PHARMACOTHERAPY OF DEPRESSION IN OLD AGE

150 Review M. Petrovic 1,2, P. De Paepe 2,3, L. Van Bortel 2 Key-words: depression, elderly, antidepressants, efficacy, adverse effects ABSTRACT This review addresses the pharmacotherapy of antidepressants in the elderly. We performed a search based on Medline and the Cochrane Library. In addition to a meta-analysis of 17 randomised controlled studies, 36 randomised controlled trials of patients over the age of 60 published between 1980 and 2005 in English met the selection criteria and were included. Existing evidence suggests that no one class of antidepressant drugs has been found to be more effective than another in the treatment of depression in the elderly. Although newer antidepressants are not more effective than older ones, they are better tolerated and are safe especially in overdose. The adverse effect data suggest modest superiority of selective serotonin reuptake inhibitors over tricyclic antidepressants. The evidence available indicates that antidepressant treatment of four weeks has a beneficial effect compared to. As to prevention of relapse and recurrence, antidepressants should be continued for at least six months after good 1 Department of Geriatrics and Gerontology, 2 Heymans Institute of Pharmacology and 3 Emergency Department, Ghent University Hospital Address for correspondence: Prof. Dr. M. Petrovic, Departement of Geriatrics and Gerontology Ghent University Hospital, De Pintelaan 185, B 9000 Ghent, Belgium Tel: 32-9-240 23 66 Fax: 32-9-240 38 95 E-mail: mirko.petrovic@ugent.be initial response. In patients with high risk of relapse, treatment should be continued for at least two years. Long-term efficacy has been shown for dosulepin, nortriptyline and. In patients with dementia with persistent and significant symptoms antidepressant treatment may be indicated. At present, clomipramine, and have been reported as being superior to. There is a paucity of data on the use of antidepressants in very elderly individuals, patients with significant comorbidity and patients with dementia. More data on the effect of antidepressants in the elderly, especially in the over 80-age group are needed. INTRODUCTION Community studies have shown that 25% of elderly persons report having depressive symptoms, but only 1% to 9% meets the criteria for major depression (1). Higher prevalence rates are reported in the hospitalised elderly (36% to 46%) and patients in long-term care facilities (10% to 22%) (2). Depression is an important risk factor for suicide in the elderly. Furthermore, depression leads to impairment in function, exacerbation of pre-existing medical conditions, excessive use of medical resources and increased mortality. The main goals of treatment of depression are prevention of suicide, alleviation of symptoms, prevention of relapse (during the period of recovery) and recurrence (after a period of being well). The next aim is to achieve restoration of social functioning (i.e. interpersonal relationships and self-care). A medicinal intervention for depression is appropriate for this population, especially those patients with severe chronic disease.

151 Antidepressants are more hazardous in old age due to age-related pharmacokinetic and pharmacodynamic changes, concomitant diseases and polypharmacy. Elderly patients are at an increased risk for adverse drug effects, which may be exacerbated by concurrent medical illnesses. Moreover, the same side effects may be more dangerous in the elderly compared to younger adults. Drug interactions are also more likely in the elderly, as the older patient often takes several medications. Because of these risks, it is advisable to start low and go slow when starting antidepressants in elderly patients. In general, it is recommended that initial antidepressant doses should be one-third to one-half of the usual adult dose and should be titrated appropriately to minimise adverse reactions (3, 4). An ideal antidepressant would have unchanged pharmacokinetics with ageing, be free of interactions with other drugs frequently used in the elderly, be safely administered even to frail elderly patients and be safe in overdose. It would have a once-daily dosage regimen, proven efficacy against, rapid onset of antidepressant action and a good side-effect profile (5). The following categories of antidepressants are available: monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and other antidepressants such as the noradrenaline and specific serotonin antidepressant (NASSA) mirtazapine, the serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine, the pure noradrenaline reuptake inhibitor (NARI) reboxetine and the modulator of serotonergic neurotransmission trazodone. METHODS We searched the electronic databases Medline and the Cochrane Library. In addition, manual crossreferencing of antidepressant treatment review articles and meta-analyses was also used to identify randomised controlled trials examining antidepressant use in the elderly. Randomised, controlled clinical trials were included if they were published between 1980 and 2005 and the language of publication was English. The electronic search strategy included the following medical subject headings (MeSH): elderly, geriatric, senile, older, older age, later life aged, 60-and-over combined (AND) with depression or dysthymia AND pharmacotherapy. Efficacy measures, number of patients, percentage of responders and diagnostic criteria used for diagnosis of depression had to be mentioned. To be included in this report, studies had to meet specific inclusion criteria. These criteria included randomisation of subjects, or active comparator control arm and study duration of four weeks or greater. They had to include subjects age 60 and over and with diagnosis of major depressive disorder or unipolar depression using defined criteria, such as DSM. RESULTS Thirty-six randomized controlled trials of patients over the age of 60 met the selection criteria in addition to a meta-analysis which included 17 randomised controlled studies. Table 1 summarises the randomised, and active comparator data for TCAs and SS- RIs. A meta-analysis of 17 trials of the main classes of antidepressants (MAOIs, TCAs, SSRIs and other antidepressants) has shown response rates of 50-60% in the elderly compared with 25% for in acute treatment of depression without significant differences between classes (6). Seven studies, mainly using, nortriptyline or, have shown the efficacy of TCAs in the elderly (7-13). Two studies demonstrated long-term efficacy of dosulepin (dothiepin) and nortriptyline in elderly patients at high risk of relapse (14, 15). Two studies in patients with depression and Alzheimer s disease have shown that clomipramine (16), but not (17) was superior to as measured by the response of depressive symptoms, but had a mild adverse effect on cognition. SSRIs have comparable antidepressant effects to TCAs, and the response rate in the elderly can be as high as 60% (6). Two studies provided the evidence that was as effective as (18) and superior to (19) in short-term treatment of depression in the elderly. Two studies demonstrated superiority of to in treatment of depression in preventing recurrence of depression in the elderly (20, 21) and in patients with dementia (22). In five studies has been shown to be as effective as and doxepin, and superior over trazodone and in alleviating depression in the elderly (23-27).

152 Table 1. Randomised controlled studies of TCAs and SSRIs in the elderly Author Year Number of patients Altamura AC et al. Cohn JB et al. Gerner R et al. Hoyberg OJ et al. Merideth CH et al. Nair NP et al. Tignol J et al. Anonymous Reynolds CF et al. Petracca G et al. Reifler BV et al. Kyle CJ et al. Nyth AL et al. Ragneskog H et al. Nyth AL et al. Klysner R et al. Tollefson GD et al. Feighner JP et al. Altamura AC et al. Falk WE et al. Taragano FE et al. Dorman T Ravindran AV et al. Schone W et al. Katona CL et al. Sheikh JI et al. Oslin DW et al. Lyketsos CG et al. Wakelin JS Phanjoo AL et al. Rahman MK et al. Schatzberg AF et al. Mahapatra SN et al. Oslin DW et al. Katona C et al. Rampello L et al. 1984 1980 1984 1995 1998 1993 1999 1998 1992 1990 2002 1995 1985 1997 1992 1993 1998 2004 2000 2003 1986 1991 1991 2002 1997 2003 1999 2005 106 63 60 115 61 109 219 219 187 21 61 196 149 123 98 121 671 157 28 27 37 60 1002 106 198 752 97 44 76 57 52 246 92 52 347 98 Drug studied nortriptyline dothiepin nortriptyline clomipramine fluvoxamine fluvoxamine fluvoxamine mirtazapine venlafaxine venlafaxine reboxetine reboxetine Comparator mianserin, trazodone, nomifensine plecebo, trazodone mirtazapine, nomifensine moclobemide milnacipran doxepin trazodone mianserin clomipramine nortriptyline mianserin dothepin dothepin Two studies provided the evidence that was equally effective as mianserin and clomipramine (28, 29). Two studies showed respectively that amelioration of depressive symptoms in geriatric patients took place more rapidly with compared with (30) and that in comparison with there was a significantly greater improvement on the Cornell Scale in demented patients taking, but a similar improvement using a general scale for depression (31). In three studies showed to be not as effective as nortriptyline, but superior to both in non-demented patients and in patients with Alzheimer disease in reducing depressive symptomatology in the elderly (32-34). Three studies with fluvoxamine have shown similar efficacy to, mianserin and dothiepin in the shortterm treatment of depression in elderly patients (35-37). The efficacy of mirtazapine in the elderly was assessed in two studies. Mirtazapine demonstrated to be as effective as in treatment of depression in the elderly (10). In comparison with, improvements were seen earlier in the mirtazapine-treated patients and they also experienced a greater reduction in sleep disturbance (38). Two studies assessed the efficacy of venlafaxine in depressed elderly. In a comparison with dothiepin, improvements were seen earlier in the venlafaxine-treated patients and they also experienced a greater reduction in suicidal ideation (39). In another trial versus sertra-

153 line, venlafaxine was less well-tolerated and less safe than without evidence of an increase in efficacy (40). Two studies assessed the efficacy of reboxetine in depressed elderly. Reboxetine demonstrated to be equally effective as and superior over in treatment of depression in the elderly (41, 42). The efficacy of trazodone in the elderly was assessed in a comparison with. The two active medication groups had similar therapeutic efficacy and both improved significantly compared to (9). The available evidence indicates that SSRIs are slightly better tolerated than TCAs. Fluoxetine has shown to be better tolerated and to have fewer side effects than doxepin (24). A controlled comparison between and amitriptilyne demonstrated that anticholinergic side effects were significantly more severe in the group. Weight gain was detected only in patients with (25). A comparison between and trazodone showed that constipation was more common in patients receiving trazodone and insomnia more common in the -treated patients (26). In a comparative study with mianserin, was associated with less anticholinergic effects (28). In comparison with clomipramine, showed less tremor and somnolence (29). In a controlled study with, trazodone was shown to have fewer side effects (9). DISCUSSION Given the consequences of depression in the elderly, effective and well-tolerated antidepressant therapy is required. These studies support the clinical observation that antidepressants can effectively treat depression in the elderly. On the other hand, these results should be interpreted with caution, as trial populations are to some extent unrepresentative of clinical populations. A limitation of the existing literature is that most studies have included medically stable patients without dementia and younger than 80 years of age. The existing evidence with regard to pharmacotherapy of depression in old age is mainly based on information that has not adequately reflected the heterogeneity of the patient sample, potential complications of age, frailty, comorbidity and multiple treatments. Many of the existing studies are efficacy trials, not effectiveness trials. Moreover, they examine antidepressant response in a well defined patient population, excluding subjects for many reasons such as significant psychiatric or medical comorbidity. Therefore, there is a paucity of data on the use of antidepressants in very elderly individuals, patients with significant comorbidity and patients with dementia. In every-day practice response rates may be lower (43). There is a significant heterogeneity in geriatric depression, and current definitions of depression do not comprehend well the whole spectrum of depressive disorders. Studies addressing comorbidity in elderly depressed populations who are not healthy and cognitively intact are required. Type of setting (i.e. community, outpatient clinics, general hospitals, psychiatric hospitals or psycho-geriatric wards, old people s homes, nursing homes) is an important factor given that it may influence illness severity, medical comorbidity, or level of cognitive function. It is also essential to examine interventions to treat depression in a variety of settings. To date, there is no one drug or class of antidepressants that will suit all older patients. The prescription should be tailored to the individual patient. A prior history of response or intolerance to a particular drug or class may help to predict efficacy in the present episode. Other prescribed medication in terms of possible drug-drug interactions and/or adverse reactions should also be taken into consideration. A particular drug could exacerbate one or more underlying medical conditions. The side-effect profile of a particular class might play an important role when choosing an antidepressant for an individual elderly patient. Although MAOIs have been found to be equally effective as TCAs and SSRIs in treatment of depression in the elderly, they are not considered to be first-line antidepressants in the elderly because of the dietary restrictions, drug-drug interactions and their extensive side-effect profile (i.e. postural hypotension and vertigo, anxiety, agitation, insomnia and daytime sedation) (5, 44). TCAs have several side effects. Anticholinergic side effects, such as dry mouth, urinary retention, blurry vision, and constipation, can lead to more serious consequences, including improperly fitting dentures, faecal impaction and increased falls (4, 45). Central anticholinergic effects may result in an anticholinergic syndrome, which is characterized by confusion and memory disturbances. This syndrome may be misdiagnosed as dementia or worsening depression. Histaminergic effects may result in sedation and weight gain.

154 TCAs may, due to their anti-adrenergic effects, cause various cardiovascular effects including arrhythmia or orthostatic hypotension. However, TCAs in doses of less than 100 mg ( equivalents) do not increase the risk of cardiac death. On the other hand, higher doses of TCAs may be associated with increased relative risk compared to SSRIs, which suggests that such doses should be used cautiously in patients at increased risk of sudden death (46). Concerning the risk of falls and consecutive hip fractures, it has been shown that TCAs do not increase the risk of hip fracture more than SSRIs (47, 48). Side effects such as sedation, hypotension and anticholinergic effects may be exacerbated if TCAs are prescribed together with other drugs with similar side effects, such as benzodiazepines. The risk of morbidity and mortality is high in overdose. Most of adverse effects associated with SSRIs appear to result from excessive blockade of peripheral and central serotonin reuptake. These effects include gastrointestinal dysfunction (nausea, vomiting and loose stools) and insomnia. Sexual dysfunction can be caused by SSRI as often as by TCAs (49). SSRIs are more frequently associated with hyponatriaemia than other classes of antidepressant drugs (50). SSRIs can decrease intraplatelet serotonin concentrations and this may affect platelet aggregation (51). This can be of importance when choosing an antidepressant in elderly who have had a recent myocardial infarction or stroke (52, 53). On the other hand, SSRIs may be associated with an increased risk of upper gastrointestinal bleeding, particularly in patients taking non-steroid anti-inflammatory drugs (54). The SSRI venlafaxine is contra-indicated in patients with heart failure, coronary heart disease and uncontrolled hypertension (55). In susceptible patients, treatment with SSRIs may also be associated with anxiety, restlessness, tremor and akathisia. SSRIs produce changes in sleep architecture (i.e. decreased sleep latency and decreased total REM sleep) (5, 56). While these effects do not have the potential for serious medical consequences, they can cause enough distress that patients discontinue therapy. Drug interactions are another important consideration in the selection of an appropriate antidepressant in the elderly. Most drugs are metabolized in the liver by the cytochrome P-450 (CYP-450) system. Drugs which might be subject to adverse interactions with TCAs are: anticholinergics, sympathomimetics, SSRIs, carbamazepine and lithium. For SSRIs there are adverse interactions with drugs metabolised via cytochrome P-450 subtypes such as warfarin, carbamazepine, theophylline, terfenadine and astemizole. Awareness of potential interactions is an important component of safe prescribing practice for older people with depression (57). There is a paucity of literature on cost-utility analysis of pharmacotherapy of depression in old age. As to the price, SSRIs cost more to purchase than TCAs, although it has been argued that they may not increase overall health care costs. High-quality cost-utility analysis should be considered for further research in pharmacotherapy of depression in old age (58, 59). At present, there have been few studies of longterm treatment of depression in the elderly. As to prevention of relapse and recurrence, antidepressants should be continued for at least six months after good initial response (14). The limited available evidence in the elderly suggests that in patients with high risk of relapse, treatment should be continued for at least two years (14, 15, 21). Indicators of high risk of relapse are two or more episodes in the previous two years, chronic physical illness or significant social stressors. Long-term efficacy in patients at high risk of relapse has been shown for TCAs dosulepin (dothiepin) and nortriptyline and for the SSRI. There is also a paucity of evidence for treating depression in dementia (60). However, in patients who have persistent and significant symptoms drug treatment may be indicated. At present, the TCA clomipramine and SSRIs and have been reported as being superior to. More data on the effect of antidepressants in the elderly, especially in the over 80-age group are needed. Further studies should include a comprehensive geriatric assessment in order to assess the effects of the treatment on geriatric outcomes (social, functional, cognitive, comorbidity, malnutrition, falls, etc.) CONCLUSIONS There is a paucity of data on the use of antidepressants in very elderly individuals, patients with significant comorbidity and patients with dementia. Existing clinical evidence suggests that the main antidepressant classes are equally effective in the treatment of older people with depression. Although newer antidepressants are not more effective than older ones, they are better tolerated and are safe especially in overdose. The adverse effect data suggest modest superiority of SSRIs over TCAs.

155 The evidence available indicates that antidepressant treatment of four weeks is likely to have a beneficial effect compared to. As to prevention of relapse and recurrence, antidepressants should be continued for at least six months after good initial response. In patients with high risk of relapse, treatment should be continued for at least two years. Long-term efficacy in patients at high risk of relapse has been shown for TCAs dosulepin (dothiepin) and nortriptyline and for the SSRI. In patients with dementia who have persistent and significant symptoms antidepressant treatment may be indicated. At present, the TCA clomipramine and SSRIs and have been reported as being superior to in such patients. ACKNOWLEDGEMENTS The authors are indebted to Prof. Dr. M. Bogaert for his revision of the manuscript and the constructive suggestions. REFERENCES 1. 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