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PSYCHOGERIATRICS 2014; 14: 261–268

doi:10.1111/psyg.12057

INVITED REVIEW ARTICLE

Risk–benefit analysis of antidepressant drug treatment in the elderly Cecilio ÁLAMO,1 Francisco LÓPEZ-MUÑOZ,1,2,3 Pilar GARCÍA-GARCÍA1 and Silvia GARCÍA-RAMOS4

1

Department of Biomedical Sciences (Pharmacology Area), Faculty of Medicine and Health Sciences, University of Alcalá, 2Faculty of Health Sciences, Camilo José Cela University, 3Hospital 12 de Octubre Research Institute 12+i, and 4Hospital Pharmacy, Principe de Asturias University Hospital, Madrid, Spain Correspondence: Professor Francisco López-Muñoz MD, PhD, Faculty of Health Sciences, Camilo José Cela University, C/Castillo de Alarcón, 49, Urb. Villafranca del Castillo, 28692 Villanueva de la Cañada, Madrid, Spain. Email: francisco.lopez [email protected]; [email protected] Received 12 June 2014; accepted 18 July 2014. This article is an invited review which is kindly provided by the authors.

Key words: antidepressant drugs, depression, elderly, risk–benefit analysis.

Abstract Depression in the elderly is a significant health issue that has the potential to seriously affect physical and emotional well-being. Therefore, the treatment of geriatric depression is necessary. Antidepressant treatment in older depressed patients is efficacious, but differences in the effectiveness of different classes of antidepressants have not been demonstrated. However, differences in tolerability profile are most recognizable in the elderly. With ageing, a series of changes occur in the elderly that modify both the pharmacokinetics and pharmacodynamics of antidepressants and may influence the efficacy, tolerability and safety of treatment in the elderly. Comorbidities require the use of other drugs, which increases the possibility of drug-drug interactions. Given these aspects, individualized therapy for each elderly patient is needed to achieve acceptable risk–benefit ratio. Effective treatment of depression in the elderly, which may require combined pharmacological with psychosocial treatment, can decrease both morbidity and mortality; it also may lead to reduced demands on family members and on health-care and social services.

INTRODUCTION 1

According to the World Health Organization, depression is the most frequent mental disorder and the most disabling medical condition among geriatric patients, but it is often under-recognized and not adequately treated in 40–60% of cases.2 Old people are usually excluded from research protocols, as age alters the symptomatology and comorbidity is common at this age.3 Approaching depression in the elderly is not an easy task, but this does not justify ignoring the problem.4 The use of antidepressants in the elderly has some risks. However, untreated or inadequately treated depression is more dangerous and can lead to other adverse health outcomes such as malnutrition, poor hydration, weakness from a lack of physical activity, functional decline, decreased quality of life, and ultimately, suicide and death.5 In general, antidepressant treatment in older depressed patients is effective and comparable with that observed in adult depression, but maintaining remission is difficult and recurrence rates are high, decreasing the years of life lived without disability in the © 2014 The Authors Psychogeriatrics © 2014 Japanese Psychogeriatric Society

elderly.6 There are no differences in the effectiveness of different classes of antidepressants, especially tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRI), but TCA can be associated with a higher discontinuation rate because of side effects.7,8 The selection of a particular antidepressant is not based on differences in efficiency; it is based on other factors such as the profile of adverse effects, comorbidities, and concomitant use of other drugs that can produce drug interactions.2 The UK’s National Institute for Health and Clinical Excellence recommends that the choice of antidepressant should be based on considerations of possible side effects and the patient’s preferences.9 In the present review, we have used Embase, PubMed, ScienceDirect, and Google Scholar databases, which are considered the most exhaustive within the biomedical field. We also reviewed our personal collections of research. This review took into account all original articles, brief reports, reviews, editorials, letters to the editor, and so on. 261

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ASPECTS INVOLVED IN THE PSYCHOPHARMACOLOGICAL RESPONSE IN THE ELDERLY There are many factors that could affect the psychopharmacological response in the elderly, including psychosocial factors, pharmacokinetics and pharmacodynamics caused by age. In some countries, there is a stigma against mental illness, and depression is viewed as a personal weakness, a character flaw, or a normal part of ageing that does not require diagnostic testing or treatment. In some cases, insurance companies do not cover the costs of the treatment of depression.10,11 Biological changes in the elderly can modify the pharmacokinetic profile of antidepressants. Changes that affect distribution, such as decreased weight, body size, muscle mass and body water, as well as a relative increase in body fat, necessitate reducing the dosage of water- and lipid-soluble agents. The decrease in plasma albumin can increase the plasmafree concentrations of SSRI, and the increase in α1-acid glycoprotein can decrease the concentration of free TCA in the plasma.12,13 Decreased hepatic and renal function can alter biotransformation and elimination, and some antidepressants can accumulate.14 The pharmacokinetics of some antidepressants can limit their use in the elderly. For example, fluoxetine is not recommended because of its long half-life and prolonged side effects.15 Ageing-induced pharmacodynamic changes increase vulnerability to the undesirable effects of antidepressants. The loss of neurons in the cortex, locus coeruleus, and hippocampus increases the sedative and psychomotor effects of psychotropic drugs, and reduced sensitivity of the baroreceptors facilitates the hypotensive effects of some antidepressants. The decline in the dopaminergic neurons and receptors in the nigrostriatal pathway increases sensitivity to the extrapyramidal effects of SSRI. The gradual loss of cholinergic transmission in the central nervous system increases sensitivity to the anticholinergic effects of drugs, such as confusion and cognitive impairment. Likewise, greater sensitivity to serotonin may cause an increase in the incidence of inappropriate secretion of antidiuretic hormone (ADH) associated with the use of SSRI.2,12,13 If doses of antidepressants are not modified to address age-related changes, the risk of adverse events and drug-drug interactions may be present. A 262

study in older nursing home residents showed that 43.1% of antidepressant prescriptions were potentially inappropriate, and dosage problems were seen in 8.8% or patients and drug-drug interactions in 25.9%.16

RISK OF ANTIDEPRESSANT DRUGS IN THE ELDERLY Some risks involving antidepressants in the elderly can affect the selection of a particular agent. In general, SSRI constitute the first-line treatment for depression in the elderly. Paroxetine and fluoxetine are highly effective, but because of fluoxetine’s long half-life and paroxetine’s potent anticholinergic effect, they are not first-line treatments in elderly patients.2 TCA are effective in elderly patients, but given their adverse effects and the likelihood of cardiotoxicity in cases of overdose, they must be used only in patients who have previously had a good response to them. TCA are contraindicated in patients with a recent history of myocardial infarction, defects of cardiac conduction, glaucoma, orthostatic hypotension, urinary retention, hypertrophy of the prostate, or cognitive impairment.2,17,18 Monoamine oxidase inhibitors have a narrow therapeutic margin and require restrictions with several drugs and nutrients that content tyramine. This group of antidepressants is not recommended in the elderly, even when prescribed by professionals with experience with this type of antidepressants.19 There are some common antidepressant side effects that are predictable and that target therapeutic alternatives. Thus, a series of predictable secondary adverse events can be bypassed as a result of antidepressants blocking several neurotransmitters receptors and inhibiting the uptake of monoamines.2,13,20 Mortality by all causes The main risk that can occur with antidepressants is a possible increase in mortality. It is important to consider mortality associated with the depressive condition, a poor adherence to medical treatment, poor self-care for diabetes and cardiovascular disease, smoking, lack of physical activity, cognitive impairment and disability. Similarly, mortality caused by voluntary or accidental overdose with suicidal intentions, should also be taken into account.21 Prospective studies have consistently shown an association © 2014 The Authors Psychogeriatrics © 2014 Japanese Psychogeriatric Society

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between depression and increased mortality in older adults,22 but this association varies with different regional population. For example, in a group of elderly Japanese American men in Hawaii, depressive symptoms were associated with significantly increased mortality.23 SSRI are considered agents of first choice in the elderly for their tolerability and safety. However, a recent cohort study of elderly depressed patients surprisingly concluded that SSRI and other antidepressants, such as mirtazapine or venlafaxine, were associated with significantly higher rates of mortality (by all causes) and increased risk of several adverse effects compared with TCA. As this was an observational study, it was susceptible to confounding by some factors, such as indications for prescription, patient characteristics, and varying antidepressants. In fact, doses tended to be lowest for TCA (70.0% of prescriptions were for less than or half of the defined daily dose), compared with SSRI (13.8%). Furthermore, patients who were not treated were likely to have less severe depression but poorer physical health; as such, they were considered too frail for antidepressant treatment.24 These data contrast with some existing guidelines. TCA have traditionally been included in Beers Criteria of Potentially Inappropriate Medication Use in older adults,25 while the National Institute for Health and Clinical Excellence and other institutions have recommended that an SSRI should normally be chosen.9 Risk of antidepressant overdose Suicide, at least in some elderly populations, has reached the epidemic proportions. In the US population older than 85 years of age, the suicide rate is five times that of the general population.26 Suicide rates have tended to decrease more in Europe and other countries where there has been a greater increase in the use of antidepressants.27–29 In fact, antidepressants reduce the risk of suicide among elderly patients,30 and when prescribed in correctly, the use of antidepressants, especially in the elderly, offers more benefits than a risks.31 Unfortunately, in some circumstances (e.g. akathisia or anxiety),26 an antidepressant overdose, either accidental (resulting from physical or cognitive limitations) or voluntary, can have an autolytic effect.32 In general, SSRI are relatively safe and the risk of overdose is minimal.33 However, clinicians should © 2014 The Authors Psychogeriatrics © 2014 Japanese Psychogeriatric Society

warn patients of the possible risk of suicidal behaviour and monitor patients closely, especially in the early stages of treatment. Also, caution should be exercised with high doses of citalopram or escitalopram because of possible relation to QT interval prolongation.34,35 In patients with high risk of overdose, it is important to avoid TCA or venlafaxine because of their cardiotoxicity. In 2003–2012, doses of drugs affecting the central nervous system were considered lethal in 8.6% of TCA-related inquiries to the Toxicological Information Center (Prague, Czech Republic); in contrast, only 1.6% of calls related to SSRI involved lethal doses.36 Appropriate antidepressant use in elderly is more a benefit that a risk, thus we must not penalize the entire population by denying effective care.26 Cardiovascular risks related to antidepressant drugs Cardiovascular adverse effects related to antidepressants are well studied, especially with regard to TCA overdoses. TCA have antimuscarinic properties, norepinephrine re-uptake inhibition, and a quinidine-like effect.2,13 They also tend to slow cardiac conduction, prolong PR, QRS and QT intervals, and can occasionally induce heart block and arrhythmia in elderly. When TCA are likely to have these effects, the alternative use of SSRI, bupropion, or mirtazapine is recommended.37 TCA, paroxetine (with anticholinergic properties),38 trazodone, and venlafaxine should be avoided in elderly patients who are at risk of arrhythmia, require blood pressure control, or use electrocardiographic control.9,39 Some studies have found an increased risk of myocardial infarction associated with TCA use.40,41 SSRI have less of a cardiovascular risk and can even have a protective effect,41–45 probably as a result of inhibitory platelet aggregation. SSRI are recommended in patients with cardiovascular diseases,9 and sertraline has had the best results in patients with a history of acute myocardial infarction or unstable angina.46 In the elderly, orthostatic hypotension is a common cardiovascular effect of TCA, monoamine oxidase inhibitors, trazodone, and nefazodone due in part to the blockade of α1-adrenergic receptors, and it is associated with an increased risk of falls and fractures.42,47 In contrast, some antidepressants, such as reboxetine, duloxetine, and venlafaxine, can induce 263

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hypertension in the elderly, probably due to the uptake inhibition of norepinephrine.39 It should be noted SSRI are associated with an increased risk of stroke,24,48 and because haemorrhagic accident does not increase, it is unrelated to antiplatelet activity.49,50 Similarly, in a case– control study in patients with intracerebral or subarachnoid haemorrhage, SSRI were not implicated.51 This risk is not present with TCA or other antidepressants.2 Bleeding risks related to antidepressant drugs Since the introduction of SSRI, bleeding has been a concern in most studies, including those involving elderly patients.52 However, this effect is mediated by the antiplatelet effect of SSRI.53 The epidemiological evidence broadly supports a moderately increased risk of gastrointestinal bleeding associated with the use of SSRI and venlafaxine, but this depends on patient susceptibility and the presence of other risk factors, such as ageing, a previous history of upper gastrointestinal bleeding or peptic ulcer, and taking nonsteroidal anti-inflammatory drugs, oral anticoagulants, antiplatelet drugs or corticosteroids.54,55 Additionally, the risk of bleeding while on SSRI was observed in a study of 520 patients who underwent orthopaedic surgery.56 Risk due to anticholinergic effects The antimuscarinic effects of antidepressants, especially TCA and paroxetine, negatively affect the physical health and quality of life of elderly and predisposed subjects.13,38 Peripheral effects include tachycardia, dry mouth and related difficulties with teeth, constipation (which could lead to ileus), urinary hesitancy, blurred vision (which can worsen existing vision loss caused by previous cataract), and age-related macular degeneration. Also, as discussed, cardiac toxicity involves the antimuscarinic properties of antidepressants.13,57 In the central nervous system, the muscarinic blockade may favour the emergence of memory disorders, confusion, and delirium, especially in the elderly.58 In contrast, SSRI, bupropion, and serotoninnorepinephrine re-uptake inhibitors (SNRI) tend not to affect cognition. The risk of delirium is greatest in those with an underlying dementia and who may become confused as their depression worsens.59 264

Hyponatraemia and inappropriate ADH secretion The excess of ADH secretion induced by some antidepressants, mainly SSRI, SNRI, and to a lesser extent TCA, cause hyponatraemia, which presents clinically as malaise, nausea, headache, lethargy, muscle pain, confusion, loss of consciousness, and seizures.2,60 Mild hyponatraemia may cause some degree of lethargy, which can be misinterpreted as worsening depression. This can wrongly indicate a need for an increased dose of antidepressant, which could worsen hyponatraemia.61 The prevalence of hyponatraemia in elderly patients treated with SSRI ranges from 12% to 25%, of which 9% have clinical symptomatology. The mortality rate among elderly patients with hyponatraemia may reach 25%.60 Because ADH secretion occurs in the first month of SSRI and venlafaxine treatment, it is recommended that elderly patients control their sodium levels to prevent more serious complications.2 Sexual dysfunction Sex remains a prominent part of the lives of older persons, despite the fact that many people believe that older adults do not or should not engage in sexual activity. Although both depression and antidepressants can worsen sexual function in the elderly, it is a side that is not usually investigated. Sexual dysfunction affects orgasm, sexual arousal and desire, ejaculation, erection, and dyspareunia. These effects may lead to failed adherence to or early termination of treatment, as well as decreased quality of life.2 Patients treated with SSRI, particularly escitalopram and paroxetine, or venlafaxine significantly have the highest rates of overall sexual dysfunction. Bupropion, mirtazapine, and agomelatine have been associated with less sexual dysfunction and are therefore valid alternatives.62–65 Risk of osteoporotic fractures Depression adversely affects bone density and increases fracture risk.66 Some studies have shown that the use of SSRI was associated with a statistically significant increase in the risk of osteoporotic fractures.67 The risk with SSRI, probably related to the degree of inhibition of serotonin re-uptake in osteoclasts, osteoblasts, and osteocytes,68,69 can be higher than with TCA or other antidepressants. Moreover, the risk of non-vertebral fractures in older © 2014 The Authors Psychogeriatrics © 2014 Japanese Psychogeriatric Society

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women is increased by treatment with SSRI or TCA,70 and the recent Canadian Multicentre Osteoporosis Study supports an association between SSRI and SNRI use and fragility fractures.71

BENEFITS OF ANTIDEPRESSANT USE IN THE ELDERLY Depression in the elderly is a serious disease that affects patients, particularly with regard to suicide risk, comorbidity, and disability. However, it also affects their families and social environment.6 Thus, treatment is imperative. Effective treatment of late-life depression can improve emotional, social, and physical functioning and quality of life. It has also been associated with better self-care for chronic medical conditions and reduced mortality.72 Antidepressant treatment in older depressed patients is efficacious, and there are no differences in effectiveness between different classes of antidepressants.73 In some studies, TCA have shown better efficacy among inpatients,74 but comparative studies have not indicated differences in achieving response or remission between different groups of antidepressants, even in more severely depressed patients.73,75 In general, response to antidepressants in the elderly is weaker than in adult patients with major depressive disorder.73,76,77 Recently, Kok et al. carried out a systematic review and meta-analysis of acute phase treatment of older depressed patients, and the results indicated all classes of antidepressant were individually more effective than placebo in achieving response and remission, although remission was less significant.73 The goal of treatment in the elderly is not only acute recovery, but also the prevention of the recurrence.78 Consensus on the duration of maintenance is limited because there have been few controlled studies with variable or an undefined duration of therapy, but most experts recommend 6–12 months of treatment after the first episode.6,79 However, this period of treatment, recommended by experts, could be longer because in depressed elderly monitored for 2–3 years in depressed elderly, recurrence rates ranged between 50% and 90%.80 Some sociodemographic and clinical features have been found to moderate antidepressant efficacy in elderly populations. In elderly men, a subgroup treated with SSRI had a worse treatment outcome than those treated with other antidepressants. Age © 2014 The Authors Psychogeriatrics © 2014 Japanese Psychogeriatric Society

effects on some neurotransmitter factors, such as serotonergic function, have been hypothesized to modulate antidepressant response.81 This reduced response has also been seen in elderly patients with long episodes of depression. This possibly could be due to side effects, especially in older patients who usually have high rates of discontinuation. In contrast, a higher response rate was found in patients with a higher baseline severity and in those treated at their first episode of illness.82 Treatment-resistant depression affects up to onethird of elderly patients with depression. Factors that can worsen long-term response include current age, high levels of acute or chronic stress, reduced social support, early age of onset, melancholic-like demonstrations, use of adjunctive medication in acute treatment, and high levels of anxiety.6,83 Because the efficacy of all antidepressants has been demonstrated relative to placebo and the effectiveness of different antidepressants is similar in the elderly, antidepressant selection is not conditioned by differences in efficiency. Rather, other factors, such as the profile of adverse effects, comorbidities, and concomitant use of other drugs that can produce drug interactions, should be considered.2 Therefore, the individualization of antidepressant therapy is necessary, especially in the elderly. In fact, some pharmacodynamic characteristics of an antidepressant that may be intolerable for some patients may offer therapeutic relief in others. Thus, mirtazapine, an antagonist with presynaptic α1-adrenergic receptors and a potent antihistaminic, can facilitate sleep and increase appetite and weight. These properties may be of particular interest in elderly patients with insomnia or weight loss. In contrast, bupropion or reboxetine, which inhibit re-uptake of catecholamine, can be used to energize patients showing excessive lassitude, lethargy, or fatigue or who receive excessive sedation during the day.2 In depressed patients with neuropathic pain, duloxetine may be useful, but nausea, agitation, insomnia, and hypertension appear when high doses are administered.75 When psychopharmacological measures aimed at the treatment of depression and comorbidity are employed along with psychological and social measures, the benefits of treating depression in the elderly are clear. Working in older depressed patients provided, Gallo et al. found that additional resources to intensively manage depression (psychotherapy, 265

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increased antidepressant dose if indicated, and monitoring symptoms, adverse effects of drugs, and adherence to treatment) reduced the risk or mortality risk more so than usual care so that is was similar to older adults without depression.21 In conclusion, antidepressants should only be prescribed to the elderly when necessary. Age should not be a reason to deprive patients of medication that can improve their health and quality of life. However, much of the data examined in this review originates from randomized trials with methodological features that may not apply in a real-world clinical practice.2

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Risk-benefit analysis of antidepressant drug treatment in the elderly.

Depression in the elderly is a significant health issue that has the potential to seriously affect physical and emotional well-being. Therefore, the t...
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