure is called a cohort. They are then monitored over time in order to learn if they develop the disease or disorder of interest (prospective cohorts), although a condition or event occurring in the past can also be tracked methodologically up to the present (retrospective cohorts). Often the observation period should last several years in order to register a sufficient number of cases. The procedure for detecting an adverse reaction will depend on the type of disease being studied, and it can be done via regular interviews, death records, clinical records, etc. Therefore, cohort studies assess a drug or group of drugs in relation to the risk of any disease or symptom that one may wish to study (Fig. 1). On the other hand, as we will see further below, in case and control studies a disease is assessed in relation to as many risk factors as one may wish to study. Cohort studies have the advantage that the groups being compared are supervised over time after exposure to the studied factor, i.e. the natural sequence of events is tracked. In addition, these types of studies make it possible to determine the incidence of diseases of interest in the studied groups. They are generally useful only for the etiological study of relatively common diseases. They have the drawback of being costly and complex to organise. The main biases one should pay attention to in a cohort study are: a)

Selection bias, which determines that the cohorts are not comparable in all forecast variables and is due to the observational nature of the study.

b) Migration bias, due to some study subjects leaving the cohort they had initially joined. c)

Observation bias, which is that when doctors make clinical observations, they do so knowing the treatment being received by every subject, which determines that, consciously or unconsciously, the observer tends to seek different clinical events with differing levels of intensity depending on the group or cohort the subject belongs to.

d) The bias due to the presence of confounding factors, which occurs when a variable (called a confounding variable or factor) is in simultaneous but independent relation with the exposure and the studied disease.

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11 16 Psychopharma acological Issues in Geriatrics

Finally, cohort studies make m it possib ble for inciddence rates aand relative risk (RR) to o be calculatted, along with w their con nfidence int ervals. Otheer incidence measures in nclude life-taable rates, ROC R curves and a hazard raatios [12].

Drug

A Adverse reaction Present

Ab bsent

A

b

C

d

Present (exposed) Absen nt (unex xposed)

Fiigure 1: Structture of cohort studies s (taken from f Vallvé C [13]).

2.4. Case-Control Studiees In n these types of studies,, patients aree selected ddepending onn whether orr not they prresent a speccific conditio on or adversse effect (Figg. 2). The caases would bbe patients with w the dissease or con ndition, and d the contrrols would be patientss selected raandomly from the same source population as thhe cases, buut who do noot present th he disease or o condition at the time they are seelected. Expoosure to thee drugs of in nterest at an interval of time t (exposu ure window)), prior to thhe onset of thhe disease (iindex day), for cases (or a random day for conntrols) is stuudied for botth groups. The T determin nation of the index, wind dow and expposure days is crucial, annd should fo ollow clinicaal and epidem miological criteria. c Prevvious exposuure to the meedications caan be obtain ned by the same s data co ollection proocedures as in the cohoort studies (p patient interv views, revisiion of clinicaal records, ddatabases). This T design is i particularrly useful when w one waants to studdy infrequennt adverse reeactions or adverse a reacctions that reequire long exposure orr induction pperiods to occcur, as it guarantees the inclusio on of a suffficient numbber of cases without neeeding to fo ollow all the subjects of the source ppopulation frrom which tthey arise, ass would occcur if a coho ort type desiign were chhosen. Anothher advantagge of case an nd control studies s is thaat they allow w the associiation of thee disease or condition with w several factors f to be analysed sim multaneouslyy. The T main biaases in a casee and control study are: the selectionn bias, the bbias due to th he presence of o confound ding factors, which have already beeen defined eaarlier, and th he informatiion bias. To o avoid the latter, l the m method for oobtaining information must m be exacttly alike for both cases and a controls..

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Drug

A Adverse reaction n Present

Absent

a

b

c

d

Presen nt (expossed) Absen nt (unexp posed)

Fiigure 2: Structture of case-co ontrol studies (ttaken from Valllvé C [13]).

Itts main difficulty lies in the adequatte selection of the controol group. Ass we have mentioned m eaarlier, contro ols should be b a sample of the sourrce population giving riise to the caases, but som metimes thiss idea is harrd to translatte into an opperational seelection proccedure. It iss interesting to note thatt case and ccontrol studiies can be co onceived as a cohort stu udy in which the experiience of perrson-time exxposure of th he incidence denominato ors has been sampled, raather than accounting forr it in full. An A associatio on measure, known as the odds raatio (OR), iss often usedd in caseco ontrol studiees; howeverr, if the conttrols have bbeen sampled randomly from the so ource populaation and thee disease is rare, r OR andd RR concur. Table T 2 desccribes the main m differen nces betweeen case andd control stuudies and co ohort studiess. Table 2: Compaarison between n case-control studies s and cohhort studies CASE- CONTRO OL STUDY

COHORT S STUDY

1. In general, lim mited in duration, relatively r cheap and easy to carry y out.

1. Generallyy long in durationn, costly, and withh a complex organisationn.

2. It may be the only o method for studying uncommon adverse reactions.

2. Generallyy useful only for sstudying relativelly common adverse reac actions.

3. Allows specifiic and detailed infformation to be collected on each h individual includ ded in the study.

3. The largee sample size prevvents the collectioon of highly detailed datta per individual ssubject.

4. Refers to a single adverse reactiion.

4. Allows ddifferent adverse rreactions to be stuudied simultaneouusly.

5. Particularly su ubject to biases in the selection of cases and controlls.

5. In generaal, less subject to bbiases.

6. May present problems in terms of recall of data on o exposure to drugs.

6. Does nott usually present bbiases in terms off recall of data on expposure to drugs.

7. Does not allow w the study of variiables that can bee altered by the dissease being studieed.

7. Allows thhe study of variabbles that can be alltered by the disease being studied.

8. From a statisticcal point of view,, it is the ideal method for study ying rare diseases in relation to drug gs with a high prevaalence of use.

8. From a sttatistical point off view, it is the ideeal method for studyingg common diseasses in relation to ddrugs with a low prevaleence of use.

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2.5. Meta-Analysis A meta-analysis is a statistical method that combines the results of various studies on a specific problem in order to provide a synthetic quantitative appraisal of all the available studies. By including a larger number of observations, a meta-analysis has greater statistical strength than the individual studies that compose it. It is applied most frequently in experimental studies (clinical trials), but in pharmacoepidemiological terms it can be applied to obtain a more accurate estimate of a relative risk (RR) (cohort studies) or an odds ratio (OR) (case-control studies). Meta-analysis poses two main methodological problems: a) the heterogeneousness of the studies included in them; and b) the possible publication bias, as an unknown number of studies go unpublished, in general those that have negative results. An example of this: a meta-analysis of randomized controlled trials was conducted to evaluate the effect of cholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine and memantine on the risk of falls, syncope and fall-related events (fracture, and accidental injury) in older adults with mild cognitive impairment and dementia. The conclusions were that cholinesterase inhibitors may increase the risk of syncope, with no effects on falls, fracture, or accidental injury. On the other hand memantine may have a favorable effect on fracture, with no effects on the other events [14]. 2.6. Intensive Monitoring Studies in Hospitals Hospitals have great value as an observatory capable of collecting pharmacovigilance data that are extremely important for the system. Therefore, it is small wonder that numerous tools have been implemented over the years to achieve this goal. Some of them have been tremendously prolific in terms of amount of severe adverse reactions, or comparative adverse reaction profiles among members of the same drug group, or even adverse reactions that had never been described before. However, they require the existence of a stable network of observers, linked to clinical services that basically perform other activities that may be considered priorities. One of the classic studies was the Boston Collaborative Drug Surveillance Program (BCDSP), which in the 1970s collected release diagnoses and information about the histories of 25,000 consecutive patients in 24 hospitals covering 45% of the beds in the Boston area, with close to three million inhabitants. The data collected in the programme made it possible to perform a broad number of epidemiological sub-analyses (cases and controls) to associate treatments with iatrogenic pathologies.

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It was a pioneering approach for its time, but which, due to the high financial cost of direct interventions, was forced to evolve toward database analysis, though with the technological limitations of the time. Most of the information collected has been integrated in the body of pharmacovigilance: bleeding during heparin treatment enhanced by acetylsalicylic acid; excessive sedation due to flurazepam in elderly patients; phenytoin and hypoalbuminaemia; tetracyclines and increased uraemia; interactions with oral anticoagulants; skin rash and metamizole; and, finally, gastrointestinal (GI) bleeding caused by drugs, a matter that remains far from being closed in spite of the time elapsed [15]. A collateral finding was the negative relationship found between the regular consumption of acetylsalicylic acid and myocardial infarction, which years later became such a hot topic. Nevertheless, it should be noted that the information generated by the study is, because of its observational design, a source of signals with the limitations inherent to it. 2.7. Prescription-Event Monitoring The Prescription-Event Monitoring (PEM) system was created by the Drug Safety Research Unit (DRSU) at the University of Southampton. It is an active prescription-related event search system. In the British National Health Service, all GPs’ prescriptions are sent to the Prescription Pricing Authority (PPA), the unit in charge of processing prescriptions. When the DRSU decides to initiate a PEM on a drug recently brought to market, the PPA sends copies of the first 10,000 prescriptions (approximately) to the DRSU, which contacts the prescriber to request the necessary information using a simple unstructured questionnaire (green card) asking about age, sex, diagnoses, reasons for discontinuing treatment and efficacy, together with a brief description of the events and the dates on which they occurred [16]. An event is any new diagnosis or reason for visiting the doctor’s office, or any deterioration or improvement involving a specific pathology, or an adverse reaction, or any other type of complaint the physician may consider being important. Among the advantages of the system is that the information collected is more comprehensive and complete than with the yellow card, since it collects data that would never be reported spontaneously and they provide a denominator to assess the impact of adverse drug reactions. The main drawback is its complexity and suitability for the British health system. There is no other similar program in the

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world, except a similar experience in New Zealand, which was recently concluded. 2.8. Use of Databases in Pharmacovigilance The term database is misleading, as it allows for a range of definitions and encompasses vastly different meanings depending on each individual context. Its use as a method in pharmacovigilance refers to its use in researching the adverse effects of drugs. For an automated database to be used in pharmacovigilance research, it has to contain three types of data: demographics (date of birth, sex, monitoring period and vitals), drug consumption (drug, dose, presentation, start and end dates) and clinical events (diagnoses, consultations with specialists, hospital admissions). From the perspective of historic development, these three types of data have been (and continue to be) generally segregated in most computer records, and in turn contained in different databases that were not designed for pharmacoepidemiological use. Therefore, they have been difficult to use for pharmacovigilance purposes. Initially, record-linkage techniques were developed to conduct such studies. Then, pharmacoepidemiological work techniques changed substantially in parallel with the computerization of doctors’ practices and the computerized recording of clinical documentation, as their use for research purposes was taken into account in the design of some of these databases. Among the various databases existing around the world, as an example for a more detailed description, we selected the British Clinical Practice Research Datalink (CPRD), the world’s biggest and best known database, and the one that has generated the largest number of research articles (over 1,100 articles published have used data from the CPRD until April 2014). The Clinical Practice Research Datalink (CPRD), former GPRD, is the English National Health Service (NHS) observational data and interventional research service, jointly funded by the NHS National Institute for Health Research (NIHR) and the Medicines and Healthcare products Regulatory Agency (MHRA). CPRD services are designed to maximise the way anonymised NHS clinical data can be linked to enable many types of observational research and deliver research outputs that are beneficial to improving and safeguarding public health. Currently, the CPRD contains more than 5 million active patient records (and over 13 million overall) drawn from over 600 primary care practices in the UK. Because the CPRD database has clinical and prescription data can provide information to support pharmacovigilance (indication, utilization, and risk/benefit profiles of drugs) and

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pharmacoepidemiologic studies, including information on demographics, medical symptoms, therapy (medicines, vaccines, devices), and treatment outcomes [17]. In addition to many other studies, the CPRD has been used to conduct pharmacovigilance studies like the comparison of suicide risks between several antidepressants, finding a greater risk for venlafaxine than for citalopram, fluoxetine and dothiepin [18]. Another study found a low risk of digestive haemorrhaging associated with selective serotonin reuptake inhibitors (SSRIs) (RR 1.3; IC95% 1.1-1.6) compared to no risk of exposure to tricyclic antidepressants (RR 1; IC95% 0.8-1.3) [19]. The CPRD has also been quite useful in conducting disease impact studies. Thus, for instance, a study found an incidence of 3.69 cases of migraine per 1,000 people/year in Britain [20]. Record-linkage is based on interconnecting diagnostic and drug treatment data in targeted patient populations for which such data are regularly and completely collected in computer readable form. As indicated earlier, these databases are designed to control billing and healthcare expenses, purposes that have few points in common with pharmacoepidemiological data collection. The design conditions the population included in the study, as well as the type of data collected and their quality. Some examples include the Group Health Cooperative of Puget Sound (Seatle, USA) [21] or the Kaiser Foundation Health Plan (Southern California) [22] (both prepaid medical insurance organizations that run their own dispensaries), MEDICAID [23], or the Saskatchewan Database (Saskatchewan, Canada) [24]. The limitations in terms of approach are the same as in any other study that uses databases: it is not a good tool for studying adverse reactions that are either very rare or are caused by seldomly prescribed drugs; it does not reflect the influence of factors like smoking, occupation or diet; there is a (sometimes very marked) delay between the use of the drug and the processing of the data; the population it serves is not representative (MEDICAID is the healthcare system for the poor and elderly in the U.S., where most of the population is covered by private insurance); and finally, the database, which contains errors, requires frequent debugging. 2.9. Post-Marketing Safety Studies Post-authorisation studies are conducted for various purposes, not only for pharmacovigilance, including: a) determining the effectiveness of the drugs (results in regular practice conditions), b) learning about the effects of the drugs from the patient’s perspective, c) obtaining data about use patterns, and d) identify and quantify any adverse effects. These studies are mostly promoted by the pharmaceutical industry, and are in good part safety-oriented (post-marketing

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safety study). The recommendations for conducting such studies require a verifiable scientific justification and abidance of the ethical postulates of biomedical research; hence no studies can be conducted with the purpose of promoting prescription or increasing consumption, nor by means of covert marketing techniques. These studies are necessary to glean knowledge not provided by controlled clinical tests, and which is fundamental for orienting clinical practice, the rational use of the drug and its safety. The limitations of many of the studies published thus far include biases in doctor selection, patient selection, lack of controls to differentiate the incidence of adverse reactions in the group treated with the study drug versus control. Therefore they require rigorous designs, similar to those of controlled clinical tests. 3. RISK ANALYSIS AND MANAGEMENT IN PHARMACOVIGILANCE The overall aim of risk management is to ensure that the benefits of a particular medicinal product (or a series of medicinal products) exceed the risks by the greatest achievable margin for the individual patient and for the target population as a whole (Fig. 3). Risk management has three stages which are inter-related and re-iterative: 1.

Characterisation of the safety profile of the medicinal product including what is known and not known.

2.

Planning of pharmacovigilance activities to characterise risks and identify new risks and increase the knowledge in general about the safety profile of the medicinal product.

3.

Planning and implementation of risk minimisation and mitigation and assessment of the effectiveness of these activities.

The risk assessment is performed by independent experts’ committees that advise the regulatory agencies. In Europe, this is handled by the CHMP (Committee for Medicinal Products for Human Use) and the European Medicines Agency (EMA) PRAC (Pharmacovigilance Risk Assessment Committee). The PRAC is responsible for providing recommendations to the CHMP on any question relating to pharmacovigilance activities in respect of medicinal products for human use and on risk management systems, including the monitoring of the effectiveness of those risk management systems.

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IMPLEMENT risk minimization /characterisation and benefit maximisation

DATA COLLECTION Monitor effectiveness and collect new data

RISK MANAGEMENT CYCLE

IDENTIFY & ANALYSE risk quantification and benefit assessment

SELECT & PLAN risk characterization /minimisation and benefit maximisation techniques EVALUATE Benefit risk balance and opportunities to increase and/or characterise

Figure 3: The risk management cycle.

The need to communicate safety information for the public and for health professionals should be considered throughout the pharmacovigilance and risk management process, and should be part of risk assessment. Information on risks should be presented in the context of the benefits of the medicine and include available and relevant information on the seriousness, severity, frequency, risk factors, time to onset, reversibility of potential adverse reactions and, if available, expected time to recovery. 3.1. Risk Management Plan In 2005, new European Pharmacovigilance legislation authorized Regulatory Agencies to require drug companies to submit a risk management plan comprising detailed commitments for post-marketing pharmacovigilance. A product Risk Management Plan is defined as a plan identifying the risks associated with a medicinal product, methods of further clarifying the safety profile of a product, and tools designed to minimise the risk to individual patients in clinical practice [26].

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The Risk Management Plan must contain the following elements which [25]: •

Identify or characterise the safety profile of the medicinal product(s) concerned;

•

Indicate how to characterise further the safety profile of the medicinal product(s) concerned;

•

Document measures to prevent or minimise the risks associated with the medicinal product including an assessment of the effectiveness of those interventions;

•

Document post-authorization obligations that have been imposed as a condition of the marketing authorization.

There is an implicit requirement that to fulfil these obligations a Risk Management Plan should also: •

Describe what is known and not known about the safety profile of the concerned medicinal product(s);

•

Indicate the level of certainty that efficacy shown in clinical trial populations will be seen when the medicine is used in the wider target populations seen in everyday medical practice and document the need for studies on efficacy in the post-authorisation phase (also known as effectiveness studies);

•

Include a description of how the effectiveness of risk minimisation measures will be assessed.

The Risk Management Plan is a dynamic, stand-alone document which should be updated throughout the life-cycle of the products. 4. ADVERSE DRUG REACTIONS IN GEROPSYCHIATRY The overall consensus is that elderly psychiatric patients are more prone to develop adverse drug reactions than younger patients as a consequence of psychopharmacological medication. Elderly persons with psychiatric disorders frequently suffer from somatic diseases and may receive polypharmacy more than younger patients. Thus, they may tend to develop adverse drug reactions more frequently [27].

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4.1. Antipsychotics Studies of relationships between age and both the frequencies and types of extrapyramidal symptoms associated with conventional antipsychotic treatment demonstrated that older patients are more likely than younger patients to experience dystonic reactions, but antipsychotic-induced parkinsonism, including tremor and rigidity, is common in older patients. The increased incidence, prevalence, severity, and persistence of tardive dyskinesia in older patients treated with conventional antipsychotic medications have been a major factor limiting the use of these medications in geriatric psychiatry [28]. When used continuously, atypical antipsychotics induce less extrapyramidal effects, although they are still present in many cases. They can be ordered from more to less production of extrapyramidal effects: risperidone > paliperidone > ziprasidone > aripiprazole > olanzapine > quetiapine [29]. The vascular adverse effect of antipsychotic most frequently reported (up to 40% of patients) is orthostatic hypotension and more frequently in elderly patients where the risk of injury from falling is greater. Antipsychotics such as chlorpromazine and thioridazine (first generation) and sertindole or clozapine (second generation) appear to have the highest propensity to cause orthostatic hypotension [30]. In relation to cardiac conduction, several epidemiologic studies have shown that use of antipsychotic drugs increases the risk of sudden cardiac death. This risk is associated in part with prolongation of the QT interval on the electrocardiogram, which increases the likelihood of developing torsade de pointes, a class of ventricular arrhythmia, especially in susceptible individuals. This tendency to prolong the QT interval is common to classical antipsychotics (first generation) and newer (second generation) [30]. Pimozide, haloperidol, droperidol, and sertindole, have been related with torsade de pointes and sudden death, although the most marked risk is with thioridazine [31]. This concern about sudden death has led to the withdrawal of some antipsychotics (e.g. sertindole) from the market in recent years, and introduction of black-box warning on labels. Ziprasidone is the second generation agent most noted for QT changes, yet the other medications may induce lesser degrees of lengthening. Aripiprazole might be the only one of these that is less likely to influence the QT duration [32]. The potential cerebrovascular risk of antipsychotics in patients with dementia, particularly in older patients, has sparked widespread controversy in recent years. In

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2004, data from clinical trials pointed to a risk of stroke for the atypical antipsychotic medications olanzapine and risperidone, along with increased mortality for olanzapine in elderly patients with dementia [33]. The ensuing publication of some observational studies and meta-analyses showed that the risk could extend as well to the rest of the atypical antipsychotics and even classic antipsychotics. All antipsychotic medications, and in particular atypical ones, can cause adverse effects on the metabolism of carbohydrates and fats, including weight gain, hyperlipidaemia, hyperglycaemia, diabetes mellitus or glucose intolerance. Patients with diabetes, dyslipidaemia or obesity should avoid using clozapine, olanzapine and first-generation antipsychotics according to Expert Consensus Guidelines. In case of treatment with second-generation antipsychotics, patients should be monitored regularly, including height, weight, abdominal girth, lipids, glucose levels and blood pressure, throughout the entire course of treatment with antipsychotics [34]. Hyperprolactinemia is a common adverse effect of antipsychotic medication. Among the first-generation antipsychotics, especially the high prolactin risk of sulpiride is known. Among the second-generation antipsychotics, amisulpride, risperidone and paliperidone are associated with the greatest elevation of prolactin. Olanzapine and ziprasidone do this with a moderate severity. Aripiprazole shows the most benign prolactin profile [35]. Regarding osteoporosis associated with antipsychotic agents, the results published are conflicting; some studies suggest a small increase in the risk of fractures in patients on antipsychotic treatment, while others do not. 4.2. Antidepressants Depression is a common condition in older people, often causing emotional distress and reduced quality of life. Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants have been related with increased fracture rates with higher rates for SSRIs than for tricyclic antidepressants. This increased risk of fractures may be due to an increased risk of falls, but some evidence also shows decreased bone mineral density in SSRIs users [36]. Antidepressant-related hyponatraemia is an adverse reaction that affects the elderly and is most commonly associated with use of SSRIs, in several studies, in which hyponatraemia developed within the first weeks of treatment and resolved within a few weeks after discontinuation of treatment. These cases are thought to

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be mainly due to the development of the syndrome of inappropriate secretion of antidiuretic hormone, preventing the reabsorption of water and sodium ions in the distal tubule of the kidney precipitated by SSRIs [37]. Risk of gastrointestinal bleeding related with selective serotonin reuptake inhibitors has been shown in some studies, including patients aged 65 years and over. A proposed mechanism for this fact is that SSRIs block serotonin reuptake by platelets, leading to an impaired platelet haemostatic response [38]. Some studies have looked at antidepressants and attempted suicide/self harm in older people. A meta-analysis of randomised clinical trials found a reduced risk of suicidal behavior and ideation associated with antidepressants in the group aged 65 years and over [39]. In addition, a systematic review of observational studies also found a reduction in risk of suicide or attempted suicide among people aged 65 or more exposed to SSRIs [40]. Citalopram may cause dose-dependent QT interval prolongation. Citalopram is not recommended for use at doses greater than 40 mg per day because such doses cause too large an effect on the QT interval and confer no additional benefit. The maximum recommended dose of citalopram is 20 mg per day for patients with hepatic impairment and for patients who are older than 60 years of age. Furthermore, it was also noted that cases of QT-interval prolongation have been reported also in association with some other selective serotonin re-uptake inhibitors (SSRIs) including escitalopram, the S-enantiomer of citalopram [41]. 4.3. Anxiolytic and Hypnotic Drugs Anxiolytic and hypnotic drugs are commonly prescribed for anxiety and sleep problems. Benzodiazepines are widely prescribed for treating these symptoms. Consumption of benzodiazepines is often chronic, despite the existence of guidelines suggesting that the duration should be limited to a few weeks. Insomnia often affects the quality of life for older people. Nowadays, benzodiazepines and short acting non-benzodiazepine hypnotics (zolpidem, zopiclone, zaleplon, the so-called “Z-drugs”) are the main medication for controlling insomnia. Older people become more sensitive to the effects of benzodiazepines on the central nervous system and (due to altered pharmacodynamics) have a higher propensity to adverse reactions. Consumption of benzodiazepines by elderly patients has been

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associated with mobility problems and decreased ability to perform the activities of daily living [42]. Older patients taking benzodiazepines should be monitored for daytime sedation and impaired motor coordination; because the epidemiological evidence strongly suggests that the use of benzodiazepines by older people increases their risk of hip fracture by at least 50% [43]. Other common adverse reactions of benzodiazepines in older patients include amnesia, confusion, paradoxical agitation and increased risk of dementia [44]. Because hypnotics, benzodiazepines in particular, can contribute to upper respiratory tract obstruction during sleep, the prescription should be avoided in patients with obstructive sleep apnoea, diagnosed or suspected. [42]. Benzodiazepines have been related to adverse respiratory effects among older patients with chronic obstructive pulmonary disease [45]. Zolpidem may cause drowsiness and slower reactions the day after taking the medicine, which could cause impaired driving ability and increase the risk of road accidents. The daily dose of zolpidem remains 10 mg a day in adults and 5 mg a day in the elderly and in patients with hepatic impairment [46]. 4.4. Alzheimer’s Dementia The prevalence of Alzheimer’s disease (AD) increases with age, and elderly people often have comorbid conditions that require multiple medications, creating potential problems both with drug interactions and with drug-related adverse effects. The two categories of drug used in treating AD are the acetylcholinesterase inhibitors (AChEIs) and the NMDA-receptor antagonist, memantine. AChEIs (donepezil, galantamine and rivastigmine) are recommended as options for managing mild to moderate Alzheimer’s disease. Memantine is recommended as an option for managing Alzheimer’s disease for people with moderate Alzheimer’s disease who are intolerant of or have a contraindication to AChE inhibitors or severe Alzheimer’s disease [47]. All treatments commonly produce dizziness and/or headache. AChEIs are associated with many more types of adverse events than memantine, particularly in the gastrointestinal category (nausea, diarrhoea, vomiting, abdominal pain/disturbance) [48]. Fatigue was also common or very common adverse event

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with AChEI treatment. Agitation is a less common adverse event with memantine treatment than with placebo (6.4% vs. 9.9%) [49]. 5. THE ROLE OF PHARMACOGENETICS IN GEROPSYCHIATRY One of the issues raised by the use of medications is why some patients respond well to a specific medication, others fail to respond at all, and others develop undesirable effects to that same medication. The explanation for these differences in response may lie in the differences in the genetic load of the individuals. From the perspective of the use of medications to treat diseases, identifying the genetic variants of patients could have practical applications, and it could further knowledge about the molecular bases of certain reactions to medications. Pharmacogenetics studies the inter-individual genetic variability that explains the different responses to drugs. Treatments based on genetic markers are still used only on rare occasions; their generalization in those cases where the markers have a predictive nature will optimize the medication, which in the end will bring more benefits to the patient as well as a reduction of adverse reactions and their healthcare and economic consequences. Intensive research is currently under way to learn which genetic factors are related to the individual response to certain drugs. 5.1. Future Prospects Thus far, regulatory agencies have approved several devices aimed at individualizing therapy for certain drugs and thus reducing the risk of onset of adverse reactions. Examples of pharmacogenetic devices being marketed include Invader UGT1A1® for irinotecan toxicity, Verigene® for adjusting warfarin dosage according to several genetic polymorphisms, or the AmpliChip®, which identifies poor metabolizers based on CYP2D6 and CYP2C19 with risk of suffering adverse reactions. Hopefully, in the future, as knowledge of the genetic factors that determine adverse reactions advances, new pharmacogenetic devices may be developed and included in clinical practice. The judicious use of pharmacogenetics in medical routine will open the way to prevention in the onset of adverse reactions that until recently were considered unavoidable, and will bring us closer to that oftmentioned ideal of individualizing pharmacological therapy [50].

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ACKNOWLEDGEMENTS Declared none. CONFLICT OF INTEREST The authors confirm that this chapter contents have no conflict of interest. REFERENCES [1] [2] [3] [4]

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Group Health Cooperative of Puget Sound. Washington State. Available at: https: //www.ghc.org/. Accesed [20/04/2014]. Kaiser Permanente. https: //healthy.kaiserpermanente.org/html/kaiser/index.shtml. Accessed [30/04/2014]. Medicaid. Available at: http: //www.medicaid.gov/. Accessed [30/04/2014]. Health services databases information document. Available at: http: //www.health.gov.sk.ca/healthdatabases-info-doc. Accessed [30/04/2014]. Guideline on good pharmacovigilance practices (GVP).Module V - Risk management systems. Available at: http: //www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129134.pdf. Accessed [20/02/2014] Frau S, Font Pous M, et al. Risk Management Plans: are they a tool for improving drug safety?. Eur J Clin Pharmacol 2010; 66(8): 785-90. Greil W, Häberle A, Schuhmann T, et al. Age and adverse drug reactions from psychopharmacological treatment: data from the AMSP drug surveillance programme in Switzerland. Swiss Med Wkly 2013; 143: w13772. Meyers BS, Jeste DV. Geriatric psychopharmacology: evolution of a discipline. J Clin Psychiatry 2010; 71(11): 1416-24. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382(9896): 951-62. Leung JY, Barr AM, Procyshyn RM, et al. Cardiovascular side-effects of antipsychotic drugs: the role of the autonomic nervous system. Pharmacol Ther 2012; 135(2): 113-22. Glassman AH1, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001; 158(11): 1774-82. Narang P, El-Refai M, Parlapalli R, et al. Antipsychotic drugs: sudden cardiac death among elderly patients. Psychiatry (Edgmont). 2010; 7(10): 25-9. Antipsychotics: use in elderly people with dementia. Drug Safety Update 2009; 2(8): 5-6. Felmet K, Zisook S, Kasckow JW. Elderly patients with schizophrenia and depression: diagnosis and treatment. Clin Schizophr Relat Psychoses 2011; 4(4): 239-50. Peuskens J, Pani L, Detraux J, et al. The effects of novel and newly approved antipsychotics on eerum prolactin levels: a comprehensive review. CNS Drugs 2014 Mar 28. [Epub ahead of print]. Coupland C, Dhiman P, Morriss R, et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011; 343: d451. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother 2006; 40(9): 1618-22. de Abajo FJ, García-Rodríguez LA. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008; 65(7): 795-803. Stone M, Laughren T, Jones ML, et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009; 339: b2880. Barbui C, Esposito E, Cipriani A. Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies. CMAJ 2009; 180(3): 291-7. doi: 10.1503/cmaj.081514. Pharmacovigilance Working Party (PhVWP) October 2011 plenary meeting. Available at: http: //www.ema.europa.eu/docs/en_GB/document_library/Report/2011/10/WC500117061.pdfAccessed [30/04/2014]. Wolkove N, Elkholy O, Baltzan M, Palayew M. Sleep and aging: 2. Management of sleep disorders in older people. CMAJ 2007; 176(10): 1449-54. Cumming RG, Le Couteur DG. Benzodiazepines and risk of hip fractures in older people: a review of the evidence. CNS Drugs 2003; 17(11): 825-37. Billioti de Gage S, Bégaud B, Bazin F, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ 2012; 345: e6231. Vozoris NT, Fischer HD, Wang X, et al. Benzodiazepine drug use and adverse respiratory outcomes among older adults with COPD. Eur Respir J 2014 Apr 17. [Epub ahead of print]. CMDh endorses new advice to minimise risk of next-morning impaired driving ability and mental alertness with zolpidem. Available at: http:

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//www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Zolpidemcontaining_medicinal_products/Position_provided_by_CMDh/WC500165639.pdf. Accessed [04/05/2014]. National Institute for Clinical Excellence (NICE). Guidance on the use of donepezil, rivastigmine and galantamine for the treatment of Alzheimer’s disease. London: NICE, 2011. Kaduszkiewicz H1, Zimmermann T, Beck-Bornholdt HP, et al. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ 2005; 331(7512): 321-7. Jones RW. A review comparing the safety and tolerability of memantine with the acetylcholinesterase inhibitors. Int J Geriatr Psychiatry 2010; 25(6): 547-53. Becquemont L. Pharmacogenomics of adverse drug reactions: practical applications and perspectives. Pharmacogenomics 2009; 10(6): 961-9.

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CHAPTER 7

Anxiolytics and Hypnotics Juan Medrano* Ezkerraldea - Enkarterri Mental Health Community Services, Bizkaia´s Mental Health Network, Portugalete, Bizkaia, Spain Abstract: Anxiolytics are a group of drugs which currently is comprised of benzodiazepine compounds, buspirone, antihistamines as hydroxyzine, some anticonvulsants and chlormethiazole. Hypnotics, in turn, include some benzodiazepines, the so-called “z-agents” and other compounds like melatonin and ramelteon and sedative antidepressants. Even though they are a relatively safe group that can provide rapid symptomatic amelioration, most of them are associated to the development of addiction and pose specific problems in old age. Therefore, the peculiars of these compounds and the characteristics of the elderly make especially accurate the classical recommendation to prescribe these drugs for short periods of time only.

Keywords: Addiction, Alprazolam, Anxiolytics, Ataxia, Benzodiazepines, Buspirone, Chlormethiazole, Clonazepam, Delirium, Diazepam, Doxepin, Eszopiclone, Falls, Gabapentin, Hydroxyzine, Hypnotics, Melatonin, Mirtazapine, Pregabalin, Ramelteon, Trazodone, Triazolam, Zaleplon, Zolpidem, Zopiclone. 1. ANXIOLYTICS 1.1. Introduction Formerly represented by the so-called minor tranquillizers of the 1950s, remarkably meprobamate, the first blockbuster of Psychopharmacology, anxiolytics are a class of drugs whose main representative are the benzodiazepines (BZD). Even though BZDs were a safer alternative than preceding barbiturates, they are associated to a widespread use in the 1970s and an addictive liability. Cognitive impairment, ataxia and paradoxical agitation are specific side effects in the elderly. Other minor tranquillizers are buspirone, antihistamines such as hydroxyzine, chlormethiazole and some anticonvulsants like gabapentin and pregabalin (Table 1). *Corresponding author Juan Medrano: Ezkerraldea - Enkarterri Mental Health Community Services, Bizkaia´s Mental Health Network, Portugalete, Bizkaia/Vizcaya, Spain; Tel: 3444596505; Fax: 3444596511; Email: [email protected] Unax Lertxundi, Juan Medrano and Rafael Hernández (Eds.) All rights reserved-© 2015 Bentham Science Publishers

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Table 1: Anxiolytics Benzodiazepines: Long-actig: Diazepam, clorazepate, clonazepam. Short-acting: Alprazolam, lorazepam Buspirone Antihystamines: Hydroxyzine Chlormethiazole Pregabalin Gabapentin

1.2. Benzodiazepines First developed by Leo Henryck Sternbach, BZDs are a controversial drug group, after having been widely used for decades. Chlordiazepoxide was the first compound, developed in 1956 and approved for clinical use in 1960, but years later it was followed by diazepam, marketed in 1963, which soon became so popular that between 1969 and 1982, it was the most prescribed drug in America, with over 2.3 billion doses sold in 1978. Chemically all BZDs share a similar chemical structure, resulting from the combination of a benzene ring and a diazepine ring to which different side chains are added. On the basis of the latter’s chemical structure, BZDs are subdivided into different subgroups [1], including 1-keto compounds (such as chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam and prazepam), 3-hydroxy compounds (lorazepam, lormetazepam, oxazepam, temazepam), 7nitro compounds (clonazepam, flunitrazepam, nimetazepam, nitrazepam), triazolo compounds (adinazolam, alprazolam, estazolam, triazolam) and imidazo compounds (climazolam, loprazolam, midazolam). 1.2.1. Benzodiazepines: Pharmacokinetics (Table 2) BZDs are generally orally well absorbed and highly protein-bound (95%) due to their lipophilic properties. Sublingual formulations have been developed following the notion that BZDs could be more rapidly absorbed by this pathway, and even in some countries crushed oral pills are encouraged to be placed under the tongue to achieve a rapid onset of action in acute anxiety, even though no significant differences were found in a study comparing several administration routes of lorazepam [2]. Intramuscular absorption is erratic, except for midazolam, clonazepam and lorazepam and intravenous administration is risky as it may result in respiratory address [3].

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Table 2: Summary of BZB pharmacokinetics Oral Absorption can be delayed by antacids Metabolism: Glucoronidation (Phase II): lorazepam, oxazepam and temazepam Nitroreduction: clonazepam Demethylation and oxidation: diazepam Volume of distribution depending on the lipophilic properties. Main isozyme involved in phase I: CYP3A4 CYP3A4 inhibitors: nefadozone, ciprofloxacin, itraconazole, clarithromycin, delavirdine, indinavir, ritonavir, efavirenz, grapefruit juice, methadone and mibefradil can increase levels of most BZDs. CYP3A4 inducers: carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine can decrease levels of most BZDs.

A high rate of protein binding though differing between compounds (between 85 and 100%) and a volume of distribution depending on the lipophilic properties of each product, which are highly variable, as well as an elimination rate that also varies between molecules, result in each BZD having a unique plasma concentration curve [4]. Those highly lipophilic, such as diazepam, tend to quickly redistribute to adipose tissue, therefore, on single dosing their effect will be short; nevertheless, after multiple dosing, redistribution will be reduced and the duration of effect will increase. On converse grounds, with less lipophilic BZDs a longer effect on single dosing can be expected, with a lesser change after chronic use [5]. Given that in the elderly there is a relative increase in body fat, those differences and their consequences are more marked, except for the case of alprazolam, whose kinetics do not seem to be significantly changed with aging [6]. Although inter-compound variability is significant, lipophilia is a general trait of all BZDs, so they will rapidly traverse the blood-brain barrier. BZDs are mainly metabolized by the liver. Glucoronidation (lorazepam, oxazepam and temazepam), nitroreduction (clonazepam) demethylation and oxidation (diazepam) are the main routes. The resulting metabolites may be active (nordiazepam) or inactive, and may, in turn, be subdivided according to their halflife (long, for instance, in the case of nordiazepam, a metabolite of diazepam). Some products are in fact pro-drugs, as in the case of clorazepate, which is hydrolyzed by gastric enzymes into nordiazepam and later, oxidized by the liver, into oxazepam, both of them active agents. In any case, agents undergoing other processes in a Phase I metabolism (CYP3A4 being the main isozyme involved) are later subjected to a Phase II glucoronidation [3]. Depending on their half-life, BZDs are usually subdivided into short (20 hours, such as diazepam or clonazepam). Glucoronidation is a less sensible process to aging, so a general rule summarizing all changes related to aging is that in the elderly short or intermediate half-life, less lipophilic agents metabolized by glucoronidation (that is, lorazepam and oxazepam) are preferred. BZDs are subjected to pharmacokinetic interactions. Antacids may delay absorption, but not extent, of BZDs. CYP3A4 inhibitors such as nefadozone (withdrawn from the market in many countries due to hepatotoxicity), ciprofloxacin, itraconazole, clarithromycin, delavirdine, indinavir, ritonavir, efavirenz, grapefruit juice, methadone and mibefradil can increase levels of most BZDs (those undergoing Phase I metabolism). Conversely, CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifampin or rifapentine) can decrease levels of most BZDs. CYP1A2 inhibitors, such as fluvoxamine can distinctively increase levels of diazepam [7]. (See chapter 4 for more information on clinically relevant interactions). Final products of metabolism are hydrophilic and are eliminated with urine, although a 10% is fecally excreted. Clearance is reduced in the elderly, especially in men [8]. 1.2.2. Benzodiazepines: Pharmacodynamics BZDs are allosteric modulators of ligand-gated ion channels GABAA receptors. Their binding site is the chloride-channel molecular complex, which possesses five transmembrane glycoprotein subunits around a central chloride channel (ligand-gated ion channel). The GABAA has multiple allosteric modulating sites as part of the complex (for BZDs, barbiturates, alcohol and anesthetics and neurosteroids). BZDs do not directly enhance GABAergic transmission, and their action is otherwise supposed to be that of increasing the affinity of GABA for its own binding site. Therefore, GABA binding is enhanced leading to a greater opening of the chloride channel and a hyperpolarization [9]. Clonazepam seems to be also a serotonin agonist, up-regulating 5-HT1 and 5HT2 receptors, which confers it additional anxiolytic and antimyoclonic properties [10]. The result of GABA binding enhanced by BZDs is the classic profile of these agents: anxiolytic, anticonvulsant, hypnotic, sedating and myorelaxant. However, those effects are obtained at a different receptor occupancy rate, with 20% needed for anxiolysis, 20-25% for anticonvulsant effect, 50% for sedation, 60% to obtain unconsciousness and 90% for anesthesia. A 25-50% occupancy rate is associated to the appearance of amnesia [11].

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Salient pharmacodynamic interactions of BZDs are with anticholinergics (with a synergistic cognitive impairment), clozapine (sedation and respiratory depression) [12] and CNS depressants and alcohol (synergistic sedation and toxicity). 1.2.3. Benzodiazepines: Efficacy BZDs are primary or adjunctive drugs for the treatment of a range of anxiety disorders, with a level of evidence for each BZD that should be differentiated depending on each condition. So, evidence for the short-term use is robust for Panic Disorder and Generalized Anxiety Disorder (GAD), intermediate for Social Anxiety Disorder and poor in Post-Traumatic Stress Disorder and ObsessiveCompulsive Disorder [9]. 1.2.4. Benzodiazepines: Adverse Effects Both pharmacokinetic and pharmacodynamic modifications make the elderly more sensitive to adverse effects of BZDs including tolerance, withdrawal syndromes, oversedation, increased falls and cognitive effects [13]. Tolerance develops to anxiolytic or hypnotic effects of BZDs even with chronic usage [14] and has been a traditional way to explain the appearance of abuse and dependence. However it was later known that BZDs act through specific GABAA receptor subtypes to activate midbrain dopamine neurons, therefore hijacking the mesolimbic reward system [15]. BZDs with a fast onset of action, including alprazolam, flunitrazepam, diazepam and lorazepam are considered to be those with a higher abuse potential, and actually the popularity of those compounds among their patients has long led those treating addicts to suspected those drugs had some special properties that made them palatable. Physical dependence can develop soon after treatment is started and is accompanied by a discontinuation syndrome typically characterized by sleep disturbance, irritability, increased tension and anxiety, panic attacks, hand tremor, sweating, difficulty in concentration, dry wretching and nausea, some weight loss, palpitations, headache, muscular pain and stiffness and a host of perceptual changes as well as more serious though less frequent phenomena such as seizures and psychotic reactions. Pétursson [16] distinguishes between three patterns of discontinuation syndrom. A first one and commonest manifestation of dependence a is a short-lived “rebound” anxiety and insomnia, coming on within 1-4 days of discontinuation, depending on the half-life of the particular drug. A second pattern is the full-blown withdrawal syndrome, usually lasting 10-14 days. A third pattern may represent the return of anxiety symptoms which then persist until some form of treatment is instituted.

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BZD usage has been associated to falls; hypnotic use in the elderly seems to be a combination especially associated to falls [17]. Risk could be higher with diazepam than with other sister compounds [18]. Use of BZDs has been estimated to increase risk of hip fracture between 50% and 110% [19], and has been associated to an increased risk of death related to fractures [20]. Overt sedation can be a major problem in the elderly. Hypnotic BZD-induced common feeling of “hang-over” can also be especially relevant in the elderly. Cognitive impairment is a common effect of BZDs, which has aroused the possibility that BZDs can provoke dementia [20]. Impairment alters particularly memory. Dysmnesia from BZDs affects both information acquisition and consolidation (that is, transference of memories from short- to long-term storage), with retrieval being preserved [21]. According to a meta-analysis of the cognitive effects in BZD users, long-term use was consistently associated with a greater impairment compared with non-users in a range of cognitive categories [22]. The amnestic effects of BZDs depend on dosage, drug levels and the time of information presentation relative to the time of administration [23]. After BZD usage is stopped, cognitive performance and memory can improve, as shown in a study by Nakao et al., [24], who gradually suspended BZDs in a group of elderly nursing home residents. Interestingly, BZD withdrawal was not accompanied by an increase in anxiety, agitation or sleeplessness. Paradoxical reactions with excitement have drawn great attention from a medicolegal viewpoint. Hypnotic triazolo-benzodiazepine triazolam has been particularly associated to disinhibition and criminal behavior; however, a detailed review could not find a distinctive link between triazolam and disinhibition [25]. The common clinical picture, characterized by increased talkativeness, emotional release, excitement, and excessive movement, is relatively uncommon and occur in less than 1% of patients; however, both children and elderly people are especially prone to develop it [26], and patients with dementia are especially vulnerable [27]. Although reducing sleep fragmentation, BZDs can worsen sleep-related breathing disorders, especially in patients with chronic obstructive pulmonary disease or cardiac failure. Their long-term use may also cause health problems, such as complete obstructive sleep apnea in heavy snorers or short repetitive central sleep apnea in patients with recent myocardial infarction [28]. A characteristic of BDZs is a high therapeutic index, which can be informally summarized with the assertion that that only way to kill an animal with a BZD is

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to smother it under a mound of tablets [29]. However, a recent study by Weich et al., [30] found a higher mortality in patients treated with anxiolytics and hypnotics including BZDs, with approximately four excess deaths linked to drug use per 100 people followed for an average of 7.6 years after their first prescription. Even though potential confounders were adjusted, causative mechanisms could not be identified. 1.2.5. Benzodiazepines: Clinical Usage BZDs, either anxiolytic of hypnotic, must be used cautiously in the elderly. As stated above, short or intermediate half-life, less lipophilic agents metabolized by glucoronidation (that is, lorazepam and oxazepam) are preferred. Lower doses than those generally used in adults should be the norm. With both anxiolytic of hypnotic BZDs, withdrawal schedules should be gradual. 1.3. Other anxiolytics 1.3.1. Buspirone Synthetized in 1968 in an attempt to develop a more effective neuroleptic, buspirone is an azapirone which failed to show efficacy in Phase II trials. However, it could be found an effective treatment for GAD, which opened the way to its reconceptualization as an anxiolytic, being marketed as such in the USA in 1986. However, traces of that “neurolepticity” persist in a dopamineincreasing liability [31] and anecdotal reports of an antipsychotic effect [32]. Buspirone is rapidly absorbed, achieving peak serum concentrations within one hour, with a serum half-life of 2 to 5 hours. It is extensively metabolized by CYP3A4 oxidation, with extensive first-pass metabolism that results in that less than 1% of an administered dose is excreted as unchanged drug [33]. CYP3A4 inhibitors including itroconazole and erythromycin [34] and grapefruit juice [35] increase buspirone levels, whereas CYP3A4 inducers such as rifampin can reduce dramatically the AUC and Cmax of buspirone [36]. Usual dosage ranges from 5 mg b.i.d. to 20 mg t.i.d. The mechanism of action of buspirone does not involve the GABAA receptor. Rather, it has some dopaminergic agonistic and antagonistic properties and binds to 5HT1A receptors in the raphe nuclei and the hippocampus, being a partial agonist. A remarkable trait is its delayed therapeutic activity, which is believed to result from increased activation of postsynaptic 5-HT1A receptors occurring only after 5-HT neurons regain their normal firing activity. Once this happens, which is

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attributable to 5-HT1A autoreceptor desensitization, 5-HT release recovers. Buspirone has been shown to augment the antidepressant effect of SSRIs by desensitizing 5-HT1A receptors which are hypothesized to be up-regulated by the extra neurotransmitter at the synaptic gap resulting from reuptake inhibition at the beginning of treatment with antidepressants [37]; however, buspirone’s mechanism of action involves a risk of serotonin syndrome stemming from interaction with serotoninergic antidepressants. By the same token, co-therapy with a MAOI is contraindicated. As an anxiolytic, buspirone is comparable to diazepam, with less sedating effects and no abuse potential [38], but its long latency to effect (up to 6 weeks) and the relative lack of effectiveness in patients who have been treated with BZDs, especially recently, reduce its clinical benefits. Dizziness or light-headedness, headache, somnolence (sometimes insomnia) and premature ejaculation have been reported as the most salient side effects. In the elderly, buspirone, not being associated with psychomotor or cognitive impairment, can be a first-line drug for the treatment of anxiety disorders and even to reduce Behavioral and Psychogical Symptoms of Dementia (BPSD) [39]. 1.3.2. Pregabalin An analogue of GABA, pregabalin is a potent ligand for the alpha-2/delta subunit of voltage-gated calcium channels in the central nervous system with no direct action on GABAergic transmission. It has anticonvulsant, analgesic, and anxiolytic properties and has been approved as an anxiolytic in Europe. Its pharmacokinetic is highly predictable and linear, with rapid, extensive oral absorption proportional to dose. Maximal plasma concentration is achieved approximately in 1 hour and steady state is achieved within 24-48 hours. Pregabalin does not bind to plasma proteins and is excreted virtually unchanged by the kidneys [40]. It is not metabolized by the liver and does not induce or inhibit liver enzymes such as the cytochrome P450 system [41]. As an anxiolytic, pregabalin has been shown significantly more efficacious than placebo for the treatment of psychic and somatic symptoms of generalized anxiety disorder, with a good tolerance [42]. In clinical usage, pregabalin seems to have some advantages over some antidepressants in the treatment of GAD [43], and is reported to be generally well tolerated in the long-term treatment of anxiety disorders, with improvement in illness severity being maintained over time. The commonest adverse effect is dizziness, but somnolence, weight gain, headache and insomnia are also reported [44].

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In the elderly, pregabalin in doses of 150-600 mg/day seems to be effective and well tolerated in the treatment of GAD, with an early onset of its anxiolytic efficacy (by 2 weeks) and a significant improvement in both psychic and somatic symptoms of anxiety [45]. As somnolence and dizziness are common adverse effects, it should be used cautiously [46]. Interestingly, in a study on potentially inappropriate prescribing among older patients with GAD, pregabalin was actually included among the appropriate treatments for this condition in the elderly [47]. In view of dose-dependent adverse reactions and since pregabalin is eliminated primarily by renal excretion, a dose reduction in patients with reduced renal function is recommended. 1.3.3. Chlormethiazole Originally developed in the 1930s, chlormethiazole (also called chlomethiazole) is a sedative and hypnotic, thiamine-related drug most commonly used to treat and prevent acute alcohol withdrawal. It is also a treatment of choice for restlessness and insomnia in the elderly [48]. It also has muscle relaxant and anticonvulsivant properties. Chlormethiazole is available in an oily suspension containing 192 mg in capsule form, or as clomethiazole edisylate syrup. In some countries it was also marketed as an intravenous solution which was widely used for its sedative and anticonvulsant action in patients with acute alcohol withdrawal, status epilepticus, pre-eclampsia and eclampsia [49]. However, it was finally suspended because of a great risk of respiratory arrest. Oral chlormethiazole is rapidly absorbed, achieving peak plasmatic concentrations in about 35 (15 to 90) minutes after administration. With a half-life of 4-6 hours and a 64% binding to plasmatic proteins, it is metabolized by the liver, resulting in inactive metabolites, although a minimal fraction (less than 5%) is eliminated unaltered in the urine [50]. The therapeutic hypnotic doses are in the range of 192384 mg. Older elderly patients show higher blood concentrations, indicating an increased bioavailability (about 10 times). Chormethiazole is an inhibitor of CYP2E1 [51]. Chlormethiazole acts by potentiating GABAA receptors. It also seems to inhibit NMDA receptors at high concentrations, but this is unlikely to occur at therapeutic doses [52].

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In the elderly, chlormethiazole showed effectiveness similar to that of thioridazine in the management of the agitational component of agitated confusional states, with a greater control of symptoms such as confusion and nocturnal awakening and a lesser incidence of adverse effects and physical disability [53]. However, it must be kept in mind that chlormethiazole is a drug with potentially fatal effects in voluntary or accidental overdose, especially if combined with alcohol. Acute lethal toxicity is mainly due to CNS depression, sometimes including signs of cardiac failure. Fatal toxicity is usually preceded by a deep coma, with absent muscle tone or deep tendon reflexes, respiratory depression, hypotension, tachycardia, hypothermia, and an increase in salivation [50]. A common side effect is nasal irritation, which can be intense enough as to interfere with treatment [54]. 1.3.4. Hydroxyzine A first- generation antihistamine of the diphenylmethane and pyperazine class, hydroxyzine has been used in pharmacotherapy since the 1950s and is still widely used for the treatment of many conditions, ranging from anxiety to itching, hyperalgesia and motion sickness-induced nausea given its antihistamine effects. It has been found to be useful in the treatment of GAD [55, 56]. Oral absorption is rapid, as well as onset of action. Hydroxyzine can also be administered via intramuscular injection. It is metabolized in the liver by alcohol dehydrogenase, resulting in cetirizine, which is also marketed as an antihistaminic. Other pathways in hydroxyzine’s metabolism are mediated by CYP3A4. Research on the effect of hydroxyzine in the elderly is scant, but a longer half-life and a larger distribution have been observed, as well as a possibly enhanced H1-receptor activity [57]. Therefore, over-sedation and confusion is a possible occurrence, and, accordingly, hydroxyzine should be used with caution in anxious elderly patients. 1.3.5. Gabapentin An anticonvulsant and analgesic labeled for epilepsy and postherpetic neuralgia, gabapentin is structurally related to the neurotransmitter GABA, by the addition of a cyclohexane ring. However it has no direct agonist effects on GABAergic transmission, being its actual mechanism of action unknown, although it can involve an action at voltage-gated calcium channels [58].

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It was widely promoted for neurologic (essential tremor) and psychiatric (mood stabilizer, anxiolytic) off-label usage [59, 60], and still is considered as a valid option for the treatment of BPSD [61] and a possible therapy for anxiety disorders in the elderly, given its favorable safety profile [62]. Newly proposed usages for gabapentin include the treatment of refractory persistent cough [63], hot flushes [64] and restless legs syndrome [65]. Gabapentin is rapidly absorbed per os. It is not metabolized by the liver, thus being excreted in urine unchanged. In patients with renal impairment or failure, dosage adjustment is required. With a half-life not exceeding 7 hours, it usually must be administered thrice a day. A suitable alternative is Gabapentin enacarbil, a prodrug designed for increased oral bioavailability over gabapentin [66]. It has almost twice the overall bioavailability of gabapentin [67], especially when taken with a fatty meal [68]. Ataxia, additive sedation if combined with CNS depressants, dizziness and peripheral edema are the most usually reported adverse effects [69]. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Multiorgan Hypersensitivity is an unusual complication that can appear in patients treated with anticonvulsants, included gabapentin [70]. Even though it seems a safe drug and it is not associated to cognitive impairment in the elderly, gabapentin is still an unapproved drug for the treatment of psychiatric conditions and must therefore be used cautiously. Informed consent is accordingly crucial. 2. HYPNOTICS 2.1. Introduction The assertion that hypnotics should not be the first response to insomnia is particularly relevant in the elderly, as all compounds used to induce sleep are associated with adverse effects. Sleep hygiene is the first step, and includes maintaining a regular sleep-wake cycle, avoiding caffeine and other stimulants or taking a hot bath. In case a hypnotic was needed, treatment should ideally be short term, to avoid tolerance development. Sleep disturbance is very common in the elderly, and hypnotic medications are disproportionately used. BZD hypnotics and newer, “z” compounds, are usually prescribed to induce sleep in the elderly, but off-label prescription are widespread [13] (Table 3).

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Table 3: Hypnotics Benzodiazepine hypnotics: lormetazepam, triazolam, loprazolam, brotizolam, nitrazepam, flurazepam, flunitrazepam, temazepam, estazolam Melatonin Ramelteon Z agents: Zopiclone and eszopiclone Zolpidem Zaleplon Other: Sedative antidepressants: Trazodone, mirtazapine, doxepin Sedative antipsychotics: Clotiapine, levomepromazine, quetiapine Antihystamines

2.2. Hypnotic Benzodiazepines Different BZD compounds are used to treat insomnia. Some of them have intermediate to long half-lives, thus triggering day sedation and “hang-over”, so short-acting agents such as lormetazepam, midazolam and triazolam are preferred. Instead, long-acting products including flurazepam, nitrazepam and diazepam should be avoided, as their effect can be cumulative and result in a range of side effects described above. Flunitrazepam, a drug that was used to intoxicate victims of sexual abuse and rape [71], has been recently suspended in Europe. All BZDs reduce the EEG slow waves and enhance the activity in the frequency range of sleep spindles [72]. So, BZD users spend less time in Stage 3 and 4 sleep, and more time in stage 2, characterized by only theta waves. In summary, under the influence of BZDs, there is less deep sleep, which makes preferable other agents sparing the normal sleep architecture. 2.3. Melatonin Chemically named N-acetyl-5-methoxytryptamine, melatonin is a hormone related to the circadian rhythms, which is useful for inducing sleep. According to a review by Buscemi et al., [73], melatonin is not effective in treating most primary sleep disorders with short-term use, although there is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome with short-term use. Also, melatonin seems to be ineffective in treating most secondary sleep disorders with short-term use. Sufficient evidence to support effectiveness in alleviating the sleep disturbance aspect of jet lag and shift-work disorder has neither been produced.

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In the USA melatonin is not regulated as a pharmaceutical drug, but in Europe there is a prescription-only, prolonged-release melatonin product for people aged >55, which was approved for use by the European Medicines Agency in 2007. It is also available in Australia. 2.4. Ramelteon A highly selective agonist for the melatonin MT1/MT2 receptors in the suprachiasmatic nucleus in the thalamus, and in the hypothalamus, ramelteon has a unique mechanism of action, with negligible affinity for the MT3 binding sites and other receptors in the brain, including the opiate, dopamine, BZD and serotonin receptors [74]. The affinity of ramelteon for MT1 and MT2 receptors is higher than that exhibited by melatonin [75]. With a rapid oral absorption, delayed if taken with food, ramelteon undergoes an extensive first-pass metabolism. It is metabolized via CYP1A2, CYP2C19, and CYP3A4, which are estimated to contribute 49, 42, and 8.6%, respectively, in liver, whereas in intestine only CYP3A4 contributes [76]. Agents inhibiting those isozymes can increase the levels and action of ramelteon. The most commonly reported adverse events are somnolence, fatigue and dizziness (5% vs 3%). At a dosage of 8 mg at bedtime, ramelteon is considered a safe hypnotic when used by elderly patients [77]; however, it has been reported that at therapeutic doses ramelteon (8 mg) significantly impairs driving performance, cognitive, memory, and psychomotor performance the morning following bedtime administration, with balance impairments [78]. 2.5. Z-Agents This umbrella term includes compounds belonging to different chemical families who modulate GABAergic transmission to induce sleep. In contrast to BZDs, which bind to both subunits, zolpidem and zalepon selectively bind with high affinity only to the α1 subunit, more closely related to sedation [79]. So, they spare the α2 subunit, related to cognition, psychomotor function and memory and are relatively free from some usual adverse effects of BZD hypnotics. Zopiclone and eszopiclone have affinity for the α1, α2, α3, and α5 subunits of the GABAA complex with varying potency at these sites, but their primary action is hypothesized to be exerted through α2 and α3 receptors and, to a lesser extent, the α1 receptor [80]. A recent systematic review and meta-analysis concluded that compared with placebo, Z drugs produce slight improvements in subjective and polysomnographic sleep latency, especially with larger doses and regardless of type of drug. The authors remarked that although

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the drug effect (and the placebo response altogether) were rather small and of questionable clinical importance, the two together produced to a reasonably large clinical response [81]. 2.5.1. Zopiclone and Eszopiclone Zopiclone is a cyclopyrrolone which has proved to increase deep sleep and significantly reduce REM density [82]. With a fast oral absorption, it is extensively metabolized by CYP3A4. It is characteristically excreted in saliva, attaining concentrations higher than in blood, and provoking the most commonly side effect seen in clinical trials, namely an unpleasant metallic, bitter taste that can be persistent [83]. In old age, zopiclone’s bioavailability and half-life are largely increased, thus a reduction of the initial zopiclone dose, especially in those with liver insufficiency [84] is recommended. It also must be taken into account that at therapeutic doses (7,5 mg at bedtime), zopiclone has been observed to significantly impair driving performance, cognitive, memory, psychomotor performance and balance the morning following bedtime administration [78]. Eszopiclone is the S-enantiomer of racemic (R,S)-zopiclone. With a rapid oral absorption, eszopiclone is metabolized mainly by CYP3A4 and CYP2E1. A mean half-life in healthy nonelderly individuals of 6.1 hour is prolonged in the elderly, in patients with hepatic insufficiency and by coadministration of CYP3A inhibitors (such as itraconazole or grapefruit juice). It may produce residual sedation and impairment of driving performance in the initial morning waking hours. As with zopiclone, a bitter or metallic taste is a common side effect related to excretion in saliva [85]. The recommended starting dose of eszopiclone is 1 mg at bedtime, which should be increased up to 2 mg in those patients with difficulty maintaining sleep [86]. Eszopliclone is not available in the European Union after in 2009 the EMA denied it new active substance status, alleging that it was too similar to zopiclone to be considered a new patentable product. 2.5.2. Zolpidem Zolpidem is an imidazopiyridine widely used for the treatment of insomnia which paradoxically has proved to be useful to arouse patients in vegetative state [87]. Zolpidem is absorbed rapidly, with a bioavailability is 67% after oral doses of 520 mg. Pharmacokinetics show age-related and sex-related variations. It is metabolized by CYP3A4, being subject to the effect of inhibitors and inducers of the isozyme [7]. Zolpidem has a half-life of 2 to 3 hours, which is increased by a delayed elimination in patients with liver or renal impairment [88]. In the elderly there is an increase in peak plasma concentration and area under the plasma

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concentrationtime curve. Elderly patients show lower clearance and volumes of distribution [89]. Zolpidem is effective in inducing sleep, but for some patients with maintenance insomnia an extended release formulation is available. Recently, the FDA approved a sublingual formulation which is the first drug indicated to treat early wakening. This drug should only be used when there are at least 4 hours of bedtime remaining. The recommended and maximum doses of this new formulation are 1.75 mg for women and 3.5 mg for men, taken once per night. Variance in dosage between men and women is because of slower metabolic clearance of the drug observed in women. Moreover, recently, the FDA [90], Healthy Canada [91] and the EMA [92] have recommended lowering doses for medications containing zolpidem, as next-morning driving ability [93] and mental alertness can be impaired with zolpidem usage. Hallucinations, confusional states and complex behaviors including sleepwalking and nocturnal eating have also been reported [94], and two homicides have been related to zolpidem [95]. In the elderly, the dose immediate release zolpidem should not surpass 5 mg, while the dose for controlled-release is 6.25 mg immediately before bedtime, and sublingual zolpidem dose should be 1.25 mg [62]. 2.5.3. Zaleplon Zaleplon is a pyrazolopyrimidine with an ultra-short half-life which minimizes the risk of next day residual effects on driving and other performance related skills. With a rapid oral absorption, delayed by food, peak levels are attained in one hour [96]. Metabolized by the liver CYP3A4, its action can be increased and decreased by the effect of co-administration with inhibitors or inducers, respectively, of the isozyme. The side effect most commonly reported is headache. Standard dosage of 10 mg should preferably be halved in the elderly [97], but dose-related illusions and hallucinations have been reported [98]. 2.6. Other Agents Antidepressants including trazodone, mirtazapine or doxepine are widely used for the treatment of insomnia, given their sedative properties, stemming generally from an H1-antihistaminic effect. Doxepin is a tricyclic antidepressant with intense antihistaminic action, than can be used as a hypnotic at low doses (6 mg at bed time). In a study with elderly subjects, doxepine improved sleep maintenance, sleep duration, and sleep quality, with a favorable safety profile [99].

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Trazodone, a triazolopyridine antidepressant, exerts at low doses a potent 5HT2A antagonism, as well as an antagonism of H1-histaminic and α1-adrenergic receptors, all resulting in an intense sedative effect, which together with a relatively short half-life makes trazodone a suitable hypnotic. However, a review found that evidence for the efficacy of trazodone in treating insomnia is very limited, whereas side effects are significant and include sedation, dizziness, and psychomotor impairment, which raise particular concern regarding its use in the elderly; also, there is also some evidence of tolerance related to use of trazodone [100]. Mirtazapine is a very strong H1 receptor inverse agonist, which results in a potent sedative and hypnotic effect [101]. Daytime sedation and dizziness can be intense and can deter the use of the drug, especially in the elderly. Other antihistamines available over the counter should be avoided in the elderly because of anticholinergic effects, daytime sedation and impaired driving performance [62]. 3. COMMENTARY Anxiolytics and hypnotics are a heterogeneous drug of psychotropics. Even in the homogeneous group of the BZDs, distinctions can be made according factors such as route of metabolisation, half-life or therapeutic effect profile, with some compounds being “predominantly hypnotic” and other “predominantly anxiolytic”, or “predominantly antiepileptic”. Tetrazepam, recently suspended in Europe after decades of marketing, following reports of serious skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome [102], was a “predominantly myorelaxant” BZD. In other cases the prevailing characteristic of a given compound varies across countries. Clonazepam, a “predominantly anticonvulsant” in Europe became a successful agent against anxiety and panic disorder in the U.S. with its “development” as a psychotropic [103]. Clorazepate, an anxiolytic in Europe, is also an anticonvulsant in the U.S., and has accordingly been given a class black box related to suicide risk along with other antiepileptics [104], while clobazam, marketed for decades as an anxiolytic and adjunctive antiepileptic in Europe, became an anticonvulsant when it was approved in the U.S. [105], soon before the F.D.A. warned, also in this case, of serious skin reactions after its usage [106], in a transatlantic version of the tetrazepam saga.

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Beyond these somewhat difficult to understand bureaucratic differences, most anxiolytics and hypnotics are rapid-acting, effective drugs that can be helpful to many patients experiencing anxiety or insomnia. However, many of them (significantly, BZDs, but also zolpidem and zopiclone [107], and also chlormethiazole [108]) are associated to the development of addiction. In the elderly, specifically BZDs, pose serious problems as ataxia, risk of falls, and cognitive impairment. The use of sedatives can also trigger confusional states [109]. Some hypnotic drugs, like zolpidem, can produce hallucinations and delirium. On the other hand, distinctive pharmacokinetic and pharmacodynamic in old age can contribute to a higher vulnerability to anxiolytic and hypnotic adverse effects in the elderly. Accordingly, even though BZDs and related drugs are generally thought to be relatively safe agents, they should be carefully used in psychogeriatric practice and the usual cautionary recommendation that they should be prescribed for short periods of time only. ACKNOWLEDGEMENTS The author is indebted to the invaluable teachings of the patients who have reported to him their personal experiences after being treated with some drugs included in this chapter. CONFLICT OF INTEREST The author confirms that this chapter contents have no conflict of interest. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8]

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Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomised, doubleblind, placebo-controlled trial. Lancet 2012; 380: 1583-9. Yadav M, Volkar J. Potential role of gabapentin and extended-release gabapentin in the management of menopausal hot flashes. Int J Gen Med 2013; 6:57-64. Kume A. Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose? Neuropsychiatr Dis Treat 2014; 10:249-62 Landmark CJ, Johannessen SI. Modifications of antiepileptic drugs for improved tolerability and efficacy. Perspect Medicin Chem 2008; 2:21-39. Cundy KC, Sastry S, Luo W, et al., Clinical pharmacokinetics of XP13512, novel transported prodrug of gabapentin. J Clin Pharmacol 2008; 48: 1378-88. Lal R, Sukbuntherng J, Luo W, Huff FJ, et al., The effect of food with varying fat content on the clinical pharmacokinetics of gabapentin after oral administration of gabapentin enacarbil. Int J Clin Pharmacol Ther 2010; 48: 120-8. Ruiz Fernández V. Gabapentina. In Salazar M, Peralta C, Pastor FJ. Tratado de psicofarmacología. Bases y Aplicación Técnica. Buenos Aires, Madrid: Médica Panamericana, 2009; 337-40 US Food and Drug Administration. Neurontin (gabapentin) Capsules, Tablets, and Oral Solution. Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) -- April 2009 and August 2011. Anglin D, Spears KL, Hutson HR. Flunitrazepam and its involvement in date or acquaintance rape. Acad Emerg Med 1997; 4: 323-6. Borbély AA, Mattmann P, Loepfe M, et al., A single dose of benzodiazepine hypnotics alters the sleep EEG in the subsequent drug-free night. Eur J Pharmacol 1983; 89: 157-61. Buscemi N, Vandermeer B, Pandya R, et al., Melatonin for treatment of sleep disorders. Evid Rep Technol Assess (Summ) 2004; (108): 1-7. McGechan A, Wellington K. Ramelteon. CNS Drugs 2005; 19: 1057-65 Kato K, Hirai K, Nishiyama K, et al., Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology 2005; 48: 301-10 Obach RS, Ryder TF. Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. Drug Metab Dispos 2010; 38:1381-91. Mets MA, van Deventer KR, Olivier B, et al., Critical appraisal of ramelteon in the treatment of insomnia. Nat Sci Sleep 2010; 2: 257-66 Mets MA, de Vries JM, de Senerpont Domis LM, et al., Next-day effects of ramelteon (8 mg), zopiclone (7.5 mg), and placebo on highway driving performance, memory functioning, psychomotor performance, and mood in healthy adult subjects. Sleep 2011; 34: 1327-34 Sanger DJ, Benavides J, Perrault G, et al., Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes. Neurosci Biobehav Rev 1994; 18: 355-72. Nutt DJ, Stahl SM. Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics. J Psychopharmacol 2010; 24:1601-12. Huedo-Medina TB, Kirsch I, Middlemass J, et al., Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ 2012; 345: e8343. Hemmeter U, Müller M, Bischof R, et al., Effect of zopiclone and temazepam on sleep EEG parameters, psychomotor and memory functions in healthy elderly volunteers. Psychopharmacology (Berl). 2000; 147: 384-96. Monchesky TC, Billings BJ, Phillips R. Zopiclone: a new nonbenzodiazepine hypnotic used in general practice. Clin Ther 1986; 8: 283-91 Gaillot J, Le Roux Y, Houghton GW, et al., Critical factors for pharmacokinetics of zopiclone in the elderly and in patients with liver and renal insufficiency.Sleep. 1987; 10 Suppl 1: 7-21. Greenblatt DJ, Zammit GK. Pharmacokinetic evaluation of eszopiclone: clinical and therapeutic implications. Expert Opin Drug Metab Toxicol 2012; 8: 1609-18 Kirkwood C, Breden E. Management of insomnia in elderly patients using eszopiclone. Nat Sci Sleep 2010; 2: 151-8. Du B, Shan A, Zhang Y, et al., Zolpidem arouses patients in vegetative state after brain injury: quantitative evaluation and indications. Am J Med Sci 2014; 347: 178-82. .

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Hoehns JD, Perry PJ. Zolpidem: a nonbenzodiazepine hypnotic for treatment of insomnia. Clin Pharm 1993; 12: 814-28. Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet 2004; 43: 227-38 US Food and Drug Administration. FDA Drug Safety Communication: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). Barakat M. Health Canada Endorsed Important Safety Information on Sublinox (zolpidem tartrate). January 3, 2014. European Medicines Agency. CMDh endorses new advice to minimise risk of next-morning impaired driving ability and mental alertness with zolpidem. Accessed [25/04/2014]. Farkas RH, Unger EF, Temple R. Zolpidem and driving impairment--identifying persons at risk. N Engl J Med 2013; 369: 689-91 Inagaki T, Miyaoka T, Tsuji S, et al., Adverse reactions to zolpidem: case reports and a review of the literature. Prim Care Companion J Clin Psychiatry 2010; 12(6). doi: 10.4088/PCC.09r00849bro Paradis CM, Siegel LA, Kleinman SB. Two cases of zolpidem-associated homicide. Prim Care Companion CNS Disord 2012; 14(4). doi: 10.4088/PCC.12br01363 Patat A, Paty I, Hindmarch I. Pharmacodynamic profile of Zaleplon, a new non-benzodiazepine hypnotic agent. Hum Psychopharmacol 2001; 16: 369-392. Rodríguez Marañón MI, Catalán Alcántara A. Zaleplon. In Salazar M, Peralta C, Pastor FJ. Tratado de psicofarmacología. Bases y Aplicación Técnica. Buenos Aires, Madrid: Médica Panamericana, 2009; 406-8 Stone JR, Zorick TS, Tsuang J. Dose-related illusions and hallucinations with zaleplon. Clin Toxicol (Phila) 2008; 46: 344-5 Lankford A, Rogowski R, Essink B, et al., Efficacy and safety of doxepin 6 mg in a four-week outpatient trial of elderly adults with chronic primary insomnia. Sleep Med 2012; 13: 133-8 Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry 2005; 66: 469-76 Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 2001; 7: 249-64. European Medicines Agency. Recommendation to suspend tetrazepam-containing medicines endorsed by CMDh. Accessed [29/04/2013]. Rosenbaum JF. The development of clonazepam as a psychotropic: the massachusetts general hospital experience. J Clin Psychiatry 2004; 65 Suppl 5: 3-6. U.S. Food and Drug Administration. Suicidal Behavior and Ideation and Antiepileptic Drugs. Update 5/5/2009 Sirven JI, Noe K, Hoerth M, et al., Antiepileptic drugs 2012: recent advances and trends. Mayo Clin Proc 2012; 87: 879-89. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA warns of serious skin reactions with the anti-seizure drug Onfi (clobazam) and has approved label changes. Accessed [12/3/2013]. Hajak G, Müller WE, Wittchen HU, et al., Abuse and dependence potential for the nonbenzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 2003; 98: 1371-8. Glatt MM. Chlormethiazole addiction. Br Med J 1978; 2(6141): 894-5. Rothberg MB, Herzig SJ, Pekow PS, et al., Association between sedating medications and delirium in older inpatients. J Am Geriatr Soc 2013; 61: 923-30.

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CHAPTER 8

Mood Stabilizers Juan Medrano* Ezkerraldea - Enkarterri Mental Health Community Services, Bizkaia´s Mental Health Network, Portugalete, Bizkaia, Spain Abstract: Mood stabilizers are those drugs used to treat and prevent acute episodes of bipolar disorder. The concept includes a host of agents: lithium, several anticonvulsants, and antipsychotics, notably, second-generation compounds. This chapter reviews the different drugs labelled as mood stabilizers and where available introduces some considerations on their use in old age. Given the lack of controlled trials enrolling elderly bipolar patients, most information derives from application to geriatric patients’ characteristics of those data obtained in studies with other age groups, and also from decades of clinical experience, especially with lithium.

Keywords: Antidepressants, Aripiprazole, Bipolar disorder, Carbamazepine, Divalproex, First generation antipsychotics, Gabapentin, Haloperidol, Hypothyroidism, Johnson syndrome, Lamotrigine, Levetiracetam, Lithium, Lyell syndrome, Mood Stabilizer, Olanzapine, Oxcarbazepine, Quetiapine, Renal impairment, Risperidone, Second generation antipsychotics, Stevens, Topiramate, Valproate, Valproic acid. 1. INTRODUCTION The group of drugs mood stabilizers (MS) consists of all the drugs used to obtain mood stabilization in Bipolar Disorder (BD), and includes a host of heterogeneous agents covered by an umbrella term that seems to reflect a practical marketing strategy rather than a scientifically-based concept. Solely lithium seems to be effective on the four treatment issues of BD, namely, acute mania, acute bipolar depression, maintenance therapy against mania and maintenance therapy against depression and should accordingly the only drug deserving to be called a MS [1]. However, a host of compound showing or attempting to show effectiveness in any aspect of BD treatment have achieved being attributed the condition of MS, what has led Fountoulakis et al., [2] to argue that a class effect is the exception rather than the rule in the treatment of BD. This chapter will review lithium and other *Corresponding author Juan Medrano: Ezkerraldea - Enkarterri Mental Health Community Services, Bizkaia´s Mental Health Network, Portugalete, Bizkaia/Vizcaya, Spain; Tel: 3444596505; Fax: 3444596511; E-mail: [email protected] Unax Lertxundi, Juan Medrano and Rafael Hernández (Eds.) All rights reserved-© 2015 Bentham Science Publishers

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self-appointed MS which were originally introduced as anticonvulsants or antipsychotics. 2. LITHIUM Lithium was introduced in the psychopharmacological armamentarium in 1949 by John Cade, in a memorable event which opened a new era and inaugurated a new branch of therapeutics that still had to wait some years to have a name coined for it. The occasion was also memorable because despite some authoritative criticisms, like those of Shepherd’s and Moncrieff’s, there is a general consensus that Cade found a useful compound, albeit not devoid of serious adverse effects, which has contributed for decades to a better course of BD in patients. Rather than discovered, lithium was first suspected by the Suede chemist Johan August Arfwedson, who when studying petalite in 1817 postulated that there had to exist an unidentified component to explain why the sum of its known parts never produced the mineral’s total weight. He coined the term lithium (from λίθος lithos, “stone”) for such an elusive ingredient that he was not able to isolate but which could finally be identified by WT Brande and Humphry Davy one year later. Lithium soon became popular with the bourgeoning of spa resorts and the recognition of the dubious virtues of lithinized waters. In 1843 Ure treated urinary calculus with lithium, which was used by Garrod in 1859 to treat gout after discovering that phalangeal uric acid deposits dissolved when immersed in a solution of lithium carbonate [3]. Uric acid was in those years a convenient research tool given its availability, so it became fashionable as a purported window to the intimate mechanisms of disease, which opened a new era where a “gout diathesis” or “uric diathesis” could be invoked to interpret both the pathogenesis and the pathophysiology of a number of illnesses [4, 5]. In the USA, in 1870s, Hammond treated successfully with lithium patients suffering from affective disorders [6], and in Denmark the Lange brothers (Carl, a neurologist and Fritz, a psychiatrist) used lithium in 1886 to treat recurrent depression and a condition that would currently be named acute depression. Their findings, however, were soon criticized by the medical authorities of those years. Nearly a century after the Langes’ first attempt, lithium was recovered for psychiatric therapeutics by John Frederick Joseph Cade (1912-1980), an Australian psychiatrist who hypothesized that the phases of manic depressive illness should be caused by the excess (mania) or lack (depression) of a substance that had to be identified. Aiming at isolating that conjectured component, Cade studied his

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manic patients’ urine, doubtlessly a suitable research material because of its availability and accessibility. After injecting guinea pigs intraperitoneally with urine from manic patients, he observed a great toxicity and thought that the urine contained that unknown pathogenic substance. After finding that urea was able to produce those same toxic effects, he tried other nitrogenated compounds, among them, uric acid, which was not soluble in water, and used in its most hydrosoluble form, namely, lithium urate. He noticed that when injected with lithium urate, urea seemed to be less toxic, which he thought proved that lithium had a protective effect. He later tried lithium urate alone, finding that it elicited a tranquillizing, not lethargic effect, on guinea pigs. Encouraged by this finding, he tried lithium urate and citrate in his manic patients, with surprising improvements that, on the other hand, could not be observed in patients with schizophrenia or melancholia treated with lithium [7-9]. Cade published his findings in an Australian journal, which in those years probably did not help that they were widely known, and in the year (1949) when the toxic effects of lithium chloride as a salt substitute became publicized. Both circumstances probably prevented the widespread use of lithium as a psychotropic. Also, Cade soon stopped using lithium, allegedly because one of his patients died [9], but his work attracted attention on the other side of the world, in Denmark, where first Strömgren, and later Schou, tried lithium. Mogens Schou (1918-2005) performed a first placebocontrolled, double-blind clinical trial, using purposely-devised scales, which showed an antimanic effect in humans, and communicated his findings in a paper that having been rejected by the editor of a first-line journal was finally published in 1954 [10]. Lithium’s prophylactic action in depression was first and separately observed by Hartigan [11] and Baastrup [12]. Accordingly, Schou devised with the latter a clinical trial to test if lithium could really prevent further episodes of manic depression. A prophylactic effect was finally shown in a clinical trial [13] that was criticized on methodological grounds [14], so Schou devised a new trial that seemed to show an indubitable prophylactic effect, as those patients treated with lithium who had been switched to placebo relapsed at a rate unobserved in those still on lithium [15], a finding that established the preventative role of lithium in manic depression, even though some experts assert that those findings can show a relapse-after-withdrawal effect rather than a protective one [16]. Recent evidence from studies comparing lamotrigine, lithium and placebo, still support the effectiveness of lithium in the prophylaxis of BD. However, results point to an antimanic rather than antidepressant action, with lamotrigine more useful for the prevention of depressive compared with manic episodes, whereas the opposite can be stated for lithium [17].

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2.1. Mechanism of Action As stated by Bellmaker [18], lithium has a myriad of biochemical and biologic effects, although many of them occur only at toxic concentrations. In fact, lithium has been able to have at least one major effect according to the shifting central focus in Neuroscience in parallel to the discovery of its effects on BD. In the 1960-1970s, when monoamines were a fashionable subject of research, lithium proved to increase deaminated norepinephrine metabolites [19]. In the 19701980s, when neurotransmitter receptors were the zeitgeist of neuroscience, lithium was found to prevent dopamine-receptor supersensitivity [20]. In the 1980-1990s, the era of second messengers, the inhibitory action of lithium both on adenylate cyclase [21] and inositol monophosphatase [22] was discovered. In the last years of the 20th century, when third messengers became the focus of research, it was found that lithium affects c-fos, c-jun [23] and increases CREB DNA binding [24]. Finally, with the advent of the 21st century, the neuroprotective effects of lithium have been identified, both in the neuroscientific [25] and the clinical [26] arenas. The possibility of a role for lithium in the treatment of Alzheimer’s disease has been suggested on the basis of its neuroprotective action [27]. Amongst its varied actions and properties, lithium inhibits glycogen synthase kinase-3 (GSK-3), which is purportedly responsible for a decrease in the induction of both amyloid beta peptide and hyperphosphorylated τprotein, which in turn have been implicated in the pathophysiology of Alzheimer’s disease [28]. An intriguing property of lithium, namely its ability to reduce suicidal behavior, has not been ascribed to any particular mechanism of action and could be merely related to a better course of the illness by treating it with lithium [29]. However, a lesser trend to self-inflicted death has also been appraised also at a larger, epidemiological and demographic level in studies showing a negative correlation between concentration of lithium in drinking water and mortality by suicide [30], which suggests that other processes could be involved. 2.2. Treatment with Lithium Lithium is a true MS that can be used in the treatment of depression, the treatment of mania, the prophylaxis of depression and the prophylaxis of mania. However, there is evidence that as an antidepressant lithium is not a good option, as improvement takes several weeks to occur, and in the last years other compounds, such as lamotrigine (see above) have proved to be more effective to prevent acute depression. Besides remaining an effective antimanic remedy and a specific prophylactic therapy for acute mania, lithium is also used for antidepressant augmentation in the face of refractory or resistant, severe depression, with

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substantial efficacy demonstrated in more than 30 open-label studies and 10 placebocontrolled trials, which could be criticized on the grounds of the relatively small numbers of study participants and also because most studies included augmentation of tricyclic antidepressants, which currently are not in widespread use [31]. Irrespective of the clinical situation for which it is prescribed, lithium is a drug with a host of side effects and must be used cautiously in all patients, regardless their age. However, it is a very experienced compound, and while decades of usage not only have conferred it evidence of effectiveness, clinicians have also learned how it should be used to minimize risks and maximize usefulness. Relative contraindications of lithium in old age include severe psoriasis, mild to moderate cardiovascular disease, preexisting thyroid disease and mild to moderate renal impairment. However, when carefully monitored, lithium can be used in all except in the most extreme circumstances [1]. An important point is that lithium toxicity is compounded by sodium depletion, therefore, concurrent use of diuretics such as thiazides should be avoided because an increase in sodium elimination can cause increased resorption of lithium in the proximal convoluted tubule, leading to elevated, potentially toxic levels. A recent review by McKnight et al., [32] found an association between lithium and an increased risk of reduced urinary concentrating ability, hypothyroidism, weight gain and hyperparathyroidism. The consistent finding of a high prevalence of hyperparathyroidism suggests that calcium concentrations should be checked before and during treatment. However, they concluded that there is little evidence for a clinically significant reduction in renal function in most patients, with a low risk of endstage renal failure. Another review by Werneke et al., concluded, after checking comparative effectiveness and safety, that lithium initiation and continuation should be recommended in most cases even in the presence of long-term adverse renal effects [33]. Table 1: Lithium’s side effects Acne Alopecia areata Arrhythmia - avoid in sick sinus syndrome Asthenia Cognitive impairment Diarrhea Dysarthria Hyperglucemia Leukocytosis

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Metallic taste Edema Polydipsia Polyuria and polydipsia, secondary to Psoriasis Thyroid dysfunction (Hypothyroidism; hyperthyroidism rarely) Tremor T-wave inversion or flat T-wave Weight gain

Before starting lithium, neurological, cardiac and renal function must be assessed. All patients should be educated about the purpose of the prescription, how lithium must be taken and how to prevent and detect side-effects (Table 1). Cardiac effects of lithium include a benign, reversible T-wave depression with no changes in the S-T segment or the Q-T interval corrected for heart rate, therefore in the absence of symptoms or signs of heart disease, routine monitoring of ECG is not necessary [34]. However, depressed sinus node function is reported, albeit clinically significant dysfunction is uncommon [35]. On the other hand, lithium can unmask Brugada syndrome [36]. Precipitation or aggravation of ventricular arrhythmias has been reported with lithium at therapeutic levels [37]. Table 2: Main drug interactions of lithium Drugs which increase lithium plasma levels and Drugs that can decrease lithium levels (toxicity can appear after these drugs are stopped) toxicity Acyclovir Angiotensin Receptor 1 Blockers Angiotensin-Converting-Enzyme inhibitors Cyclooxygenase-2 inhibitors Furosemide Metronidazole Nonsteroidal Anti-Inflammatory Drugs Spironolactone Tetracyclines, Thiazide diuretics Topiramate Triamterene

Acetazolamide Caffeine Theophylline

Drugs that can trigger serotonin syndrome when co-prescribed with lithium

Drugs that can increase lithium’s neurotoxicity

Monoamine Oxidase Inhibitors Selective Serotonin Reuptake Inhibitors

Antipsychotics Calcium Channel Blockers Carbamazepine

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Table 2: contd…

Tricyclic antidepressants

Selective Serotonin Reuptake Inhibitors Valproate

Drugs than can increase lithium’s cardiotoxicity Verapamil

Lithium decreases thyroid hormone synthesis and release, as well as peripheral deiodination of tetraiodothyronine (T4) or thyroxine by decreasing the activity of type I 5’ de-iodinase enzyme. In patients on long-term lithium, hypothyroidism and goitre are the most prevalent thyroid abnormalities. Hyperthyroidism is a very infrequent, although possible, occurrence in patients on lithium. An augmentation of B lymphocytes activity and reduction of the ratio of circulating suppressor to cytotoxic T cells has been linked to a higher propensity to thyroid autoimmunity in susceptible individuals. Accordingly, more frequent assessment of thyroid function status and size during the course of lithium therapy is recommended among middle aged females, patients with a family history of thyroid disease or those positive for thyroid auto-antibodies [38]. Information on drug-drug interactions relevant to lithium therapy should be given both to patients and to other providers involved in their healthcare (Table 2). Angiotensin - Converting - Enzyme inhibitors, Angiotensin Receptor 1 Blockers, Cyclooxygenase-2 inhibitors, metronidazole, Nonsteroidal Anti-Inflammatory Drugs, tetracyclines, thiazide diuretics and topiramate can increase lithium level, so toxicity can arise when these compounds are added to the therapeutic regimen of a patient on lithium. Other compounds sharing an ability to increase lithium levels are triamterene, spironolactone, eplerenone, furosemide, and acyclovir. Caffeine, theophylline and acetazolamide, on the other hand, can decrease lithium levels, which can accordingly arise if these compounds are stopped. Combination of lithium with Monoamine Oxidase Inhibitors, Selective Serotonin Reuptake Inhibitors and Tricyclic antidepressants can cause serotonin syndrome. Co/prescription of lithium with Calcium Channel Blockers can increase risk of cardiac and neurological toxicity. Neurotoxicity can arise also with antipsychotics, carbamazepine, Selective Serotonin Reuptake Inhibitors, and valproate [39]. Baseline laboratory evaluation should include electrocardiogram, especially in the elderly, as well as urianalysis, complete blood count (CBC), creatinine, thyroid stimulating hormone and ions. Lithium should be initiated at low doses to minimize intolerance. Forms vary across countries. Slow release forms improve lithium

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digestive tolerance compared with immediate release forms. A total 400 to 600 mg twice daily can be a good starting strategy with increments every 4-7 days guided by blood levels monitoring till an effective, safe therapeutic range is achieved. Polyuria has been estimated to appear in 15-40% of patients treated with lithium, whereas clinically established nephrogenic diabetes insipidus has been found in about 12% of all patients treated [40]. Single daily dosing (SDD) can be a useful strategy to decrease urine production, and subsequently, polyuria and nicturia. A recent review found that multiple daily doses were associated with more pathologic damage to the kidneys, while SDD regimens are generally well tolerated, and are not associated with a reduction in efficacy. The authors recommended that given its added benefits, such as improved compliance, patients newly started on lithium should be converted to a SDD of lithium at bedtime once an appropriate daily dose is determined [41]. Lithium blood levels must be monitorized. Blood drawings should be obtained 12 hours after the last dose. Plasma concentrations in excess of 2.5 mEq/L are usually associated with serious toxicity and require emergency treatment. Earlier work by Schou and clinical wisdom established a maintenance range of 0.6-1.2 mEq/L that was later supported by controlled empirical studies, such as Gelenberg et al., [42], which compared the outcome of two regimes of lithium maintenance, one at low levels (0.4-0.6 mEq/L) and other at standard-range levels (0.8-1.0 mEq/L), finding that those patients with the low level regime had a 2.6 fold risk of relapse. Side effects, including tremor, diarrhea, polyuria, weight gain, and a metallic taste, were more frequent in the standard-range group. The clinical superiority of the standard-range was detected in patients with two or fewer prior episodes, whereas in patients with more episodes no significant prophylactic effect was observed. Maj et al., [43], however, found that in maintenance treatment, plasma lithium levels could be adjusted to a lower range of 0.46-0.75 mEq/L, thus obtaining a greater tolerance and safety without losing any prophylactic effect. Schou [44] adhered to a reduction on maintenance levels by proposing a range of 0.5-0.8 mEq/L, while Severus et al., suggest that within a 0.5-0.8 range, relatively lower levels are optimal for prevention of depression, whereas relatively higher levels may be best in the prophylaxis of mania [45]. Nevertheless, these proposals can be flawed, because as Sachs [1] points out, the concept of a therapeutic range suffers from three assumptions that may confound findings. First, it is assumed that lithium determinations reflect true steady-state concentrations; second, it is inferred that the relationship between serum plasma lithium levels and brain levels vary little between individuals; finally, a small

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variation in the brain to serum lithium concentration ratio within an individual is accepted over time. In spite of these pitfalls that cast doubt as to whether a narrow, precise therapeutic range can be determined, obtaining serum lithium levels is mandatory as it allows to fix dosage and to prevent toxicity. It should be done whenever there has been a change in dosage, allowing for seven days to attain steady-state serum concentrations [46], every two-four weeks during the first two months of therapy and every three to six months in stable patients. Abrupt lithium discontinuation involves a high risk of relapse in the interval immediately after withdrawal [47, 48]. Some authors argue this is a withdrawal phenomenon rather than a demonstration that lithium confers protection against new acute bipolar episodes [16, 49]. In any case, whenever an effective lithium maintenance treatment is to be stopped, either due to the emergence of toxicity or at the patient’s request, discontinuation should be slow and carefully monitored. In the case of antidepressant lithium augmentation, combination treatment should be maintained for at least 1 year to prevent early relapses, with a slow, careful discontinuation [31]. Discontinuation has also been related to refractoriness in patients who after having had a good long-term response, suffer a major recurrence following discontinuation, and subsequently do not again respond as well or at all to lithium once it is restarted at doses which had been once been effective. A connected issue is the development of tolerance after long-term lithium therapy, where with lithium doses consistently maintained and after an extended period of excellent responsiveness, affective episodes of increasing severity, frequency, or duration emerge [50]. However, the effect of lithium prophylaxis does not seem to decrease over time, at least in the majority of patients. In the elderly, no age-related decrease in lithium efficacy was found in a retrospective study. Even though manic symptoms increased in prevalence and severity with age, authors interpreted this finding as a feature of the natural history of BD [51]. In addition, based also in a retrospective literature review, lower-range lithium levels seem to be effective in the elderly. In any case, lowrange maintenance would be a wise strategy to minimize side effects [52]. Lithium overdose, either accidental or voluntary, must always be considered a serious occurrence that should be immediately addressed (Table 3).

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Table 3: Lithium overdose Based on [39] Mild intoxication (1,5 - 2 mEq/L) Abdominal pain Ataxia Dysarthria Letargia Motor restlessness Muscle weakness Tremor of attitude Vertical nistagmus Moderate intoxication (2 - 2,5 mEq/L) Clonus and choreoathetosis Deep tendon hyperreflexia Delirium EEG changes Fasciculations Persisting vomits Syncope Severe intoxication (≥ 2,5 mEq/L) Coma Generalized convulsions Oliguria - Acute renal failure Death

3. VALPROIC VALPROMIDE

ACID,

SODIUM

VALPROATE,

DIVALPROEX,

The anticonvulsant action of valproic acid (VPA) was discovered when it was used to dissolve another product and it was found that the drug on trial had the same anticonvulsant activity at whatever concentration it was dissolved, which implied that it was the solvent who had the antiepileptic effect [53]. Its pharmacological forms are varied. Valpromide is a slowly absorbed pro-drug with less marked fluctuations in plasma levels [54]. However, its stronger inhibition of epoxide oxidase as compared with VPA entails a more complex drug-drug interaction profile that contraindicates the combination of valpromide with carbamazepine [55]. In some European countries, sodium valproate is available alone or in a mixture with VPA acid in a 2.3:1 molar relationship. In other countries, such as the U.S. or the United Kingdom, an equimolar combination of VPA and sodium valproate (divalproex or valproate semisodium) is available. Oral absorption seems to be faster and with less marked plasma fluctuations with

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sodium valproate. About 80% of absorbed valpromide is metabolized to VPA [56], which is also the form to which sodium valproate is converted, so all compounds and forms exert their therapeutic action as VPA. The usefulness of VPA in the treatment of BD was suspected almost 50 years ago [57], when being used as an adjunctive sedative in the treatment of manic states with chlorpromazine it was noted that on maintenance therapy patients left on valpromide showed a better compliance than those on chlorpromazine [58]. More recently valpromide emerged as a drug useful in the treatment of manic states and in the maintenance of BD [59]. In other countries valproate started to be used in the treatment of affective disorders [60]. VPA effectiveness has been demonstrated in the treatment of mania (as valpromide [61] and valproate [62]) and mixed bipolar episodes (as divalproex [63]). VPA is a compound with a varied set of side effects. A rare adverse effect, hepatotoxicity can range from reversible hepatic dysfunction to irreversible liver failure, but most of the reported cases involved boys younger than 10 years and with mental retardation, with a higher risk in those younger than 2 years and those concomitantly on other anticonvulsants. The U.S. Food and Drug Administration has recently warned that hepatic failure resulting in fatalities has occurred in patients receiving VPA and its derivatives, usually during the first six months of treatment [64]. Accordingly, the agency recommends close monitoring at a clinical and serological level. However, in the elderly this is an unusual occurrence, as 90% of patients developing hepatotoxicity are younger than 20 years [65]. VPA can induce pancreatitis, with increased serum amylase and/or lipase levels, as well pancreas enlargement. Symptoms can appear after both short-term and long-term use, but generally subside after discontinuation [66]. VPA has been associated to an increased risk for hypocoagulation and hemorrhagic complications, especially in long-term therapy. Prevalence of thrombocytopenia (platelet count, 97 μg/dL), the risk being higher than with other anticonvulsants or MS [69]. The risk can be higher in patients also on topiramate, which could interact with VPA increasing the inhibition by either drug on the urea cycle [70]. The US Food and Drug Administration warned that the combination of both drugs can increase the risk of hyperammonemia and recommended that patients should be encouraged to contact their healthcare professional immediately if they experience symptoms related to oligohydrosis or hyperthermia [71]. In both psychiatric and epileptic patients, weight gain with an increase in body mass index is a common side effect of VPA, which seems to be associated with metabolic disturbances such as hyperinsulinemia and insulin resistance, and hyperleptinemia and leptin resistance. Dyslipidemia can appear, as well as metabolic syndrome, with a higher risk of long-term vascular complications such as hypertension and atherosclerosis [72]. Finally, VPA can precipitate alopecia in up to 12% of patients in a dose-dependent relationship, so that incidences up to 28% are observed with high concentration exposures to the compound [73]. Alopecia is thought to be caused by an interference with vitamins or trace metals such as zinc or selenium, and therefore patients should be warned to avoid taking valproate during meals to prevent its chelating effect on food [74]. Biotin supplement can be another strategy, given that VPA can cause biotin deficiency and may lead to low serum and liver tissue biotinidase enzyme [75]. 3.1. Treatment with VPA After initiation or change of dose, steady state is achieved in 3-4 days. Classically therapeutic serum levels of 50-125 μg/mL are targeted, with blood drawings obtained 8-12 hours after the last dose. In the elderly, however, target levels in the range of 65-90 μg/mL are recommended, which are usually obtained with daily dosages between 750 and 1500 mg. Serum levels with CBC, platelets and liver function tests, are recommended every 1-2 weeks in the first two months of treatment. In long-term treatment, serum levels should be checked every three months, and a CBC with platelets and liver function tests should be obtained every six months [76].

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4. CARBAMAZEPINE In Japan, in the 1960s, the anticonvulsant carbamazepine (CBZ) was observed to improve the mood in patients with epilepsy. In 1971, a first, open-label study in BD patients was published [77]. In 1980 it was demonstrated that CBZ could be effective for the treatment of BD, its action being hypothesized to be based on a selective limbic activity and an antikindling effect [78]. In double-blind, placebocontrolled trials, CBZ proved superiority over placebo for the treatment of mania, and an efficacy comparable to that of lithium [79]. Its effectiveness for maintenance, prophylactic treatment of BD is controversial [80, 81], as well as its efficacy in the treatment of depression. Table 4: Carbamazepine’s pharmacokinetic interactions Drugs whose metabolism is induced by carbamazepine

Drugs inducing metabolism of carbamazepine

Anticoagulants Aripiprazole Buprenorphine Bupropion, with increased levels of toxic metabolite Clozapine Cyclophosphamide Haloperidol Lamotrigine Lapatinib Mianserin Nefazodone Sertraline Temsirolimus tacrolimus

CYP3A4 inducers Phenobarbital Phenytoin

Drugs inhibiting metabolism carbamazepine (risk of toxicity)

Other significant interactions

of

CYP3A4 inhibitors (macrolides, antifungals, protease inhibitors). Fluoxetine Grapefruit juice Isoniazid

Clozapine: Could have an increased risk of agranulocytosis with carbamazepine. MAOIs: Hypertensive crisis. Tricyclic antidepressants: Additive heart side effects and anticholinergicity. Valproic Acid: Increased 10,11-epoxide levels, especially with valpromide.

After oral absorption, CBZ achieves steady plasma levels after 2-5 days [82]. Its metabolization by the liver generates some toxic compounds. CBZ is a CYP450

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inducer, thus it may increase clearance of many drugs (Table 4), decreasing their concentration in the blood to infratherapeutic levels and reducing their desired effects. CBZ can also induce its own metabolism, and therefore in long-term use its effectiveness can decrease. About 50% of patients on CBZ suffer from a host of side effects. Some of them are dose-dependent, such as leukopenia (affecting to 15-20% of patients, more frequently in the first months of treatment), lethargy, diplopia, cognitive and motor coordination impairment and nausea, vomiting and/or constipation. Less commonly, cardiac arrhythmias can occur, with conduction delay and congestive heart failure [83]. Elderly women seem to be especially at risk of cardiac side effects, even at slightly elevated plasma levels [84]. Aplastic anemia and agranulocytosis are rare. CBZ is a drug than can often precipitate hyponatraemia. About half of elderly patients with hyponatraemia, irrespective the causes, have features typical of the syndrome of inappropriate antidiuretic hormone secretion [85]. CBZ is also associated to changes of serum T4 concentrations that have been attributed to induction of the hepatic P-450 enzyme system [86]. In patients with no thyroid disorder, there seems not to be any clinical relevance, due to adaptive response, but in T4-supplemented hypothyroid patients this adaptation is lacking, thus subclinical or overt hypothyroidism can be precipitated by CBZ, therefore thyroid function monitoring is recommended [87]. Severe hypersensitivity reactions such as Stevens-Johnson syndrome have also been reported, while CBZ is the compound more frequently associated to Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) [88]. Predictors of response to CBZ in acute treatment are dysphoric or mixed mania, multiple episodes, rapid cycling, a lack of family history, an abnormal EEG, and secondary mania [89-91]. CBZ is considered the last choice MS in the treatment of elderly BD patients, given its side effect profile [76]. Before starting treatment, a laboratory evaluation with CBC, platelet count, liver function tests and urianalysis should be obtained. EEG, electrolyte studies, and TSH are also useful at baseline [1]. Treatment can be initiated in most patients at 200 mg twice daily followed by weekly increments of 200 mg. Therapeutic levels are not well established, but peak values are recommended not to exceed 10-12 μg/mL [92]. Serum CBZ level should be checked every 1-2 weeks during the first 2 months of treatment, along with monthly CBC, platelets and liver function tests. In long-term therapy, serum CBZ

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levels should be obtained every 3 months, and CBC, platelets and liver function tests every six months [76]. 5. LAMOTRIGINE A phenyltriazine, lamotrigine (LTG) was originally synthesized based on the observation that folate was proconvulsant and that many anticonvulsants then available were folic acid antagonists, so new compounds were developed derived from pyrimethamine, an antifolate antiprotozoal drug. LTG was one of those derivatives and was found to have considerable anticonvulsant activity in animal models, although it ultimately proved to be only a much weak inhibitor of dihydrofolate reductase compared with the parent compound. It was first tried as a MS after there was a general trend to try anticonvulsants in BD and on the basis of its potent anti-kindling effects and in the belief that its sodium channel blockade and resultant anti-glutamatergic activity might be helpful for the treatment of the disease [93]. A wide, ambitious Phase II development program showed effectiveness in maintenance therapy for patients with bipolar I disorder, with a significant delaying in time to intervention for any mood episode. It also showed significantly delayed time to intervention for a depressive episode, but limited efficacy in delaying time to intervention for a manic/hypomanic episode, compared with placebo. Efficacy in the short-term treatment of mood episodes could be found for LTG but no so in the treatment of acute mania [94]. Further experience has confirmed that LTG is more effective than placebo in preventing depressive relapses, with fewer total side effects than lithium [95]. LTG exhibits first-order linear kinetics, with a half-life of 13.5 hours and a volume of distribution of 1.36 L/kg [96]. Oral absorption is rapid and complete, with an absolute bioavailability of 98% and a plasma Cmax occurring from 1.4 to 4.8 hours. Its bioavailability is not affected by food. The metabolism pathway is glucuronic acid conjugation, its metabolite being an inactive 2-n-glucuronide conjugate. LTG has fewer drug interactions than other anticonvulsants, but its half-life can be shortened by CBZ of phenytoin. In turn, LTG causes an increase in concentrations of carbamazepine-10,11-epoxide, the main metabolite of CBZ [97]. VPA markedly increases the half-life of LTG and decreases its clearance, so a slower titration when combining both drugs is advisable, in order to prevent serious side effects (see below). LTG, in turn, seems to cause a small but significant 25% decrease in steady-state VPA plasma concentration [98]. Sertraline can delay the metabolism of LTG, but this interaction seems to lack clinical significance [99].

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Side effects of LTG include ataxia, dizziness, gastrointestinal malaise, and rarely hepatic failure [100]. Rash can appear in 10% of patients, and can be severe. Stevens-Johnson syndrome (SNS) is a rare hypersensitivity reaction with severe rash, fever, lymphadenopathy, hepatic dysfunction, blood disorder, and disseminated intravascular coagulation with multi organ dysfunction. Concomitant use of VPA raises the risk of this side effect as a result of an increase of LTG plasma levels due to enzymatic interaction [101]. SNS can progress to Toxic Epidermal Necrolysis or Lyell Syndrome [102], a severe condition with a mortality of about 30-40%. Although some reviews find that the occurrence of serious drug eruptions are rare with LTG, special caution is advisable given their life-threatening consequences [103]. Severe reactions with serious outcomes, such as multiorgan hypersensitivity reactions, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and septic meningitis have been reported in patients treated with LTG, as has been warned by the U.S. FDA [104]. 5.1. Treatment with LTG Before starting treatment no specific workout is required. Periodic checking of blood urea, creatinine, as well as liver function tests can be a cautious approach. To avoid the occurrence of rash, initial dosage must be at 25 mg twice daily (12,5 mg in co-therapy with VPA), and titration must be slow with fortnightly increments of 25 mg twice daily, to reach a maximum dosage of 200-400 mg daily. In case of emergence of rash, LTG should be immediately stopped. The more common forms are fine red spots that do not merge together, are not tender to the touch, but may be itchy, with no accompanying fever or flu-like symptoms, either before or at the same time as the rash. In this case the rash peaks within days and settles in 10-14 days. Rarer, more serious rash are associated with a severe, potentially life-threatening reaction, and are those variants that are accompanied by fever, flu-like symptoms or lack of appetite, or involve the lining membranes of the eyes, lips, mouth, nostrils, genital or anal areas, or are prominent on the neck and upper trunk, or consist of merging, widespread red swollen rashes sometimes with round red target-like spots, or comprise purplish, small spots or larger areas of skin discoloration that, when pressed with the finger, do not go white as other rashes do, and are tender to the touch, or skin swelling and redness all over the body, with or without widespread shedding of the skin (sometimes in large sheets) [105]. Specialist consultation and, if necessary, hospitalization should be considered. Rechallenging is a controversial issue.

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Although successful trials have been reported, it is advised to avoid restarting LTG within four weeks of the initial rash [106, 107]. 6. OTHER ANTICONVULSANTS LABELLED AS MS 6.1. Oxcarbazepine and Eslicarbazepine A 10-keto-congener of CBZ, Oxcarbazepine (OXC) has a ketone in place of the carbon-carbon double bond on the dibenzazepine ring at the 10 position. This structural difference seems to be the cause for a different interaction and hematological profile as compared to that of CBZ, a compound with which OXC shares its mechanism of action, namely, sodium channel inhibition. Metabolism consists in a rapid reduction to form monohydroxy derivatives (MHD), i.e., eslicarbazepine (80%) and (R)-licarbazepine (20%) [108], the former being is the main active agent during OXC therapy. MHD are eliminated by renal excretion ( 50%) and, marginally, by hydroxylation [109]. The limited involvement of oxidative microsomal enzymes, explains why OXC has fewer drug interactions compared with other anticonvulsants, especially CBZ [110]. An inducer of the CYP3A4 isoenzyme, (thus reducing the effect of combined oral contraceptives [111]) it also acts as an inhibitor of the 2C19 isoenzyme (with the potential to raise levels of other agents, for example, phenytoin [112]). OXC has been tried in BD more than 20 years [113]. Available studies predominantly analyze the effectiveness and safety of OXC in the treatment of mania. A study found it as effective as VPA, and better tolerated, in patients with acute mania [114]. In a Cochrane review, the compound did not differ from other active agents in adults and seemed to have a poorer tolerability profile compared to placebo [115]. A pilot, randomized clinical trial, found that OXC could be useful as adjunctive therapy to lithium both in acute and long-term treatment of BD [116]. Another, 52 week randomized assignment study, compared OXC added to lithium, versus placebo added to lithium in euthymic type I and II BD subjects with at least 2 episodes in the previous 12 months. The authors found that OXC was well tolerated and might have some prophylactic efficacy with regards to impulsivity and perhaps mood episodes in patients on lithium [117], thus confirming the impression that the compound can be particularly useful as an add-on treatment in BD for whom previous treatments have failed, or in patients who have difficulty tolerating adequate dosages of standard approved treatments [118]. However,

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another Cochrane review concluded that the insufficient methodologically rigorous evidence base impedes to provide guidance on the use of OXC in the maintenance treatment of BD, and called for good quality randomized controlled trials examining the therapeutic potential of this agent [119]. Therapeutic drug monitoring of MHD is not routinely warranted but may be beneficial in optimizing seizure control at the extremes of age, in renal insufficiency, or to determine the significance of potential drug interactions, or to rule out noncompliance [120]. In any case, treatment with OXC in BD is an offlabel use, so it would be wise to consider all those pretreatment and monitoring tests recommended for CBZ. Eslicarbazepine (ELZ) acetate is a new antiepileptic drug related to CBZ and OXC which also stabilizes the inactivated state of voltage-gated sodium channels [121]. Unlike OXC, ELZ acetate is extensively converted to ELZ. At clinically relevant doses (400-1,600 mg/day) ELZ has linear pharmacokinetics (PK) with no effects of gender or moderate liver impairment. Dose adjustment is recommended for patients with renal impairment, as ELZ is eliminated primarily (66%) by renal excretion. Clearance is induced by phenobarbital, phenytoin, and CBZ. On the other hand, ELZ decreases plasma exposure of oral contraceptives and simvastatin in a dose-dependent manner [122]. As an anticonvulsant, ELZ has shown a greater tolerability and efficacy than CBZ and OXC [123]. However, experience in the treatment of BD is minimal [124]. 6.2. Levetiracetam An (S)-enantiomer of the ethyl analog of piracetam, levetiracetam (LVT) is an anticonvulsant whose mechanism of action has not been precisely determined. It is a relatively safe drug which does not require dose adjustment in patients with mild to moderate liver impairment, although reduction to half of the usual dose is proposed to initiate therapy in patients with severe cirrhosis [125]. LVT is predominantly eliminated renally as unchanged drug. Therefore, in patients with altered renal function dosage should be reduced [126]. LVT has a favorable interaction profile, with no modifications in plasma concentrations of CBZ, VPA, topiramate, or LTG in co-therapy [127]. Pretreatment tests and monitoring requirements are minimal, with periodic CBC and liver function tests being recommended [76]. The most commonly reported side-effects are neurobehavioral, with fatigue, nervousness, generalized weakness, irritability, agitation, emotional lability, depression, mood swings, vertigo, anxiety,

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unsteadiness, seizures, memory loss, confusion, increased reflexes, paresthesias, aggression, cognitive decline, and increased risk of suicide [128], as well as psychosis [129]. LVT has been reported to be effective in the treatment of mania in elderly BD patients [130], and has also been found to be helpful as and adjunctive to treat manic behavior in patients hospitalized with dementia [131]. However, in other recent study LVT as adjunctive therapy could not be shown to be superior to placebo in the short-term treatment of middle-aged depressed BD patients [132]. Even though it seems to be a well-tolerated drug in the elderly [133], until new findings disprove it, off-label LVT should be a last choice drug in the treatment of BD in this group, as experience is scarce and dissimilar. 6.3. Topiramate Topiramate is an anticonvulsant which was reported to be effective in monotherapy [134] or as an adjunctive for some rapid-cycling patients [135]. However, it is less effective than lithium for the treatment of mania [136], and a Cochrane review concluded that there is insufficient evidence on which to base any recommendations regarding the use of topiramate in any phase of BD, either in monotherapy or as an adjunctive therapy [137]. On the other hand, as treatment of BD with this agent is an off-label use of a drug with a well-established risk of neuropsychological impairment [138], it seems that topiramate should be a lastresort for elderly BD. 6.4. Gabapentin Gabapentin was very popular as a MS, as it showed an anticonvulsant effectiveness comparable to that of CBZ and VPA, and after an improvement in general well-being was reported by epileptic patients treated with it [139]. As a result, prescriptions sky-rocketed in a few years [140]. However, two clinical trials found negative results with this agents in monotherapy [141] and as an adjunctive [142], and currently gabapentin is invoked to demonstrate the wide use of promotional tactics by the industry [143, 144]. 7. ANTIPSYCHOTICS As recently pointed out by Belmaker [145], the effectiveness of older antipsychotics in the treatment of BD, and specifically for the treatment of depressive episodes, was already noted by Kein and Davis in the first edition of Diagnosis and Drug Treatment of Psychiatric Disorders, which was the first

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textbook of psychopharmacology [146], and use of other first-generation antipsychotics (FGA) for prophylaxis of BD has been widespread around the world, especially for patients non-adherent with lithium or where blood testing was unavailable [147]. FGA have been for decades considered the fastest-acting treatment for acute manic agitation, and it was shown that even though lithium was equally effective after three weeks, FGA have a more rapid onset of action [148]. Second-Generation Antipsychotics (SGA) seem to be equally effective and better tolerated in the shortterm as they are less prone to causing extrapyramidal symptoms. In the treatment of acute mania, haloperidol has been proved to be equally effective as SGAs such as risperidone [149], olanzapine [150], and quetiapine [151], all of them wellestablished antimanic agents. In a placebo-controlled study, haloperidol showed greater efficacy than ziprasidone, which in turn showed a superior tolerability profile [152]. On the other hand, in another study, aripiprazole, which is an effective antimanic agent [153], was found to be superior to haloperidol [154]. Another SGA, asenapine, has been found to be useful for the treatment of mania [155], for which it has been approved, as has paliperidone for the manic symptoms of schizoaffective disorder. Amisulpride, finally, has been shown to be effective as an adjunctive to VPA in the treatment of acute mania [156]. To summarize these findings, a comprehensive study which reviewed 68 randomised controlled trials (16,073 participants) concluded that in the treatment of acute mania antipsychotic drugs are significantly more effective than MS, and that risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes [157]. Some antipsychotics are also useful in the treatment of bipolar depression and mixed states. Quetiapine is effective in both bipolar I and bipolar II depression [158], and is approved as an adjunctive in major depression, whereas lurasidone has been proved effective for bipolar depression both in monotherapy [159] and as an adjunctive [160] to lithium and VPA. In contrast, ziprasidone monotherapy has not been found to have any statistically significant advantage in efficacy over placebo as an antidepressant [161]. Maintenance, however, is a more controversial issue. Studies are generally too short to allow for evaluation of a true prophylactic action. The use for maintenance of agents like risperidone [162], despite being common, is not adequately supported by randomized trials comparing them with other treatments. In a Cochrane database review, olanzapine was found to prevent further mood

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episodes in patients who had responded to the agent during an index manic or mixed episode and who had not previously had a satisfactory response to lithium or VPA. However, the authors concluded that the current evidence was stronger for lithium as first line maintenance treatment of BD [163]. Such a poor impression must be relativized, as the same group of authors concluded in other study that the evidence supporting the efficacy of VPA, a well-established MS, in the long-term treatment of BD was “limited” [164]. A study by Keck et al., analyzed the effectiveness of aripiprazole for maintenance treatment of patients with BD in a randomized, double-blind, parallel-group, placebo-controlled, multicenter study enrolling 633 bipolar I patients in three countries. After meeting stabilization criteria for 6 consecutive weeks, 161 patients were randomly assigned to aripiprazole or placebo for a 26-week, doubleblind phase. The requirement for six weeks of clinical stabilization allowed to discard that relapse on placebo could be caused by withdrawal effects. The primary endpoint was time to relapse for a manic, mixed, or depressive episode (defined by discontinuation caused by lack of efficacy). Patients who received aripiprazole had significantly fewer relapses than those on placebo, and aripiprazole was superior to placebo in delaying the time to manic relapse, with no significant differences in time to depressive relapse [165]. This study, which has been widely cited in discussing the use of aripiprazole for BD, was criticized on the grounds of an insufficient duration to demonstrate maintenance efficacy; a limited generalizability due to its enriched sample; a possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment despite the 6-week stabilization phase; and a low overall completion rate [166]. Long-acting injectable antipsychotics have often been used for the maintenance treatment BD as a strategy to reduce non-adherence. Although long-acting FGA have been studied and used, none of them has been approved for use in this disease. Among the long-acting SGA, only depot risperidone has been studied and approved for the maintenance treatment of BD [167], while other long-acting SGA, like olanzapine, paliperidone and aripiprazole are not currently approved. 8. COMMENTARY BD is a heterogeneous, common, generally long-standing disorder. Clinical heterogeneity stems from the varied possible phases and states (manic, depressive, mixed, euthymic), and the division of the illness into bipolar I disorder, when if there is at least one manic episode, and bipolar II disorder if there are at least one

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hypomanic episode and one major depressive episode, with a cyclothymic disorder category for those with less severe symptoms [168]. The description of its possible clinical presentations is compounded by the co-occurrence of psychotic symptoms, either mood-congruent or mood-incongruent, the comorbidity with other disorders (especially addictions), the different course and outcome patterns (with the possibility of rapid and even ultra-rapid cycling [169] and a higher risk of death by suicide [170]). BD is a common disorder, as pointed out for a lifetime prevalence of DSM-IV BD, according to the U.S. National Comorbidity Survey Replication, of 3.9%, which is a pretty high prevalence even though according to the same study, about half of Americans will meet the criteria for a DSM-IV disorder sometime in their life [171]. If we expand the concept, up to an eighth to a quarter of the general population [172] would satisfy the criteria defining the umbrella term of bipolar spectrum [173]. BD is on the other hand a long-standing condition which can start even in childhood, with its onset peaking in late adolescence and early adulthood [174]. In the elderly two forms can be distinguished depending on age of onset. Early-onset BD (EBD) elderly patients have a high familial rate of BD, a clinical presentation with predominating manic and mixed symptoms, and longer inpatient stays, whereas those with Late-onset BD (LBD) have a weaker family history, fewer manic and mixed symptoms, more psychotic symptoms in the context of depression and shorter inpatient stays. Both EBD and LBD elderly patients show a high medical and neurological comorbidity [175]. Pharmacological treatment of BD is complex and changes in the different phases and states of the illness. Antidepressants often precipitate and accelerate mood swings. Lithium is a perilous drug with a narrow therapeutic window and in the last decades a number of challengers attempt to dispute its preeminency in longterm, prophylactic treatment of BD. However, such a display of alternative drug therapies seems not to be a panacea, but rather a source of polypharmacy, as some years ago a symposium on BD treatment posed the question whether this condition could be treated with less than five drugs [176]. Elderly patients with EBD will have certainly been exposed to a significant amount of different drugs (antidepressants in depressive episodes, antipsychotics for psychotic symptoms and acute manic agitation, MS, whatever they be, in any moment or for maintenance treatment), and such an accumulative long-term dosage will probably have caused a host of iatrogenic phenomena (tardive dyskinesia due to antipsychotics, thyroid or renal impairment derived from

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chronic lithium exposure). On the other hand, old age increases the vulnerability to neurologic adverse effects and is associated with progressive organ dysfunction, which decreases resilience to all kind of side effects. Patients with BD treated with SGA have rates of metabolic syndrome as high as those with schizophrenia treated with this same group of agents, which suggests a shared susceptibility to antipsychotic-related metabolic dysregulations that is not primarily related to psychiatric diagnosis or concomitant MS treatment [177]. This is an important issue given that obesity and the metabolic syndrome are common in patients with BD, who may be under-evaluated for cardiovascular risk [178]. A retrospective study on pharmacotherapy trends and treatment response in a series of 138 acutely ill, elderly BD patients, found that standard MS (lithium, valproate, CBZ, and LTG) were the most prescribed medications (68%), followed by antipsychotics (54%) and antidepressants (34%). Interestingly, even though an aggressive treatment can be inferred and combination therapy was more common than monotherapy (57% vs. 38%), remission was achieved in only 35% of subjects, with 32% showing no significant improvement [179]. In a European, 2-year prospective, observational study which included 475 elderly patients (>60 years of age), LBD elderly used less often lithium, FGAs and anticholinergics compared to EBD elderly, whereas there were no marked differences at baseline between LBD elderly and EBD elderly regarding anticonvulsant, SGA and antidepressant use. However, after an acute manic or mixed relapse there was a tendency to an increase in the prescription of SGA and a concomitant decrease of FGAs in EBD. This implies that elderly patients with a longer BD career are maintained on drugs that are thought to be especially hazardous in old age [180]. As acute treatment of BD is expected to be short-term, maintenance and relapse prevention is the critical issue in planning drug treatment for elderly people suffering from the condition. Unfortunately, clinicians are not helped by reliable evidence, as elderly patients are usually excluded from clinical trials which are the source for guidelines that periodically attempt to shed light on this issue, such as those recently issued by the Canadian Network for Mood and Anxiety Treatments (CANMAT) and the International Society for Bipolar Disorders (ISBD) [181]. A comprehensive analysis by Geddes and Bries [136] concludes that lithium reduces relapse in BD compared with placebo, whereas valproate, CBZ, and LTG seem as effective as lithium in reducing relapse. Cognitive therapy and patient or family education may reduce the risk of relapse, but studies have given conflicting

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results. It is uncertain whether antidepressants can prevent relapse, but they may induce mood instability or manic episodes. Finally, olanzapine may reduce relapse, but long-term use may be associated with weight gain. On the other hand, as Shulman argues [28], the use of lithium is decreasing at a significant rate in older adults, even though all evidence-based treatment guidelines and systematic reviews still recommend lithium as a first-line treatment for BD. Although lithium poses significant concerns in the older population, including the risk of drug interactions that cause toxicity associated with decreased creatinine clearance, evidence has accumulated suggesting that lithium may have neuroprotective properties and little evidence supports the use of alternatives to lithium such as other MS, including SGAs, in the elderly. Accordingly, the author argues that before lithium is discarded as a first-line agent, it should be ensured that the guidelines for lithium treatment are safe, practical and effective. In the uncertainty about which is the most accurate therapeutic attitude towards BD elderly, a careful, judicious application of information obtained with other age groups, tailored to the individual patient, together with an attentive supervision to prevent and detect adverse effects, seems currently to be the only possible strategy in long-term treatment. A wise approach will be not to discard older drugs to adopt newer ones that could be insufficiently tested in elderly patients. ACKNOWLEDGEMENTS The author is indebted to the invaluable teachings of the patients who have reported to him their personal experiences after being treated with some drugs included in this chapter. CONFLICT OF INTEREST The authors confirm that this chapter contents have no conflict of interest. REFERENCES [1] [2] [3] [4] [5]

Sachs GS. Bipolar mood disorder: practical strategies for acute and maintenance phase treatment. J Clin Psychopharmacol 1996; 16 (suppl 1): 32-47. Fountoulakis KN, Gonda X, Vieta E, et al. Class effect of pharmacotherapy in bipolar disorder: fact or misbelief? Ann Gen Psychiatry 2011; 10(1): 8. Lazarus JH. Endocrine and metabolic effects of lithium. New York: Plenum Publishing Corporation, 1986 Healy D. The creation of psychopharmacology. Cambridge, Massachussets: Harvard University Press, 2002. Jefferson JW. Lithium: A therapeutic magic wand. J Clin Psychiatry 1989; 50: 81-6.

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[165] Keck PE Jr, Calabrese JR, McQuade RD, et al. A randomized, double-blind, placebo-controlled 26week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry 2006; 67: 626-37. [166] Tsai AC, Rosenlicht NZ, Jureidini JN, et al. Aripiprazole in the maintenance treatment of bipolar disorder: a critical review of the evidence and its dissemination into the scientific literature. PLoS Med 2011; 8(5): e1000434. [167] Gigante AD, Lafer B, Yatham LN. Long-acting injectable antipsychotics for the maintenance treatment of bipolar disorder. CNS Drugs 2012; 26: 403-20. [168] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington: American Psychiatric Publishing, 2013. [169] Bauer M, Beaulieu S, Dunner DL, et al. Rapid cycling bipolar disorder--diagnostic concepts. Bipolar Disord 2008; 10: 153-62. [170] Chesney E, Goodwin GM, Fazel S. Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry 2014; 13: 153-60. [171] Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSMIV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62:593602. [172] Angst J, Gamma A, Benazzi F, et al. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 2003; 73: 133-146. [173] Akiskal HS, Cassano GB, Musetti L, et al. Psychopathology, temperament, and past course in primary major depressions. 1. Review of evidence for a bipolar spectrum. Psychopathology 1989; 22: 268-77. [174] Goodwin FK, Jamison KR. Manic-depressive illness. Bipolar disorders and recurrent depression, Second Edition. New York: Oxford University Press, 2007. [175] Depp CA, Jeste DV. Bipolar disorder in older adults: a critical review. Bipolar Disord 2004; 6: 34367. [176] Gershon S (Chair). Symposium I. Rational Polypharmacy: Can we treat bipolar disorder with fewer than five medications? Bipolar Disord 2005; 7(Suppl 2): 15-21. [177] Correll CU, Frederickson AM, Kane JM, et al. Equally increased risk for metabolic syndrome in patients with bipolar disorder and schizophrenia treated with second-generation antipsychotics. Bipolar Disord 2008; 10: 788-97. [178] Fiedorowicz JG, Palagummi NM, Forman-Hoffman VL, et al. Elevated prevalence of obesity, metabolic syndrome, and cardiovascular risk factors in bipolar disorder. Ann Clin Psychiatry 2008; 20: 131-7. [179] Beyer JL, Burchitt B, Gersing K, et al. Patterns of pharmacotherapy and treatment response in elderly adults with bipolar disorder. Psychopharmacol Bull 2008; 41: 102-14. [180] Oostervink F, Boomsma MM, Nolen WA; EMBLEM Advisory Board. Bipolar disorder in the elderly; different effects of age and of age of onset. J Affect Disord 2009; 116: 176-83. [181] Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord 2013; 15: 1-44.

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CHAPTER 9

Antidepressants Juan Medrano* Ezkerraldea - Enkarterri Mental Health Community Services, Bizkaia´s Mental Health Network, Portugalete, Bizkaia, Spain Abstract: Antidepressants are drugs used for the treatment of depression and many other psychiatric conditions. Albeit belonging to different chemical families and with a number of mechanisms of action, all of them enhance neurotransmitters at the synaptic cleft. They have a range of adverse effects and effectiveness compared with placebo, according to meta-analysis. However, they have shown to be efficacious in the elderly. Second-generation antidepressants are safer and better tolerated, but not devoid of side effects, something not to be forgotten when treating a population in which frailty and polypharmacy are common.

Keywords: Antidepressants, Arrhythmia, Bipolar disorder, Bupropion, Citalopram, Depression, Duloxetine, Early onset depression, Escitalopram, Hypericum perforatum, Hyponatremia, Late onset depression, Lithium, Mirtazapine, Monoamine oxidease Inhibitors (MAOIs), Obsessive-compulsive disorder, Pharmacokinetic interactions, Rapid cycling, Seizures, Selective serotonin reuptake inhibitors, Serotonin and noradrenalin reuptake inhibitors (SSRIs), Sertraline, Suicide, Trazodone, Tricyclic antidepressants. 1. INTRODUCTION Antidepressants (ADPs) or thymoleptics are a group of drugs belonging to different chemical classes and with different mechanisms of action which converge in an optimization of synaptic transmission. Some of them inhibit neurotransmitter reuptake, some others block neurotransmitter metabolizing, while others agonize or antagonize different receptors. They act on several pathways and systems, with varied selectivity. Even though when ADPs entered the pharmacopeia, less than 60 years ago, depression was considered a rarity, nowadays, according to WHO, it is estimated to affect more than 350 million people of all ages all over the world, being the leading cause of disability *Corresponding author Juan Medrano: Ezkerraldea - Enkarterri Mental Health Community Services, Bizkaia´s Mental Health Network, Portugalete, Bizkaia/Vizcaya, Spain; Tel: 3444596505; Fax: 3444596511; E-mail: [email protected] Unax Lertxundi, Juan Medrano and Rafael Hernández (Eds.) All rights reserved-© 2015 Bentham Science Publishers

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worldwide, and a major contributor to the global burden of disease [1]. The same source remarks that such a ubiquitous disease can benefit from effective treatments, amongst which ADPs obviously occupy a preeminent place. Therefore, ADPs are widely used agents which have impregnated the culture [2] and the environment (see chapter 2). They are successful agents from a mere business perspective, although their real-life usefulness are more than criticized as in many clinical trials their effectiveness is similar to that of placebo [3]. On the other hand, their safety is being scrutinized as to whether their use is associated with suicidal behavior. In any case, ADPs are so relevant a group that the years of their rise were dubbed “The Antidepressant Era” by David Healy [4]. Finally, ADPs are drugs under suspicion of biased research and fabricated publication of findings, with some recent examples of meaningful data that have not been published and were not available in clinical trial registry reports [5], and of a loss of information due to the coding systems for adverse effects [6]. From the clinical perspective, perhaps the most salient feature of ADPs is their long latency of action, or their slowness to produce their therapeutic effect when they are used to treat depression (2 to 3 weeks). This latency of action is purportedly due to adaptive changes in neurotransmitter receptor sensitivity and has been approached by several means in an attempt to achieve a faster therapeutic response. An outstanding characteristic of the years of the “antidepressant era” after the upcoming of fluoxetine was that clinicians became used to the name ADPs by their identified mechanism of action. Although it was preceded by other mechanism-of-action label, such as MAOI, speaking of SSRI and other categories became somewhat catchy. Based on a serotoninergic theory of depression that was later shown to be flawed, agents able to potentiate serotonin transmissions were developed to be thereafter accompanied by “Serotonin and Norepinephrine Reuptake Inhibitors” (SNRIs) that were supposed to be more efficacious ADPs as they acted on two neurotransmitter systems. However, the equation is not that simple and sometimes learning that a given compound has effects on two pathways only means that it can be assumed that the agent has a richer range of side effects and not exactly a greater therapeutic activity. ADPs can also be divided according to their clinical profile. Some of them are “disinhibitors” and can be especially useful in inhibited depressions with psychomotor retardation. This is the case of agents like bupropion, fluoxetine, and imipramine. On the other hand, other ADPs are “sedative” and can be useful to

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treat agitated depressions or depressions with anxiety and insomnia. Trimipramine, mianserin, mirtazapine, are sedative ADPs. Apart from depression, ADPs are used to treat a host of conditions, especially anxiety disorders. In fact, far from being specific remedies, ADPs show a range of actions, some beneficial, some untoward. That richness of actions has helped some agents to be re-converted into ADPs when they were initially intended to be marketed for other indications, as was the case of duloxetine [7]. Another distinctive feature is that ADPs are very frequently used in combination. ADPs are increasingly a part of polypharmacy cocktails in chronic, elderly people, which raises concerns given their pharmacokinetic and pharmacodynamic interactions. On the other hand, they are frequently used with other ADPs to obtain a more intense therapeutic action, or with adjunctive agents that are added to the patient’s regime in an attempt to augment thymoleptic action. ADPs are usually divided into different classes, but no homogeneous criteria are used for classification. The most clearly delineated classes include some classes defined by mechanism of action (Monoamine Oxidase Inhibitors [MAOIs], Selective Serotonine Reuptake Inhibitors [SSRI], Serotonin and Neorepinephrine Reuptake Inhibitors [SRNI]), and other defined by chemical structure (Tricyclics) (Table 1). 1.1. Tricyclic ADS (TCAs) Introduced in Psychopharmacology in the late 1950s with imipramine, TCAs have been replaced in clinical use in most countries by newer ADPs. The main TCAs are tertiary amines such as imipramine, clomipramine and amitriptyline and secondary amines like desipramine or nortriptyline. Some tertiary amines like imipramine and clomipramine inhibit more selectively serotonin reuptake, while others like amitriptyline and doxepin display a balanced action on norepinephrine and serotonin. Secondary amine desipramine (a metabolite of imipramine) and nortriptyline (a metabolite of amitriptyline) are more selective norepinephrine reuptake inhibitors. Some others, like amineptin, are norepinephrine and serotonin reuptake inhibitors, a mechanism of action it shares with bupropion, a nontricyclic ADP. Table 1: Antidepressants Tricyclic ADPs: Imipramine, Amitriptyline, Clomipramine, Desipramine, Notriptyline, Doxepin, Lofepramine, Protriptyline, Amoxapine, Dosulepin/Dothiepin, Melitracen, Amineptine MAOIs: Irreversible:

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Table 1: contd…

Hydrazinic: Phenelzine Non-Hydrazinic: Tranylcypromine Reversible Reversible MAO-A inhibitors: Moclobemide, toloxatone, befloxatone Reversible MAO-B inhibitors: Selegiline SSRI: Fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, escitalopram SNRI: Venlafaxine, duloxetine, milnacipran, desvenlafaxine Others: Selective Norepinephrine inhibitors: Reboxetine Dopamine and norepinephrine inhibitors: Bupropion Tetracyclic compounds: Maprotiline, mianserin, mirtazapine Melatoninergic ADPs: Agomelatine Other: Trazodone, mirtazapine, nefazodone, vilazodone, vortioxetine

TCAs are considered the most potent ADPs, but they are also associated with potentially serious side effects, such as anticholinergic toxicity, and cardiovascular untoward effects. On the other hand, they are frequently lethal in overdose. Finally, they require a careful, slow titration that makes them difficult to use. 1.2. Monoamine Oxidase Inhibitors (MAOIs) MAOIs act by inhibiting the activity of the enzyme monoamine oxidase (MAO), and preventing the breakdown of monoamine neurotransmitters, which thereby increase their availability at the synaptic cleft. An enzyme isoform, MAO-A, preferentially deaminates serotonin, melatonin, epinephrine and norepinephrine, while MAO-B preferentially deaminates phenylethylamine and trace amines, whereas dopamine is equally deaminated by both types. Tyramine, a trace amine, present in the diet, can accumulate in patients taking MAOIs, triggering the tyramine pressor response or “cheese effect” (so-called because the large quantity of tiramine contained by cheese), which consists in an increase in systolic blood pressure of 30 mmHg or more that under certain conditions can be serious. Some agents selectively inhibit MAO-A, like clorgyline (not marketed), while others are selective MAO-B inhibitors (pargiline). On the other hand, MAO inhibition can be irreversible, with the MAOI covalently bonding to the enzyme and blocking it irreversibly, so that MAO activity will be blocked until the cell produces new enzymes, which takes approximately two weeks. Early MAOIs (either hydrazines, like phenelzine, or non-hydrazines, like tranylcypromine) were irreversible inhibitors. More recent MAOIs are reversible, which means that they

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can detach from the enzyme. There are selective MAO-A reversible MAOIs, like moclobemide, while other compounds, such as selegiline, selectively inhibit MAO-B in a reversible way. Combination of MAOIs with drugs enhancing serotonin transmission (ADPs, but also other agents like some opioids) can precipitate a serious, potentially fatal serotonin syndrome. To avoid such reaction, classically, a MAOI washout period of two weeks has been required before introducing another class of ADP (and vice versa). MAOI are effective ADPs which have been replaced by other alternatives, as they are difficult to use, and perilous in combination, while they require a special, low-tyramine diet. After moclobemide was introduced, more than 20 years ago, the only novelty has been transdermal selegiline, a new formulation for a MAO-B selectively inhibitor used before in the therapy of Parkinson’s disease. 1.3. Selective Serotonine Reuptake Inhibitors (SSRI) A chemically heterogeneous group, SSRI are agents whose therapeutic actions are related to potentiation of serotonin transmission by inhibiting reuptake from the synaptic cleft in a more or less specific way. Starting with zimelidine, a pioneer which was suspended after an association with Guillain-Barré syndrome was reported [8], and following with blockbusters like fluoxetine, paroxetine, sertraline and citalopram and escitalopram, SSRIs revolutionized the treatment of depression (and other conditions) with an easier therapeutic regime and a safer, more acceptable side-effect profile. However, they have been associated with a host of untoward effects, some of them potentially serious (as EKG QTc interval prolongation), and their pharmacokinetic interactions can be troublesome. They are also related to a discontinuation syndrome (more common with paroxetine and less frequent with fluoxetine) that can complicate treatment cessation. 1.4. Serotonin and Norepinephrine Reuptake Inhibitors (SRNI) Venlafaxine and its active metabolite, desvenlafaxine, as well as duloxetine and milnacipran and its stereoisomer levomilnacipran, are the available SRNIs. They are frequently used to treat pain and pain disorders and are also associated with discontinuation syndromes. 1.5. Other ADPs There is a range of ADPs not included in the above groups. Their chemical structures and mechanisms of actions demonstrate that heterogeneity is a characteristic of ADPs that precludes generalizations other that clinical action (or

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lack of efficacy, according to critics) and latency. Tetracyclic ADPs are those with a four-ring chemical structure. Maprotiline is a tetracyclic related to TCAs, while on the other hand mianserin is chemically and clinically similar to mirtazapine. Bupropion is a Dopamine and Norepinephrine Reuptake Inhibitor also used for tobacco cessation. Reboxetine is a Norepinephrine Reuptake Inhibitor. Agomelatine has a novel mechanism of action which combines its melatonin MT1 and MT2 agonist properties with a serotonin 5-HT2C antagonist effect. There are other ADPs with different mechanisms of action. Tianeptine acts by increasing serotonin uptake in the brain and reducing stressinduced atrophy of neuronal dendrites [9]. Trazodone is a Serotonin antagonist and reuptake inhibitor (SARI), which has hypnotic actions at low doses due to blockade of 5-HT2A receptors, as well as H1 histamine receptors and α1 adrenergic receptors, while higher doses recruit the blockade of the serotonin transporter (SERT) and turn trazodone into an ADP [10]. Nefazodone is an antagonist at the 5-HT2A receptors. Vilazodone is thought to act both by inhibiting serotonin reuptake and by partial agonism of 5-HT1A receptors. Vortioxetine is considered a multimodal serotonergic ADP as it shows actions including partial 5-HT1s receptor agonism, 5-HT7 antagonism, 5-HT3 antagonism, and inhibition of the serotonin transporter [11]. Some other substances used as ADPs, either alone or as add-on, include nutraceuticals such as folate [12], or omega-3 fatty acids [13], substances like S-Adenosyl-Methionine [14], and herbal remedies such as St. John’s wort or hypericum perforatum (which was a very popular treatment in Germany, where 2.7 million recipes were dispensed in 1993 [15], and 66 million daily doses were consumed in 1994, with a total cost of 61 million marks) [16]. 2. PHARMACOKINETICS For most ADPs, oral absorption is rapid and complete, and interaction with food is not significant, except for some agents as vilazodone, which is more completely absorbed on a full stomach or even with a light meal [17]. Generally, lipophilic substances have a large volume of distribution and their half-life is prolonged in elderly patients. Except for venlafaxine and desvenlafaxine, ADPs are highly protein- and tissue-bond. Liver metabolism is extensive [18]. Metabolism [9, 17-25] is summarized in Table 2. Some ADPs are strong P450 isozyme inhibitors. Fluvoxamine is a potent 1A2 inhibitor which can increase blood levels of substrates such as clozapine or olanzapine, which can become toxic. A significant interaction is that of paroxetine (a strong 2D6 inhibitor) with tamoxifen, a pro-drug which is converted into its active metabolite by 2D6. A study found that women treated with paroxetine while on tamoxifen showed an increased risk of death from breast cancer [26].

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Paroxetine at therapeutic dosage significantly inhibits as well the metabolism of tramadol to its active metabolite, thus reducing, albeit not abolishing, the hypoalgesic effect of tramadol. Pharmacodynamic interactions are also significant, with TCAs augmenting cardiovascular effects of antiarrythmics or antihypertensives and adding up anticholinergic effects to those of first-generation antipsychotics. Serotonin syndrome (see below) is a dramatic drug-to-drug interaction of serotoninergic ADPs. Table 2: Metabolism of ADPS Tricyclic ADPs Agent

Metabolism

Isozymes Inhibited

Amitriptyline

2C19, 1A2, 3A4, 2D6

2C19 (moderate), 2D6, 1A2, 2C9

Clomipramine

2C19, 1A2, 3A4, 2D6

2C19 (moderate), 2D6, 1A2, 2C9

Desimpiramine

2C19

2D6, 2C19

Dothiepin

2C19, 1A2, 3A4, 2D6

2C19, 2D6, 1A2

Doxepin

2C19, 1A2, 3A4, 2D6

2C19, 2D6, 1A2, 2C9

Imipramine

2C19, 1A2, 3A4, 2D6

2C19 (moderate), 2D6, 1A2, 3A4, 2C9

Lofepramine

CYP2D6 and/or CYP3A4

Nortriptiline

2C19

2D6, 2C19 MAOIs

Moclobemide

2C19, 2D6

Selegiline

CYP2B6, CYP3A4, CYP2A6.

CYP2D6 SSRIs

Citalopram

2C19, 2D6, 3A4

2D6 (weak)

Escitalopram

2C19, 2D6, 3A4

2D6 (weak)

Fluoxetine

2D6, 2C9, 2C19, 3A4

2D6 (strong), 2C9 (moderate), 2C19 (weak to moderate), 3A4 (weak to moderate), 1A2 (weak)

Fluoxetine

2D6, 2C9, 2C19, 3A4

2D6 (strong), 2C9 (moderate), 2C19 (weak to moderate), 3A4 (weak to moderate), 1A2 (weak)

Fluvoxamine

1A2, 2D6

1A2 (strong), 2C19 (strong), 2C9 (moderate), BA4 (moderate), CYP2D6 (weak)

Paroxetine

2D6, CYP3A4

2D6 (strong), 1A2 (weak), 2C9 (weak), 2C19 (weak), 3A4 (weak)

Sertraline

2C9, 2C19, 2D6, 3A4

2D6 (weak to moderate), 1A2 (weak), 2C9 (weak), 2C19 (weak), BA4 (weak)

Juan Medrano

194 Psychopharmacological Issues in Geriatrics Table 2: contd…

SNRI Desvenlafaxine

3A4

Duloxetine

2D6, CYP1A2

2D6 (moderate)

Milnacipran

50-60% unmetabolized, 3A4

3A4/5 (weak)

Venlafaxine

CYP2D6 and CYP3A4

2D6 (weak to moderate), 1A2 (weak), 2C9 (weak), 2C19 (weak), BA4 (weak)

Agomelatine

1A2, 2C9/19

None known

Bupropion

2B6

2D6 (moderate)

Other ADPs

Mianserin

CYP2D1, 2D4, and 2D6.

Mirtazapine

CYP2D6, CYP1A2, and CYP3A4

None known

Nefazodone

CYP3A4

CYPBA4 (strong), CYP2D6 (weak)

Reboxetine

CYP3A4

CYP2D6 (weak)

Tianeptine

Not metabolized by liver

None known

Trazodone

3A4, 1A2

None known

Vilazodone

3A4, 2C19, 2D6

CYP2D6 (weak)

Vortioxetine

CYP2D6, CYP3A4/5, CYP2C9, CYP2C19, CYP2A6, CYP2C8 and CYP2B6

CYP2D6 (inducer)

Hypericum Perforatum is an enzyme inducer which can reduce levels and effectiveness of warfarin and phenprocoumon (by 2C9 induction), of cyclosporine (by induction of 3A4 and the transport protein P-glycoprotein), of oral contraceptives (by induction of 1A2 and 3A4), of theophylline (by induction of 1A2), of digoxin (by induction of transport protein P-glycoprotein), HIV protease inhibitors (as an inducer of 3A4), of HIV non-nucleoside reverse transcriptase inhibitors (by induction of 3A4), and of anticonvulsants such as carbamazepine, phenobarbitone and phenytoin (by induction of 3A4). On the other hand, as a serotoninergic agent, Hypericum Perforatum can interact with other products as SSRIs and Triptans, increasing serotonin effects [27]. 3. CLINICAL USES 3.1. Depression ADPs are indicated for the treatment of depression in all its variants. There is controversy as to whether ADPs can be used in bipolar depression, as they have been shown to be associated with induction of rapid cycling [28]. For mild depression,

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current guidelines recommend exercise or watchful waiting, with psychotherapy or ADPs as an alternative if those measures fail. For moderate major depression, first-line treatment recommendations disorder include monotherapy with ADP, psychotherapy, and the combination of both. Finally, for severe depression, guidelines consider the combination of an ADP and an antipsychotic, electroconvulsive therapy (ECT), or the combination of an ADP and psychotherapy [29]. Classically TCAs are considered to be more effective than SSRIs, and the latter are perceived as better tolerated. However, recent comparative studies on effectiveness found no clinically significant differences between both groups, and therefore, treatment decisions are proposed to rely on considerations of relative patient acceptability, toxicity and cost [30]. On the other hand, the advantage in clinical trial drop-out rates with SSRIs may have been overvalued as it is relatively modest [31]. MAOIs have classically been found especially useful in atypical depression [32], a syndrome characterized by mood reactivity (i.e., mood brightens in response to actual or potential positive events) and at least two of the following: significant weight gain or increase in appetite; hypersomnia; leaden paralysis; and a longstanding pattern of interpersonal rejection sensitivity (not limited to episodes of mood disturbance) [33]. However, a recent analysis of the literature shows that atypical depression can also benefit from SSRI therapy and that MAOI differential superiority can only be shown over TCAs [34]. Antidepressant polypharmacy therapy is a growing trend in the treatment of depressive disorders, which in a systematic review and meta-analysis was found to be more effective than a single ADP and as well tolerated. However, there are still very few clinical trials to conclude definitively that this practice is safe and efficient [35]. After an ADP has been unsuccessful, switching strategies or augmentation with other agents (lithium, T3, second-generation antipsychotics as quetiapine and aripiprazole) can be attempted. Both switching and augmentation achieve remission rates between 25% and 50%. Adjunctive lithium and thyroid hormone have established efficacy for use in combination with TCAs, whereas T3 augmentation seems to be the option with the best benefit/risk ratio for augmentation of modern antidepressants [36]. Finally ADPs are also used in combination to enhance the therapeutic efficacy of ECT, with agents as mirtazapine having been shown safe and useful [37]. 3.2. Maintenance Therapy in Depression After acute treatment, maintenance on ADPs is usually recommended for at least six months. This policy has demonstrated utility to prevent depressive relapse

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[38], even though some critics assert that the fact that depression reappears after stopping treatment can also imply a discontinuation effect, rather than a protective action of ADPs [39]. On the other hand, depression is a commonly recurrent disorder. Therefore, patients with proven recurrent major depression should receive maintenance ADP drug treatment. There is evidence that new episodes are prevented by continuing therapy at the same dose as used in acute treatment beyond six months in patients with at least three episodes in the past five years or more than five episodes altogether. However, with increasing number of episodes, patients seem to develop a relative resistance against the prophylactic properties of ADPs [40]. The elderly may benefit from longer treatment, and after a severe old age depressive episode, indefinite treatment has been considered an option [41]. 3.3. Anxiety Disorders Since the identification of panic disorder and the discovery that it is responsive to imipramine [42], ADPs have been and are still used in the treatment of most anxiety disorders. With the advent of SSRIs, benzodiazepines (BZDs) were finally discarded as the major treatment of some anxiety conditions, such as Generalized Anxiety Disorder. Currently SSRIs are the considered the first-line treatment for most anxiety disorders, with SNRIs and pregabalin as the preferred second-line treatments [43]. Social anxiety disorder can be treated with escitalopram, fluvoxamine, paroxetine, sertraline, and venlafaxine with similar efficacy, even though these drugs differ in their adverse event profiles [44]. 3.4. Posttraumatic Stress Disorder ADPs, and specifically SSRIs, are currently the first-line agents in the pharmacotherapy of PTSD, having been proved as a valuable long-term treatment, even though a review found important gaps in the evidence base [45]. 3.5. Obsessive-Compulsive Disorder (OCD) Almost fifty years ago, Fernández-Córdoba and López-Ibor communicated the utility of clomipramine to treat OCD [46], a condition which seems to be associated with serotonin system dysregulation. Clomipramine is still considered a first-line agent for this disorder, along with SSRIs. Even though meta-analyses have reported a larger treatment effect for clomipramine relative to the SSRIs, head-to-head comparator studies do not support that superiority [47]. In fact, SSRIs are preferred for long-term treatment in most cases, given their superior safety and tolerability.

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Trichotillomania, a disorder related to OCD in DSM-5, has also been treated with ADPs. Preliminary evidence suggests treatment effects of clomipramine and other therapies, such as N-Acetyl Cysteine and olanzapine, although with very small sample sizes [48]. Body dysmorphic disorder, another OCD-related condition, can also benefit from SSRIs [49]. 3.6. Insomnia Sleep disorder is a common symptom of depression, therefore ADP therapy can colaterally be helpful to overcome insomnia. On the other hand, the sedative properties of some ADPs can be distinctly useful to treat insomnia (see chapter 7). A critical review found that no single ADP or class of ADPs have been shown to be most effective for the treatment of insomnia in patients with depression [50]. 3.7. Eating Disorders ADPs are usually prescribed for the treatment of eating disorders. The rationale is multiple [51]. On the one hand, in anorexia nervosa (AN), TCAs have been used out of the consideration of the disorder as a variant of affective disorder, or after the common overlapping of AN with depressive symptomatology, an association also invoked to propose prescription of SSRIs. The presence of obsessive features in AN patients and the identification of serotoninergic changes in this condition has also been a justification for the use of SSRIs, whereas dopaminergic abnormalities found in AN have been cited as a reason for prescribing bupropion. On the other hand, Bulimia Nervosa (BN) patients could obtain benefit from TCAs as this group has been associated with an anti-bulimic effect uncorrelated with thymoleptic action. SSRIs could also be useful, as they are said to suppress the binge - purge cycle characteristic of BN, and MAOIs could be helpful to treat atypical depression traits often found in BN. However, available evidence seems insufficient to conclude whether ADPs can be beneficial in AN, and the way they should be used to obtain maximal benefit [52]. However, a systematic review of 6 trials with TCAs (imipramine, desipramine and amitriptyline), 5 with SSRIs (fluoxetine), 5 with MAOIs (phenelzine, isocarboxazid, moclobemide and brofaromine) and 3 with other classes of drugs (mianserin, trazodone and bupropion) found that the use of a single ADP was clinically effective for the short-term treatment of BN when compared to placebo, with an overall greater remission rate but a higher rate of dropouts, secondary to side effects. No differential effectiveness or tolerability among the various classes of ADPs analyzed could be found [53].

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Binge-eating disorder, a distinct form of eating disorder included in recent nosologies, has also been treated with ADPs, but a systematic review and metaanalysis found that available data are not sufficient to formally recommend these drugs as a single first-line therapy for both long-term remission of binge-eating episodes and weight reduction in patients with this disorder, as it is a chronic condition and the available evidence is very short-term studies (8 weeks) and therefore of limited value [54]. 3.8. Pain ADPs are often used in the treatment of pain based on empirical and neuroscience findings. Depression and pain share a common pathophysiology. Anatomical structures that are activated and/or altered in response to both depression and pain include the insular cortex, the prefrontal cortex, the anterior cingulate cortex, the amygdala, and the hippocampus. Both depression and pain activate common neurocircuitries such as the hypothalamic-pituitary-adrenal axis, the limbic and paralimbic structures, and ascending and descending paintracks. Likewise, both share common neurochemicals such as monoamines, cytokines, and neurotrophic factors. Finally, both are associated with common psychological alterations [55]. Growing evidence points out that depression and pain also share genetic factors [56], and vulnerabilities in the interaction with environmental adversity [57]. Amitriptyline is the ADP most classically used to treat painful conditions, but other agents have been shown to be efficacious in the treatment of pain syndromes [58]. Neuropathic pain is frequently treated with ADPs, with TCAs having been found more consistently effective than SSRIs [59]. SRNI duloxetine is useful to treat pain secondary to diabetic peripheral neuropathy [60]. Headaches are also commonly treated with ADPs, with TCAs having been found to be more effective than SSRIs, their effectiveness increasing over time [61]. 3.9. Fibromyalgia TCAs such as amitriptyline and SNRIs are often proposed for the treatment of fibromyalgia. Duloxetine and milnacipran have been approved by the U.S. FDA for this indication. A revision of ten studies on amitriptyline, four on duloxetine and five on milnacipran found the three drugs superior to placebo except duloxetine for fatigue, milnacipran for sleep disturbance and amitriptyline for health-related quality of life, but the significant effects of amitriptyline and duloxetine were considered small and those of milnacipran, not substantial [62].

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3.10. Narcolepsy TCAs have been proposed for decades in the treatment of narcolepsy [63]. However, a review on the effectiveness of ADPs in this condition found scarce evidence of a positive effect despite clinical consensus recommending ADPs [64]. 3.11. Other Uses ADPs have been used for the control of behavioral disorders, both in people with intellectual disability and in older people with dementia. The rationale for using ADPs is that serotonin dysregulations can purportedly be the origin of conduct disturbance. A review found weak evidence of greater efficacy of TCA clomipramine versus placebo in people with intellectual disability and self-injury behavior [65]. Similarly, ADPs have been used to mitigate behavioral and psychological symptoms of dementia, with sertraline and citalopram having demonstrated efficacy to reduce symptoms of agitation when compared to placebo. Trazodone, as well as sertraline and citalopram, seem to be reasonably well tolerated when compared to placebo, typical antipsychotics and second-generation antipsychotics [66, 67]. Citalopram has been recently shown to be beneficial for behavioral disorders in dementia patients not suffering from anxiety or depression [68]. 4. SIDE EFFECTS 4.1. Cardiovascular TCAs are the ADPs with a higher known risk of cardiovascular side effects, having been shown to be related to orthostatic hypotension, and conduction delay, while they also show a potent antiarrhythmic effect [69], being in fact class I antiarrhythmics. Therefore they have even at therapeutic doses the risks associated with this class, being proarrhythmic under anoxic conditions [70]. A dose-response, albeit modest, association with QTc prolongation has been shown for citalopram and escitalopram which has not been found with other ADPs, except for amitriptyline [71]. Accordingly, both the U.S. FDA and the European EMA have issued warnings informing of a risk of ventricular arrhythmias and fixing a maximal dose in older people of 20 mg/d for citalopram and 10 mg/d for escitalopram (40 and 20 mg/d in adults, respectively). The clinical significance of that EKG modification was put into question [72] in a clinical study that was subsequently criticized on the grounds that its methodology

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precluded detection of potentially fatal arrhythmias [73]. In a study designed to assess its effectiveness in treating behavioral disorders in patients with dementia citalopram was also found to be associated with QTc interval prolongation [74]. ADPs, on the other hand, have not been found to be related to coronary heart disease in postmenopausal women [75]. 4.2. Cerebrovascular disease (CVD) Some studies have reported that SSRI have a very low rate of cerebrovascular adverse reactions [76], while others have found an increased risk of hemorrhagic and fatal stroke, albeit absolute risks are low [75]. A recent study concluded that in some populations treatment with SSRIs is associated with a reduced risk for stroke, as compared with TCAs. This finding fits with the known effect of SSRI on the pathophysiology of both depression and platelet aggregation. All SSRIs have been found to significantly reduce the 5-HT concentration in patient platelets, thus inhibiting aggregation [77]. This has a twofold consequence, as SSRI treatment may increase the risk of bleeding, while on the other hand has a protective effect against thrombotic events [78], especially when used to treat depressed patients, in whom a prothrombotic phenotype has been reported, with an upregulation of platelet biomarkers linked to aggregation, and a downregulation in the majority of them after treatment with SSRIs, even though alterations in viscoelastic parameters of clot formation remain unaffected by treatment [79]. Conversely, inhibition of platelet aggregation by SSRIs could induce cerebral microbleedings, but recent findings are reassuring as the risk has been found to be minimal [80]. In summary, SSRI are known to inhibit platelet aggregation, which can be beneficial for depressed patients, as depression can be conceived of as a platelet hyperaggregation state. 4.3. Abnormal Bleeding As in the proverb “one man’s meat is another man’s poison”, antiaggregation by SSRI can be beneficial for patients with a thrombogenic risk but deleterious for those at risk of bleeding. A significant association between degree of serotonin reuptake inhibition by ADPs and risk of hospital admission for abnormal bleeding as the primary diagnosis has been found [81]. Preoperative use of ADPs enhancing serotoninergic transmission is associated with increased bleeding risk and requirement of transfusion [82, 83]. Given the risk, some authors recommend

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stopping SSRIS in stable patients two weeks before a planned surgical operation, even though a discontinuation syndrome (see below) may appear [84]. However, others consider unwarranted to halt the treatment, as perioperative complications are not serious, at least in some forms of surgery [85]. ADPs acting on serotonin physiological processes have also been reported to modestly increase risk for other bleeding complications in patients not undergoing surgery. Apart from actions on platelet aggregation, gastrointestinal bleeding has been hypothesized to be secondary to SSRI-induced increase in gastric acid secretion [86]. Accordingly, other ADPs with lower serotonin receptor affinity could be the first-choice agents for patients at risk [87]. Following acute myocardial infarction, combined use of SSRIs with drugs acting on platelet aggregation, such as acetylsalicylic acid or dual antiplatelet therapy, has been found to increase risk of bleeding [88]. Co-prescription of SSRIs or SNRIs and warfarin has also been found to increase risk of bleeding. A dual interaction could be invoked to explain this potentiation, as ADPs acting through serotonin not only antagonize platelet aggregation, but also interact at the CYP2C9 isozyme to inhibit the oxidative metabolism of S-warfarin [89]. A study found that the serotonin-related ADPS with a relevant interaction with warfarin were, in decreasing order: paroxetine, venlafaxine, fluoxetine, and duloxetine [90]. 4.4. Anticholinergicity ADPs can affect cholinergic transmission by muscarinic blockade. Most TCAs are potent anticholinergic drugs which can cause xerostomia; hypohydrosis and increased body temperature; mydriasis with photophobia; loss of accommodation; increased intraocular pressure with a risk of acute crisis in patients with narrowangle glaucoma; tachycardia; constipation and occasionally ileus; and urinary retention. Co-prescription with other anticholinergic drugs such as some antipsychotics increases the risk of anticholinergic syndrome. Antimuscarinic effects can also occur with some SSRIs (very infrequent with citalopram and sertraline and more usual with paroxetine) [91]. SNRIs are weaker anticholinergic drugs, but acute angle-closure glaucoma has been reported with duloxetine, albeit it was attributed to other mechanisms such as mydriasis [92]. 4.5. Serotoninergic Syndrome ADPs enhancing serotoninergic transmission can trigger symptoms as gastrointestinal upset secondary to an excess of serotonin. A less frequent, serious, and potentially life-threatening reaction called serotonin syndrome (SS)

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may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of certain serotoninergic agents, or the recreational use of certain drugs. SS is not an idiopathic reaction, but a predictable consequence of excess serotonergic activity at central nervous system and peripheral serotonin receptors [93]. Severe cases are generally due to the combination of two or more serotoninergic drugs, one of them being a MAOI, either an ADP, or another, nonADP, MAO-inhibiting drug, such as linezolid [94], or blue methylene [95]. Symptom onset is usually rapid, often occurring within minutes after intake or administration. SS includes a range of clinical findings. Milder symptoms comprise tachycardia, tremor, diaphoresis, mydriasis, myoclonus and hyperreflexia. In moderate cases, hypertension, hyperthermia and clonus are common, as well as mental status changes such as hypervigilance and agitation. In severe SS, great escalations in heart rate and blood pressure occur that may lead to shock, with a great increase in body temperature in life-threatening cases. Metabolic acidosis, rhabdomyolysis, seizures, renal failure, and disseminated intravascular coagulation can occur as a consequence of hyperthermia [93]. Diagnostic is guided by the Hunter toxicity criteria [96], which in the presence of a serotoninergic drug contemplate spontaneous or inducible clonus, diaphoresis, agitation, hypertonia, hyperthermia, tremor and hyperreflexia. Treatment should focus on cessation of the serotonergic medication and should include supportive care. Some antiserotonergic agents have been used in clinical practice, with intravenous chlorpromazine being the most commonly used drug for severe SS. However, the preferred agent, dose and indications are not well defined [97]. Prevention is essential, with a careful watch to polypharmacy including serotoninergic agents, amongst which opioids must not be forgotten (see above). 4.6. Addiction ADPs, especially those acting on dopamine transmission, have been associated with addictive potential. Use of tranylcypromine and amineptine was advised against years ago in patients with an abuse of substance misuse [98], and amineptine was finally suspended after a number of abuse cases were reported. Bupropion, chemically a cathinone, has also been reported to be misused not only orally, but also intravenously [99] and intranasally [100]. 4.7. Neurological Untoward Effects Extrapyramidal symptoms, including parkinsonism, can appear in patients treated with several groups of ADPs, although the risk seems to be greater with the SSRIs

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than with TCAs [101]. Other agents, such as duloxetine, nefazodone, and bupropion, have also been reported to be related to this untoward effect [102]. Akathisia or inner restlessness may be induced by ADPs. Predisposing factors include co-prescription of multiple drugs associated with this adverse effect (the most characteristically akathisia-inducing agents are antipsychotics), recent increases in SSRI dose, history of previous development of akathisia, baseline psychiatric disorders, and brain trauma [103]. SSRI-induced akathisia has been proposed as an etiological mechanism for serious behavioral disorder in patients receiving this class of ADPs [104]. Treatment with some ADPs can facilitate the occurrence of seizures. Maprotiline has been associated with seizures when administered at high dosages, sometimes after many weeks at a stable dose. Neither rapid dosage escalation nor high drug plasma levels have been considered related to seizure occurrence, which has been attributed to a long-acting metabolite might be responsible for seizures [105]. Bupropion immediate-release, at dosages of 450 mg/d or less, was associated with an incidence rate of seizures ranging from 0.35% to 0.44%, compared with a firstseizure incidence of 0.07% to 0.09% in the general population [106]. However, when daily dosages exceed 450 mg/d, the seizure incidence is estimated to increase tenfold, while the number of seizure occurrences is twice as high in patients who took extra doses of bupropion IR on an “as needed” basis [107]. Instead, bupropion sustained-release, a formulation approved for tobacco cessation, reduces seizure incidence rates to 0.1% [108]. Apart from occurrence in therapeutic use, seizures have also been reported in subjects misusing bupropion intranasally [109]. The risk of seizure linked to this agent being considered high, bupropion modified-release has been approved for the treatment of depression in Europe with at a maximal daily dose of 300 mg. Finally, Both TCAs and SSRIs are tremorogenic drugs [110], and treatment with some ADPs has been reported to trigger restless legs syndrome, especially if the agent, notably mirtazapine, is co-administered with tramadol or dopamineblocking agents such as antipsychotics [111]. 4.8. Suicidal Behaviors Clinical wisdom has classically identified that treatment with ADPS can trigger suicidal attempts and death by suicide, with a higher risk at the moment of initial improvement. Some years ago, an association with suicidal behaviors was reported in young people started on ADPs, after a meta-analysis showed a higher relative risk for suicidal behavior or ideation for young people treated with ADPs

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compared with those given placebo [112]. Later findings were conflicting, and a recent study has shown that safety warnings about this association and widespread media coverage reduced ADPs use, with simultaneous increases in suicide attempts among young people. This findings suggest a protective effect by ADPs against suicidal behavior in that population [113]. No such concerns have been raised in older people. Some studies have found a consistent age-associated decrease in people treated with ADPs [114, 115], which has been interpreted as a sign of a better response to treatment in older than in younger cohorts, especially considering that death by suicide is far more frequent in the elderly. In fact, some authors point out that the also age-associated increasing gap between estimated prevalence of depression and ADPs prescription rate in persons dying by suicide underscores the need for assessment of depression in the oldest old [115]. 4.9. Rapid Cycling Use of ADPs in bipolar depression has been correlated to switch to manic / hypomanic acute episodes. Some reports estimate that 8% of patients with unipolar major depressive disorder who are treated with an ADP switch to a hyperthymic episode, which entails a subsequent diagnostic change to bipolar disorder [116]. TCAs seems riskier than SSRIs, with data for other types of ADPs having found to be inconclusive [117]. Akiskal defined a bipolar III disorder in which hypomania first appeared in association with ADPs and which has later been found to require a familial diathesis for bipolar disorder [118]. Accordingly, the use of ADPs must be cautious in patients of all ages with a family history of bipolar disorder. 4.10. Sexual Dysfunction Sexual dysfunction (SD) is a very common side effect of ADPS at all ages, and can have a significant impact on the person's quality of life, relationships, mental health, and recovery. Montejo et al., [119] found a 59.1% overall incidence of SD when all APS were considered as a whole. According to their findings, the incidence of SD with SSRIs and SNRI venlafaxine ranged between 58% and 70% (with the highest rates with paroxetine and citalopram), whereas nefazodone, mirtazapine and especially moclobemide, showed the lowest incidence of sexual dysfunction. Men tended to report SD slightly more often than women, duloxetine-associated SD rates are comparable to those of SSRIs [120], whereas agomelatine shows better acceptability than paroxetine [121].

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Priapism, a painful condition with persistent penis erection, usually considered a medical emergency, has been found with the use of a range of drugs [122], amongst them antipsychotics and ADPs, most characteristically trazodone. ADP-induced SD can be taken advantage of for the treatment of certain conditions, such as paraphilia, where TCAs and especially SSRIs are considered “reasonable choices” [123]. SSRIs can also be a useful approach for premature ejaculation, with some drugs as paroxetine having been found efficacious, albeit with a substantial and prolonged side-effect profile. A novel SSRI, dapoxetine, overcomes these problems, as a short-acting agent with a pharmacokinetic profile allowing for an on-demand treatment [124]. 4.11. Hyperprolactinemia Treatment with SSRIs has been reported as increasing the risk of hyperprolactinaemia. Some authors recommend to enquire about treatment with SSRIs when investigating the aetiology of hyperprolactinaemia, and call for the risk of hyperprolactinaemia to be mentioned in the labelling of all SSRI compounds [125]. 4.12. Hepatotoxicity Drug-induced liver injury is a rare event in ADP-treated patients, with only 0.5%−3% of those exposed developing asymptomatic mild elevation of serum aminotransferase levels. An interval between treatment initiation and onset of liver injury between several days and 6 months has generally been found. Hepatotoxicity is a possible occurrence with all ADPs, and the risk is higher in elderly, polymedicated patients. The agents with a greater risk of hepatotoxicity are iproniazid, nefazodone (suspended in some countries for this reason), phenelzine, imipramine, amitriptyline, duloxetine, bupropion, trazodone, tianeptine, and agomelatine (with mandatory liver function tests in Europe). Instead, the ADPs that seem to have the least potential for hepatotoxicity are citalopram, escitalopram, paroxetine, and fluvoxamine [126]. 4.13. Blood Dyscrasia Nomifensin, a norepinephrine-dopamine reuptake inhibitor, was suspended after an association with hemolytic anemia was communicated [127]. Mianserin has also been reported to be associated with aplastic anemia [128], and the NICE guide for depression in adults remarks that hematological monitoring is needed in elderly people treated with mianserin [129].

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4.14. Weight Gain Treatment with ADPs is associated with weight gain, with small, modest differences between compounds [130]. Amongst second-generation ADPs, modest weight loss are described with bupropion and modest weight gain with mirtazapine and paroxetine [131]. On the grounds of that side effect, mirtazapine has recently been suggested as the first-line ADP for depressed, underweight elderly [132]. 4.15. Hyponatremia Arbitrarily defined as a serum sodium of less than 135 mmol/L, hyponatremia is an adverse effect of many drugs which occurs especially in the elderly. Amongst ADPs, hyponatremia has been reported with all SSRIs, venlafaxine, duloxetine and desvenlafaxine. The risk of developing hyponatremia increases with age, female gender, previous history of hyponatremia and the concomitant use of other medications known to be related to this side effect. After discontinuation of the offending agent, the sodium concentrations of most patients return to normal within days to weeks, and a few reported cases of rechallenging suggest that hyponatremia may sometimes be a transient effect and tolerance could develop over time [133]. 4.16. Discontinuation Syndrome The first report of a withdrawal syndrome linked to ADPs dates back to 1961 and describes the appearance of discontinuation symptoms after withdrawal of imipramine [134]. Symptoms appearing after cessation of an ADP could be a result of the suppression of anticholinergic effects by TCAs [135]. However, some 15-20 years ago, a new syndrome was recognized, correlated to SSRI and SNRI cessation and more commonly associated with paroxetine and venlafaxine, in which a range of different symptoms are commonly included, with dizziness being the commonest one. Other symptoms usually described by patients are nausea or emesis, fatigue, headache, gait instability and insomnia. More uncommon symptoms include shock-like sensations, paresthesia and visual disturbances [136]. Slow discontinuation or switching to another product is recommended to prevent this disturbing syndrome. 5. USING ANTIDEPRESSANTS IN THE ELDERLY Depression is a prevalent disorder in the elderly which can be responsive to ADPs and other therapies. Two variants are usually described: the one preceded by

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depressive episodes earlier in life and reappearing in old age (Early Onset Depression: EOD) and the other which occurs for the first time in Old Age (Late Onset Depression: LOD). Both have similar symptomatic profiles and prognosis, even in their most severe presentations [137]. Compared with clinical presentation at other ages, the most salient characteristic of geriatric depression is a dominance of cognitive impairment, which is not a mere epiphenomenon of the disease [138] and consists in a general retardation of mental processes which very often calls for differential diagnosis with dementia. As Mahendra pointed out [139], the relationship between depression and dementia is multi-faceted. First, depression can appear in dementia, either as a co-morbidity or as a part of the dementia syndrome, with diagnostic criteria for depression in Alzheimer’s disease having been proposed [140]. Second, depression can be a prodromos of dementia. Third, depression is a risk factor for dementia [141]. Even though it could be assumed that LOD should be the variant most usually followed by dementia, depression at any age of life (that is, EOD) has been found to be a risk factor for subsequent development of dementia in late life [142]. Finally, in old age depression cognitive dysfunction can be so salient that as to mimic dementia, in a clinical presentation often called “depressive pseudomentia” [143]. Clinically, the severe cognitive syndrome of depression often replicates a subcortical-dementia pattern [144]. The use of ADPs in dementia is conditioned by polypharmacy, which in the elderly is very prevalent. Antihypertensives, antiaggregants, anticoagulants, opioid analgesics, are drugs commonly used in the elderly which can determine the selection of APD (see above). Clinical severity and the presumed duration of illness (see below) must be the features guiding prescription. TCAs, SSRIs and MAOIs have been effective in the treatment of older community patients and inpatients with physical illness [145, 146]. Even though response can be rapid, with clinical improvement apparent two weeks after onset of treatment, courses of at least six weeks are recommended to achieve optimal therapeutic effect, and it could be necessary to wait up to 12 weeks before switching APD, choosing a combination or augmentation strategy or even increasing dosage. Agent choice depends on factors such as comorbidities and current drug regime. TCAs and SSRIs seem to be equally effective in old age depression, with a better tolerance profile for the latter [147]. Therefore a SSRI seems to be the first-choice unless there is a history of intolerance or another agent has been documented to be

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previously effective and safe [129, 148]. In a meta-analysis on ADPs in adults which also comprised patients over 65 years, sertraline was considered the best choice when starting treatment for moderate to severe major depression as it had the most favorable balance between benefits, acceptability, and acquisition cost [149]. Sertraline’s advantages may be even more noticeable in the elderly, and could accordingly be also a best choice in geriatric depression, especially after citalopram and escitalopram have been discovered to be associated with QTc interval prolongation. Mirtazapine is a usually well tolerated drug in the elderly [150], and could therefore be a second choice. In patients not responding to the first trial of treatment, either a SRNI or combination with mirtazapine could be recommended. In adult outpatients, switching to a third ADPs monotherapy regimen after two consecutive unsuccessful trials has been found to result in low remission rates (