Serotonin-selective reuptake inhibitors in the treatment of geriatric depression and related disorders

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1 International Journal of Neuropsychopharmacology (1999), 2, Copyright 1999 CINP Serotonin-selective reuptake inhibitors in the treatment of geriatric depression and related disorders REVIEW ARTICLE J. Jeffrey Mulchahey 1, 2, Mohammad S. Malik 2, Mya Sabai 2 and John W. Kasckow 1, 2 Cincinnati VAMC, Psychiatry Service, 3200 Vine Street, Cincinnati, OH USA University of Cincinnati College of Medicine, Department of Psychiatry, 231 Bethesda Ave (ML 559), Cincinnati, OH USA Abstract Depression is a common disorder in late life which can be successfully treated with antidepressant agents. Other disorders such as behavioural agitation associated with dementia may also be treated with antidepressants. In this review, we have examined the use of five serotonin-selective reuptake inhibitors in the treatment of late-life depression and related disorders in the elderly population. Medications examined include citalopram, fluoxetine, fluvoxamine, sertraline and paroxetine. Comparisons of these agents efficacy in the elderly are made. In addition, comparisons of these agents side effects, pharmacokinetics and potential for drug drug interactions are also discussed. Received 6 December 1998; Reviewed 18 January 1999; Revised 31 January 1999; Accepted 14 February 1999 Key words: SSRI, geriatric, depression, dementia. Introduction Depression in late life is a common psychiatric disorder. Prevalance rates of clinically significant subsyndromal depression are as high as 27% in individuals greater than 64 yr of age. Prevalance rates of major depression are lower, i.e. 1 2% (Johnson et al., 1992; Judd et al., 1994). The consequences of depression left untreated in the elderly include despair and suffering, increased medical co-morbidity, increased suicide risk, risk of institutionalization and excessive caregiver stress (NIH Consensus Development Panel, 1992). Despite the important individual and public health implications of latelife depression, depression in the elderly is often underdiagnosed and undertreated. The reasons for this include lack of awareness of the disorder from the point of view of physicians, denial on the part of the patient, occurrence of medical co-morbidity which often places the treatment of depression at a lower priority than medical problems, plus the fact that depression in late life presents differently than depression in young adults (Bayer and Pathy, 1989; Blazer, 1980). Depression is an illness, however, which responds favourably to treatment and thus requires aggressive intervention especially in the elderly (Baldwin and Jolley, 1986; Cole, 1990). Address for correspondence: Dr J. W. Kasckow, Cincinnati VAMC, Psychiatry Service, 3200 Vine Street, Cincinnati, OH, USA Tel.: (513) Fax: (513) JKasckow pol.net The serotonin-selective reuptake inhibitors (SSRIs) are some of the newest classes of antidepressants which are important in the treatment of depression in all age groups. Within this past decade they have become the first line agents in the treatment of late-life depression. SSRIs and the older tricyclic antidepressants (TCAs) demonstrate equivalent efficacy in younger and older adults although the side effect burden of TCAs is troublesome in both populations (Anderson and Tomenson, 1995). General principles of SSRI use in the elderly In general, it is recommended that pharmacologic management of the elderly is undertaken cautiously. This does not mean, however, being hesitant in commencing pharmacologic treatment of depression in a geriatric patient. Of course, the Start Low and Go Slow strategy needs to be followed (Young and Meyers, 1996). The reason for starting at lower doses can be accounted for by typical pharmacokinetic and pharmacodynamic changes that may occur with ageing as summarized below (Young and Meyers, 1996). These changes influence the approach taken in pharmacologic treatment. This includes the choice made in deciding upon a starting dose, and the rate of titration as well as the length of treatment needed for an adequate response. The process of drug demethylation, as well as other

2 122 J. J. Mulchahey et al. metabolic steps of drug inactivation, may decline with age (Abernethy et al., 1985). Increases in the ratio of body fat to water will also increase the volume of distribution for lipophilic psychotropic drugs in the elderly. Furthermore, glomerular filtration rate decreases with ageing (Rowe, 1980) and may account for higher concentrations of drug metabolites. All of these age-associated pharmacokinetic changes may reduce drug clearance and metabolism and prolong drug half-life. In addition to the above pharmacokinetic effects, pharmacodynamic changes with ageing may make the elderly brain more sensitive to medications (Young and Meyers, 1996). Essentially, recommended starting doses are usually one-half of that utilized in younger adults. For the frail elderly patient, the starting dose should probably be less, of the order of one-fourth the typical starting dose in young adults (Dunner, 1994). As in younger patients, the aim is towards achieving the maximal positive therapeutic effect with the lowest dose while minimizing side-effects. It may also take more time to achieve a therapeutic effect in the elderly in comparison to younger individuals. In contrast to younger populations, the treatment of depression in an elderly patient may require 9 wk or longer before improvement is noted (Georgotas et al., 1986). Efficacy studies of SSRIs in late-life depression There are few comparative controlled geriatric studies which examine the differences between the available antidepressants (Skerritt et al., 1997). There are five SSRIs which are available as antidepressants. These are fluoxetine, fluvoxamine, sertraline, paroxetine and citalopram. As mentioned, the SSRIs have been demonstrated to have equal efficacy to that observable for the TCAs (Anderson and Tomenson, 1995; Montgomery, 1993; Montgomery et al., 1994b). Although the number of efficacy studies with SSRIs in the elderly are few in number, there is no reason to suspect why an antidepressant which works well in young adults would not also work well in the elderly (Skerritt et al., 1997). The following summarizes SSRI antidepressant studies in the elderly. One 4-wk study utilizing a small number of patients compared fluvoxamine, the TCA imipramine and placebo; both the SSRI and TCA were better than placebo. Another larger study compared fluoxetine and placebo and demonstrated a 35% improvement rate of fluoxetine over placebo (Skerritt et al., 1997; Tollefson and Holman, 1993). One study which compared fluoxetine, doxepin, amitriptyline and trazodone demonstrated comparable efficacy between these drugs (Altamura et al., 1989; Falk et al., 1989; Feighner and Cohn, 1985). Paroxetine has been compared to doxepin, chlomipramine, amitriptyline, mianserin and fluoxetine in several studies involving elderly populations (Dorman, 1992; Dunner et al., 1992; Guillibert et al., 1989; Hutchinson et al., 1992; Schonne and Ludwig, 1993). Based on a meta-analysis of all of these studies, paroxetine was reported to be of comparable efficacy to the other antidepressants (Dunner et al., 1992). Sertraline has also been demonstrated to be as efficacious as amitryptiline in elderly depressed patients. The attrition rate in this latter study was 50%; this high attrition rate is a common problem in clinical trials which evaluate antidepressants in the elderly and is comparable to that observed in other studies (Cohn et al, 1990). Citalopram has also been evaluated in controlled trials involving geriatric patients. In one 6-wk double blind, placebo-controlled trial in 133 elderly depressed individuals, significant improvements were observed when patients were evaluated with the Montgomery Asburg Rating Scale. Significant improvements were observable on symptoms of apparent and reported sadness, concentration troubles and suicidal thoughts. Based on the Clinical Global Impression Scale, at week 6, 60% of patients on citalopram had significantly improved symptoms compared to 24% on placebo (Gottfries et al., 1992; Nyth et al., 1992). Andersen et al. (1994) also examined the effects of citalopram on rates of post-stroke pathological crying. Sixty-six patients in one study with post-stroke depression were randomized to citalopram or placebo treatment. The citalopram-treated group had a statistically significant fall in both Hamilton Depression Rating scores and Melancholia Scale scores as early as 3 wk compared to the placebo group. All of these studies demonstrate the efficacy of SSRIs in treating depression in the elderly. Use of SSRIs to treat patients with behavioural disturbances associated with dementia A review of the current literature indicates that rates of agitation in the elderly with dementia range from 10 to 90% with a median rate of 44% (Tariot and Blazina, 1994). Research reveals that dysregulation of serotonin is associated with a variety of subtypes of dementia. It is hypothesized that treatment with SSRIs improves the symptoms of dementia by restoring serotonergic function to premorbid levels (Nyth and Gottfries, 1990; Tariot, 1996). The data below summarizes the trials which have investigated the use of SSRIs in the treatment of behavioural disturbances in dementia. One study investigated 98 subjects with dementia having behavioural disturbances treated in a double-blind fashion with citalopram or placebo. A dose of mg d of the medication improved emotional blunt-

3 SSRIs in treating geriatric depression 123 ness, confusion, irritability, anxiety, fear panic, depressed mood and restlessness in patients with Alzheimer s dementia but not those with vascular dementia. Very few mild side-effects were reported (Nyth and Gottfries, 1990). Another 6-wk placebo-controlled study examined the effects of citalopram on depression in patients with and without dementia. Montgomery Asburg Scale and Clinical Global ratings were improved in the citalopramtreated group (Nyth et al., 1992). Pollock et al. (1997) performed an open label assessment of patients with dementia and behavioural disturbance treated with citalopram. Thirteen out of 16 patients completed the 17 d study and 9 of those had an improved response based on assessments with the Neurobehavioral Rating Scale and Clinical Global Impression Scale. Fluvoxamine has been investigated in a double-blind, placebo-controlled, parallel-group study of 46 patients with dementia. No significant effect was found with fluvoxamine although there were trends towards improvement in co-morbid confusion, irritability, anxiety, fear panic, mood level and restlessness (Olafsson et al., 1992). Another open-label trial involved 5 patients with probable Alzheimer s disease and mg d of fluoxetine was administered for 4 wk. No benefits were observed. Three patients withdrew as a result of side effects (Geldmacher et al., 1994). An open-label study undertaken with sertraline reported improvement in 6 out of 10 patients with Alzheimer s dementia. Minimal sideeffects were noted. Improvement was noted with symptoms of irritability, depressed mood, attention and food intake. Another open-label study with 3 patients with Alzheimer s dementia treated with sertraline revealed decreases in depressive symptoms and psychosis without any accompanying side-effects (Burke et al., 1994). These studies indicate that citalopram and possibly sertraline are useful in reducing behavioural disturbances associated with dementia. Pharmacokinetics and dosing of SSRIs in geriatric patients The elimination half-life of citalopram is approx. 35 h. There are two metabolites which are clinically inactive demethyl-citalopram and didemethyl-citalopram. The volume of distribution is 12 l kg (Baumann and Larsen, 1995; Preskorn, 1993; Scates and Doraiswamy, 1998). There are no significant differences between the pharmocokinetics of citalopram in the elderly vs. young adults based on the analysis of C max, T max and area under curve (AUC) (Gutierrez, 1997; Hakkarainen, 1998). In the treatment of the elderly depressed patient, initial doses are recommended to be the same as that in young adults, i.e. 20 mg d. Of course, in some elderly patients, lower starting doses may be required. Doses exceeding 40 mg d are generally not recommended for the treatment of depression in the elderly. The volume of distribution of fluvoxamine is 5 l kg; it is thus distributed to tissues with high blood flow such as the liver, lungs and kidney. In addition, it has a half-life of approx. 16 h (Benfield and Ward, 1986). In elderly patients, the clearance is reduced by about 50% and the half-life increases to h after chronic dosing (Jackson, 1995). In addition, fluvoxamine has no active metabolites (Benfield and Ward, 1986). In the treatment of depression in the elderly, initial recommended daily doses of fluvoxamine start at mg (Benfield and Ward, 1986). In order to decrease the likelihood of adverse effects, if doses greater than 100 mg d are required, the drug may be administered in divided doses (Jackson, 1995). Sertraline is a potent inhibitor of serotonin reuptake with much less activity on dopamine reuptake blockade; it has minimal effects on norepinephrine reuptake (Richelson, 1994). The oral bioavailability of this agent may be increased with food. Its volume of distribution is rather large, 20 l kg (Jackson, 1995) and the half-life of sertraline in young adults is 25 h. Sertraline plasma clearance in elderly patients is about 40% lower in comparison to that seen in younger adults (Preskorn, 1993). Initial recommended dosing of sertraline for the treatment of depression is 25 mg d in the elderly population. After initial dosing, sertraline can be titrated upward, if necessary to a maximal dose of 200 mg d (Jackson, 1995). Paroxetine is a potent inhibitor of serotonin reuptake (Dechant and Clissold, 1991). There is no apparent difference in the bioavailability and volume of distribution between older and younger patients with paroxetine administration (Dechant and Clissold, 1991). The half-life of paroxetine is approx. 24 h (Jackson, 1995). Paroxetine can be initially dosed in elderly patients at 10 mg d and increased weekly to a maximum of 40 mg d, as tolerated (Dechant and Clissold, 1991). The active metabolite of fluoxetine is norfluoxetine. Both fluoxetine and its active metabolite are potent SSRIs. Fluoxetine s half life is approx. 2 4 d while that for norfluoxetine is 7 9 d. The rate of fluoxetine demethylation in the elderly may decrease and may also reduce clearance. In the elderly the greater amount of time needed to eliminate the drug is of is of concern, particularly should side-effects arise. The initial dosage of fluoxetine may start at 10 mg d and then gradually be increased, if necessary to a maximal dosage of 60 mg d. In the elderly, fluoxetine may cause a decrease in appetite as well as slight weight loss of about kg in magnitude (Newhouse, 1996).

4 124 J. J. Mulchahey et al. Adverse effects of SSRIs The SSRIs, as the name implies, act specifically at the serotonin transmitter. Common side-effects of these agents include nausea, nervousness and insomnia (Kerr et al., 1991; Rasmussen et al., 1993). All of these may occur in the geriatric population; the elderly may be more sensitive to these effects. The most commonly observed side-effect is nausea which is usually mild in severity. Often it is only transient during treatment (Cooper, 1988; Hindmarch, 1990). Dry mouth can occur but it is related to indirect effects on noradrenergic influences on the salivary gland. Blurred vision may also be caused by serotonin effects on the innervation of the pupil (Altamura et al., 1989). If anxiety symptoms occur, they are usually only present transiently. Sedation can also be a problem with SSRIs; paroxetine appears to be more sedating than the other SSRIs (Dechant and Clissold, 1991; Guillibert et al., 1989). Of the five SSRIs, paroxetine exhibits the most muscarinic blockade with a binding affinity less than imipramine but greater than nortriptyline (Richelson, 1994). Despite the anti-muscarinic action of paroxetine documented in vitro, studies in elderly patients have suggested that cognitive dysfunction is not compromised with paroxetine as is observed with other antidepressants with anticholinergic action (Dunner, 1994; Dunner et al., 1992). Adverse effects on sexual function can occur with SSRIs and these include most commonly, anorgasmia as well as delays in orgasm (Herman et al., 1990). This is still relevant in the geriatric population since sexual interest and activity may continue into old age for both sexes (Renshaw, 1996). In addition, abrupt discontinuation of some of the SSRIs has been noted to lead to withdrawal side-effects which include dizziness, fatigue and nausea (Haddad, 1997). Rates of a withdrawal syndrome which can occur following abrupt discontinuation of three of the SSRIs have been compared. The rate reported for fluoxetine is 14%, that for sertraline is 60% and for paroxetine, the rate is 60% (Rosenbaum et al., 1998). It should be noted that these results were based on populations of young and old adults. The SSRIs lack the same degree of sedative-related and weight gain-related adverse effects observed with the TCAs (Grimsley and Jann, 1992). The lack of all SSRIs effects on cognition also make them more attractive agents for the elderly population (Hindmarch, 1990). Overdose risk with all of the SSRIs is a great deal lower when compared to the TCAs (Barbey and Roose, 1998). In addition, all SSRIs may cause movement disorders, particularly extrapyramidal symptoms and even tardive dyskinesia (Leo, 1996). A less common adverse effect also associated with SSRI use includes hyponatraemia. This is thought to be due to inappropriate secretion of antidiuretic hormone (Bouman et al., 1998) and the elderly are at risk for this. SSRIs do not have significant effects on cardiac conduction like the TCAs (Feighner and Cohn, 1985; Hindmarch, 1990; Wakelin, 1986). Meta-analyses have been performed evaluating the effects of SSRIs vs. TCAs on discontinuation rates due to adverse events. The evidence from these analyses suggests that discontinuation rates are higher with the tricyclic compounds (Montgomery et al., 1994a; Song et al., 1993). Although the frequency of adverse effects of SSRIs is higher than that observed with TCAs, the impact of the TCAassociated side-effects on functioning and tolerability is much greater (Altamura et al., 1989; Dunner et al., 1992; Falk et al., 1989; Feighner and Cohn, 1985; Guillibert et al., 1989). Although these latter studies have not included enough geriatric patients to warrant any definitive conclusions with regards to late life, these results can be generalized to the elderly population. Drug drug interactions All SSRIs have potential interactions with the cytochrome P450 enzyme system. This effect, in turn, can lead to potential drug drug interactions. Fluoxetine, norfluoxetine, citalopram, sertraline and paroxetine, but not fluvoxamine are all in vitro inhibitors of the 2D6 isoenzyme system (Nemeroff et al., 1996). This isoenzyme system is responsible for the metabolism of type Ic antiarrhythmics, α-adrenergic blockers, dextromethorphan, chemotherapeutic agents, TCAs and some antipsychotics. Cytochrome P450 3A4 is responsible for the metabolism of numerous drugs, including various benzodiazepines, i.e. alprazolam and triazolam as well as carbamezepine, terfenadine, astemizole and cisapride, calcium channel blockers and others. These enzymes are inhibited by fluoxetine, sertraline and fluvoxamine (Murray, 1992; Pollock, 1994). Co-administration of these inhibitors with terfenedine, astemizole and cisipride is contra-indicated since elevated blood levels of these three compounds can lead to lethal arrhythmias. Cytochrome P450 1A2 is the liver isoenzyme responsible for dealkylating theophylline, caffeine and phenacetin. Tacrine and clozapine are also metabolized by this enzyme system. Of the SSRIs, fluvoxamine has the most inhibitory action on the 1A2 enzyme. Cytochrome P450 2C is a subfamily of isoenzymes which include 2C9, 2C10, 2C19 and others. This system metabolizes some antidepressants as well as warfarin, phenytoin and

5 SSRIs in treating geriatric depression 125 diazepam (Rettie et al., 1992; Smith, 1991). Inhibitors of this system include fluvoxamine, fluoxetine, sertraline and paroxetine (Jalil, 1992; Skjelbo and Brosen, 1992; Preskorn, 1993). Thus there are differences between the SSRIs in terms of their effects on the cytochrome P450 system. Concomitant use of serotonergic-acting drugs and monoamine oxidase inhibitors (MAOI) should be avoided. When used in conjunction, these medications can cause a serotonin syndrome. Hyperpyretic crises, seizures, coma, and death are potential consequences. Furthermore, when switching from a serotonin-acting drug to an MAOI, it is important to completely eliminate the serotonergic agents. In young adults, a 7 d washout is needed when switching from fluvoxamine, and 14 d when switching from sertraline, citalopram and paroxetine. With fluoxetine the washout period is 35 d. Given the propensity of elimination half-lives in the elderly to be prolonged as much as 2- to 3-fold, it is advisable to proceed conservatively and extend these washout periods accordingly. In young adults, a 14-d washout is recommended between discontinuing an MAOI and initiating a serotonergic-acting drug (Benfield and Ward, 1986). In the elderly, the waiting period may also need to be prolonged. Conclusions Clearly the SSRIs share distinct advantages for the treatment of depression in late life in comparison to the other antidepressants. This is also true when treating behavioural agitation associated with dementia with antidepressants. SSRIs have an improved adverse event profile and lack of lethality in overdose. There are not many controlled trials which have examined the use of these agents in geriatric patients; however, most of our understanding of the applicability of SSRIs to geriatric depression is derived from studies involving non-geriatric or populations with young and older adults. The shorter half-life SSRIs, i.e. citalopram, sertraline, paroxetine and fluvoxamine could be eliminated more rapidly should adverse events arise. This is important since half-lives of medications are likely to be longer in geriatric patients given the pharmacokinetic changes which occur with ageing. On the other hand, use of the longer acting agent, fluoxetine may be advantageous if compliance is a problem. For instance, the reduced washout rate could lead to prolonged retention of the drug and a lower propensity to relapse. The interaction of the five SSRIs with other drugs that the patient may be taking should also be considered when choosing pharmacotherapy. The use of multiple pharmacologic agents often cannot be avoided given the higher rates of medical co-morbidity in geriatric patients. Other considerations which are important in choosing an SSRI are effects on discontinuation symptoms as well as the side-effect of somnolence. More research is needed to improve our treatment of geriatric patients with SSRIs. For instance, relative rates of adverse events between the SSRIs need to be determined as well as the relative ability of each of these agents to prevent relapse in chronic conditions. Relative differences, if any, in onset of response also needs to be determined with these five agents. Furthermore, studies of effective augmentation strategies with SSRIs need to be evaluated in the elderly population. Continued research in this area would better help optimize our therapeutic options when using SSRIs in geriatric patients. Acknowledgements This work was supported by an unrestricted educational grant from Forrest Pharmaceuticals. 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