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Treatment of depression in late life
Treatment of Depression in Late Life CHARLES
F. REYNOLDS
III,
M.D.,
Pittsburgh,
Pennsylvania
Depression is a common, but treatable, source of suffering, excess disability, and caregiver strain in late life. It is important to take a long-term view of the treatment of late-life depression because of the high risk for relapse, recurrence, and chronic illness. Elderly patients with medical and neurological illness or bereavement-related depressions also merit greater attention. Recent data highlight several important caveats: (a) the role of medical and psychosocial factors in the course of major depression; (b) variability in etiology, clinical presentation, and treatment response; (c) need for additional studies of syndromal and subsyndromal depression in primary and long-term care facilities, particularly in patients >76 years of age; and (d) importance of continuation and maintenance treatment to maintain quality of life and to lower the risk for chronic illness. Nortriptyline, desipramine, and the newer selective serotonin reuptake inhibitors (SSRIs), paroxetine and sertraline, are preferred pharmacotherapy for short-term and long-term treatment. The newer SSRIs should be further studied in controlled trials of elderly depressed patients, including those >76 years and those with medical or neurological illness. Psychotherapy also appears to be of major importance in successful outcome but, as does pharmacotherapy, merits further controlled investigation in both short- and longterm clinical trials.
From the Departments of Psychiatry and Neurology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania. Rearrests for reprints should be addressed to Charles F. Reynolds Ill, MD, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PennsyC vania 15213.
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D
epression is a common but treatable source of excess disability in the elderly population of ambulatory patients and those who reside in longterm care facilities [l]. It is important to take a long-term view of the treatment of late-life depression, particularly with respect to maintenance therapy, because of the high risk for relapse, recurrence, and chronic illness 123. Special populations of elderly persons, particularly those with medical and neurological illness, and those with bereavementrelated depressions, also merit greater clinical and research attention than they have received to date. Recent studies of depression in late life have highlighted four themes. First, medical and psychosocial factors have great salience in the onset, symptomatic presentation, and offset of major depression in the elderly [3,4]. Secondly, there is considerable variability in etiology, clinical presentation, and treatment response. Third, clinicians need the guidance of additional investigations of both syndromal and subsyndromal depression in primary and long-term care facilities, particularly in the very old and medically and neurologically frail elderly. Finally, studies increasingly emphasize the importance of continuation and maintenance treatment, beyond therapy of the acute episode, to prevent recurrence of symptoms and to maintain quality of life. Epidemiologic studies of major depression in late life have observed a prevalence of ~3% in community-dwelling elders. In contrast, a l&25% prevalence among nursing home residents and a 13% annual incidence of new episodes of major depression among residents of long-term care facilities underscore the importance of major depression in the institutionalized elderly [5,6]. However, the burden of depressive illness in late life is not limited to major depression. Studies estimate an 8-15% prevalence of subsyndromal depression among community samples. Such symptoms represent an important source of excess disability, suffering, caregiver burden, and diminished quality of life. Within the context provided by recent literature, the goals of treating depression in elderly patients should be not only the reduction and resolution of depressive symptoms, but also the prevention of relapse and recurrence, improvement in quality of life, enhancement in the ability to function, and improvement in medical health status, with a reduc-
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tion in mortality and healthcare costs. These treatment goals were articulated by the consensus panel at the NIH Consensus Conference on the Diagnosis and Treatment of Depression in Late Life [7]. Treating depression in elderly patients also needs to be understood within the broader context of their actual lives. Data from Kennedy and associates [4] have suggested, for example, that deterioration in health, persistent sleep disturbance, and lack of formal support services predicted persistence of depressive symptoms in a sample of 1,885 adults 265 years of age participating in the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area study.
SELECTINGAN ANTIDEPRESSANT FORELDERLY PATIENTS:RISKVERSUSBENEFIT Tricyclic Antidepressants Among the tricyclic antidepressants (TCAs), nortriptyline and desipramine are safer for the elderly because they are associated with a more tolerable side-effect profile than the tertiary amines, amitriptyline and imipramine. Therapeutic blood levels of nortriptyline (SO-120 ng/mL) and desipramine (2125 ng/mL) can usually be achieved and sustained in ambulatory elderly patients without orthostasis or excessive sedation, constipation, or dry mouth. The ability to monitor blood levels of these compounds facilitates assessment of both compliance and adequacy of treatment. For example, in an ongoing maintenance study of nortriptyline and interpersonal psychotherapy at the University of Pittsburgh, 78% of 61 patients aged 60-80 years with medically complicated, recurrent, unipolar depression responded to treatment with a HAMD total score of 10. Steady-state therapeutic concentrations of nortriptyline were maintained in the range of 80120 ng/mL during the open, acute, and continuation phases of the study [8]. Moreover, approximately 90% of patients who suffered a recurrence of major depression (after randomization to a maintenance placebo condition) were successfully treated to remission using combined therapy with interpersonal psychotherapy and nortriptyline prescribed at the same dose used to treat the index episode 191. The use of a biological measure-constancy of level-to-dose (L:D) ratios-has been evaluated as a means of providing a more complete assessment of compliance. Measurement of constant L:D ratios has successfully determined patient adherence to therapy. A larger variability in L:D ratio is associated with behavioral measures of noncompliance and poorer clinical outcome [lo]. For example, two succesive L:D values exceeding the group mean by 6A-4OS
1.5 standard deviations provides an indicator of potential noncompliance [lo]. Adequate pharmacotherapy in late-life depression depends not only on steady-state levels of such agents as nortriptyline, but also the duration of treatment. The findings of the University of Pittsburgh study demonstrate that the median time to recovery in the acute treatment of the index episode is 12-13 weeks 181. Thus, patients and their families should be encouraged to comply with pharmacologically adequate treatment for a sufficient period in order to ensure maximal therapeutic response. Evaluation of the University of Pittsburgh database has also shown that three atropinic side effects of nortriptyline (dry mouth, constipation, and modest increases in heart rate of 7-8 beats/min) persisted over an average of approximately 210 days of acute and continuation therapy [ll]. These symptoms are generally experienced by ambulatory depressed patients as minor nuisance symptoms that can be ameliorated by supportive countermeasures, such as stool softeners or bethanechol. In addition, nortriptyline is neither a strong promoter of weight gain in ambulatory depressed patients nor a cause of systolic orthostasis [12]. Thus, the experience of the University of Pittsburgh maintenance therapy trial in late-life depression supports the generally benign side-effect profile of nortriptyline in ambulatory elderly patients with major depression selected with due cognizance of the medical contraindications to nortriptyline (e.g., electrocardiogram conduction disturbances, acute narrow angle glaucoma, and prostatic hypertrophy with urinary retention). It is important to note, however, that the adverse effects of the TCAs, particularly amitriptyline and imipramine, may be exaggerated in the elderly. These adverse effects are principally orthostatic hypotension (which may be associated with falls), sedation, anticholinergic symptoms (including delirium), and cardiac toxicity. Recommendations for a long-term perspective of the treatment of late-life depression also require consideration of the risk-to-benefit ratio of the long-term use of any antidepressant medication. Selective Serotonin Reuptake Inhibitors The tolerable side-effect profile of the newer selective serotonin reuptake inhibitors (SSRIs), paroxetine and sertraline, supports their use in the treatment of depression in elderly patients. The newer SSRIs have been studied in comparative trials with doxepin [13] and amitriptyline [14,151. The efficacy of paroxetine treatment of depression in the elderly has been demonstrated in a 6-week,
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double-blind study, involving doxepin as an active comparator [13]. The mean age of the 271 patients involved in this study was 68 years. The mean daily doses of paroxetine and doxepin were 23.4 mg and 105.2 mg, respectively. Overall, paroxetine and doxepin were equally effective in the relief of depressive symptoms (Figure l), with paroxetine-treated patients showing significantly greater improvement in the Clinical Global Impression measure of severity of illness score, the Hamilton depression retardation factor, and the Hamilton depressed mood item. Paroxetine was also well tolerated, with lower rates of dry mouth (p
vs 28%). December
One study has directly compared two SSRIs in the treatment of late-life depression. &hone and Ludwig [171 compared paroxetine and fluoxetine in 106 elderly depressed patients. There were no significant differences in terms of 6-week endpoint HAMD total score. However, at 3 weeks, the mean HAMD total score was significantly lower (p ~0.05) in the paroxetine group (Figure 2). In addition, there were significant improvements in cognitive function as measured by Mini-Mental State examination and the Sandoz Clinical Assessment Geriatric Scale in the paroxetine-treated patients at week 3 (p ~0.04). There were no significant differences in the incidence or type of adverse effects. In this context, it is appropriate to issue several caveats about the use of SSRIs in elderly patients. Lower starting doses of paroxetine (10 mg), sertraline (25 mg), or fluoxetine (5 mg) and more gradual dosage increases may be necessary in elderly patients. However, just as in a younger population, the dose of SSRI should be increased until the optimal therapeutic response is attained. The elderly, particularly the very old, frail, or medically ill patient, may be less tolerant of long-acting
HAMD TOtal SCOE
104 0
1
2
3
/ 6
4
Week
Figure 1. Efficacy of paroxetine and doxepin In depressed elderly patients. Differences in treatment arms not statistically significant. (Reprinted from 1131, with permission.)
W
Paroxeline (N=54)
C-O
Fluoxetine (N=52)
22. 20 Baseline
Week 1
Figure 2. Paroxetine and fluoxetine pnnted from [171, with permission.)
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SSRIs and may experience extrapyramidal side effects [18], apathy [191, anorexia [20], and inappropriate antidiuretic hormone secretion [211.
CONTINUATION AND MAINTENANCETHERAPY Depression in the elderly is often a chronic illness with a tendency to recur. The risk for recurrence is particularly great among patients with onset of depression after the age of 60 [2]. Hence, most elderly patients will benefit from maintenance therapy that ensures continued remission of depressive symptoms, prevents recurrence of depression, and reduces the likelihood of chronic invalidism and psychosocial dysfunction [6]. The purpose of continuation therapy (i.e., that phase of treatment administered for 4-6 months after symptomatic resolution of the acute or index episode) is to prevent return of depressive symptoms and relapse back into the index episode. Maintenance therapy is the phase of treatment that begins after full remission of the index episode is achieved and sustained for 4-6 months. The objective of maintenance therapy is to preserve recovery and to prevent recurrence of new episodes of major depression [22]. In the ongoing University of Pittsburgh maintenance therapy study, relapse rates following discontinuation of nortriptyline after 16 weeks of continuation therapy of 24% have been reported among placebo-randomized patients. In contrast, none of the patients randomized to continue on full-dose nortriptyline experienced a return of depression [8]. Other data bearing on this point have been reported by the Old Age Depression Interest Group in the United Kingdom [23]. These investigators have observed that elders with major depression are 2.5 times less likely to suffer recurrence on dothiepin maintenance (75 mgiday for 2 years) than on placebo. In addition, although maintenance therapy with the SSRIs in late-life depression has not yet been evaluated, the efficacy and tolerability of these agents in a younger population [24-261 is promising. Elderly patients at risk of recurrence should be treated with the same dose of medication during continuation and maintenance therapy that attained a response during acute therapy. Relapse rates of 17% for nortriptyline and 20% for phenelzine were reported in one series for elderly depressed patients during 4-8 months of continuation therapy [271. Similarly, based on open-trial pilot data in 27 elderly depressives, recurrence rates of 15% occurred during 18 months of nortriptyline maintenance therapy at steady-state levels of 50150 ng mL 1281.
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Obstacles in Treatment of Late-Life Depression to Full Recovery Obstacles to adequate treatment include poor compliance, adverse effects associated with treatment, inadequate family support for proper compliance, comorbid medical illness, occult self-medication, and such psychosocial factors as bereavement and interpersonal isolation. In addition, there is an appreciable clinical risk for suicide among elderly depressed patients [29]. The rate of completed suicides is disproportionately higher in elderly patients than in younger individuals. The suicide rate among 80-&&year olds was 26.5 in 100,000 persons in 1988, which is more than double the rate of 12.4 in 100,000 in the general population. Elderly white males are at greatest risk of suicide [6]. Adverse effects of antidepressant medication treatment can generally be minimized by proper choice of agent and by the use of supportive countermeasures to render such side effects tolerable. Although it is important to consider both the medical burden in the elderly patient and the potential for drug-drug interactions, these factors need not compromise the quality of the ultimate response to antidepressant treatment [30]. Even with appreciable chronic medical burden, it is likely that most depressed elderly patients will benefit from appropriate therapy (either pharmacotherapy, psychotherapy, or a combination of both) as long as concurrent medical conditions are treated appropriately. The most important obstacle to adequate treatment is patient compliance. As many as 70% of elderly patients take only 50-75% of their prescribed dose [6]. Attrition rates due to treatment refusal or noncompliance have been minimized in the ongoing University of Pittsburgh trials. In this database, dropouts are highest during acute treatment (10.2%) but are markedly lower during continuation therapy (3.6%) and maintenance treatment (2.5%). Several factors may promote compliance and retention in treatment among elderly patients with major depression (Table I). First, there must be a consistent focus on compliance during clinic visits by all members of the treatment team, including psychiatrists, therapists, and pharmacists. Patient education about the rationale for compliance, particularly with long-term therapy, in order to increase credibility and acceptance, should be stressed. The message “Getting well is not enough. It is staying well that counts” should be conveyed to all patients and family members. Compliance is enhanced by attention to side effects and to the use of appropriate countermeasures to improve the quality of life (stool softeners, betha-
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nechol). The creation and maintenance of an alliance with family members serves as a means of education about depression in late life and the need for treatment. Educational workshops, monthly telephone calls, and family support groups are useful in this regard. Collaboration with the primary care physician will enhance awareness about the challenge and treatment of depression in late life and will elicit support for participation in long-term treatment. An attitude of caring and enthusiasm among clinicians is very important in eliciting adequate compliance that will ultimately ensure a high response rate. It is reasonable to hypothesize that compliance with long-term treatment will probably reduce suicide rates among patients with chronic mood disorders [31,32]. This point is of particular salience to depression in late life because of high rates of suicide among the elderly. In this context, it is useful to point out that the SSRIs are safer in overdose than the TCAs, with lower potential for lethality. This consideration may persuade many clinicians that the SSRIs are appropriate first-line agents for the treatment of major depression in late life.
Psychosocial Factors and Psychotherapy Stressful life events and ongoing difficulties contribute significantly to delayed response and stabilization during acute therapy of recurrent major depression in late life. Other factors may contribute to delayed treatment response, including perceived lack of social support and eccentric personality features (e.g., schizoid or paranoid types) [33]. Psychotherapy is therefore an important and perhaps critical adjuvant to pharmacotherapy in the treatment of depression in late life. However, psychotherapy should not be considered a substitute for the pharmacotherapy of depression. Interpersonal psychotherapy and cognitive behavior therapy are promising modalities that are particularly useful in depression associated with bereavement, role transitions, interpersonal conflicts, and social isolation. Psychotherapy of late-life depression is also useful for addressing feelings of hopelessness that characterize elderly depressed patients, particularly those with a history of suicide attempts and those who are likely to drop out of treatment 1341. The ongoing maintenance therapies study of recurrent major depression in the elderly at the University of Pittsburgh is designed to test the prophylactic value of nortriptyline and interpersonal psychotherapy. Initial data suggest that both modalities, separately and in combination, may be su-
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TABLEI Factors Associated with Patient Compliance During Therapy for Late-life Depresstion * Teamapproach -Psyc$atrist -Therapst -Pharmaast * Patlenteducation -Explainratlonalefor therapy -“Gethng wellISnotenough.lt is stayingwellthat counts.” * Mlmmueside effectsof TCAs -Stool softeners -8ethanechol * Familymembereducation -Workshops -Telephonefollowup -Support groups * Collaborationbetweenpsychiahistandprrmarycare -Increase awarenessof latelIfedepression -Ellclt support @Caringclinicianattitude
perior to placebo in preventing recurrence during the first year of maintenance treatment [35]. Treatment of Bereavement-Related Depression in Late Life Bereavement can be a significant factor in latelife depression [36]. The temporal course of depressive symptoms and grief intensity in late-life spousal bereavement have recently been described. The findings of a 2-year, naturalistic, follow-up study of the temporal course of depressive symptoms and grief intensity in late-life spousal bereavement suggested that the two processes follow different courses [37]. In addition, although antidepressant medication reduces symptoms of depression, pharmacotherapy appears not to diminish the intensity of bereavement per se. These findings suggest that early intervention with antidepressant medication to reduce the burden of depressive symptoms may better position patients to do the psychological work of bereavement without the additional burden of major depression. A randomized, double-blind, placebo-controlled clinical trial to address these issues further is ongoing at the University of Pittsburgh. Treatment of Depression in Alrheimer’s Dementia Depression and its related functional impairment and behavioral disturbances (including sleep disruption) pose clinically significant problems for patients with Alzheimer’s dementia. Depression in the demented patient is associated with a degrada-
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tion in quality of life, greater burden on patients long-term treatment of depressed patients with Alzheimer’s dementia, with improvement in funcand caregivers, and increased likelihood of early placement in long-term care. Depression and de- tional impairment, diminution in caregiver burden, and perhaps prolongation of community tenure. pressive symptoms are common among patients with Alzheimer’s dementia. Approximately ZO-40% .These hopes need to be investigated, however, in controlled, randomized, clinical trials addressing of cognitively impaired elders exhibit depressive both short- and long-term management. symptoms or depression [38], which are important In open-label, acute treatment studies, nortriptysources of excess functional disability in this populine appears to ameliorate depressive symptoms in lation [39]. depressed patients with Alzheimer’s dementia, The SSRIs may be strong candidates for antidepressant therapy in patients with Alzheimer’s de- thereby improving functional status and allowing mentia, although further controlled studies are many patients to remain in the community [41]. needed. Limited published data suggest that de- There was a reduction in Hamilton depression ratpression in Alzheimer’s dementia may be responings, but no change in Folstein mini-mental state sive to acute therapy with the TCAs such as imiprascores, among patients whose nortriptyline plasma mine [40] and nortriptyline [41] and to the SSRI levels were maintained in the range of 50-150 inhibitor; citalopram 1421, which is not currently ng/mL for 6-8 weeks. Moreover, improvement in available in the United States. The imipramine and Hamilton depression ratings correlated with imcitalopram studies were double-blind and placeboprovement in functional status as measured by the controlled, whereas the nortriptyline work was Blessed dementia rating scale. Improvement in open-label. The study by Reifler and colleagues [40] functional status was particularly evident in showed no significant difference between imipraBlessed items measuring regard for the feelings of mine and placebo with respect to acute antidepresothers, re-engagement in hobbies, and improved sant effect, but did show adverse cognitive effects initiative. Improvement in Hamilton items was of imipramine. most apparent in mood, early-morning awakening, The study by Nyth and colleagues 1421 was a anxiety, and appetite factors. 6-week, double-blind, placebo-controlled trial of In the treatment of depression in patients with citalopram of depressed elderly patients also sufferAlzheimer’s dementia, it is important to consider ing from somatic disorders or “senile dementia.” the possibility that the atropinic side effects of Improvements in cognitive and emotional function TCAs may mask improvement in cognition. In this were significantly greater in the citalopram-treated regard, therefore, it appears that the SSRIs may subgroup of patients with dementia than in the pla- provide a useful contrast to conventional TCA thercebo-treated subgroup. For example, citalopramapy. For example, the comparatively lower antichotreated patients with concomitant dementia and linergic, histaminergic, and adrenergic effects of depression showed more improvement than pla- the SSRIs create a clinically useful contrast to norcebo-treated patients in measures of orientation to triptyline and may make these agents safer, better time, recent memory, ability to increase tempo, and tolerated, and less likely to exacerbate cognitive frequency of fear and panic reactions. By 6 weeks of dysfunction than nortriptyline. treatment, 60% of citalopram-treated patients were In general, paroxetine therapy is well tolerated rated as much improved on the Clinical Global Im- by elderly patients [13,16,1’7]. Moreover, unlike norpression scale versus only 24% of patients in the triptyline, fluoxetine, sertraline, and bupropion, placebo group (p
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function has also been demonstrated in depressed elderly patients [1’71. At a dose of 20-40 mg daily, paroxetine produced significantly greater improvement in cognitive function (p ~0.05; Sandoz Clinical Assessment Geriatric Scale) at week 3 than fluoxetine 20-60 mg daily during a 6-week treatment period in 106 patients ~65 years of age. Finally, but very importantly, in placebo-controlled trials, paroxetine has been shown to be an effective maintenance therapy for preventing recurrence of major depression in mixed-age patients [25]. Thus, based on all of these considerations, paroxetine appears to be a reasonable candidate for further clinical study of acute and maintenance therapy in depressed Alzheimer patients. A final consideration pertaining to pharmacotherapy of depression in Alzheimer’s dementia relates to the concurrent use of tacrine. The specific effect of tacrine on depression has not been assessed in large controlled clinical trials. However, tacrine has the potential to interfere with the activity of anticholinergic medications, including the TCAs. Thus, in theory, the potential for negative effects on the efficacy of tacrine does exist when a TCA is administered concomitantly. Such an interaction would appear to be less likely with an SSRI agent.
CONCLUSION The benefits of treating depression in elderly patients clearly outweigh the risks of not treating or of inadequate treatment. The risks of no treatment include chronic depression, cognitive impairment, medical illness, poor compliance with medical treatment, social dysfunction, and suicide. Thus, patients should be vigorously treated, and complete remission of symptoms should be the therapeutic goal. Secondary TCAs, such as nortriptyline or desipramine, and the newer SSRIs, paroxetine and sertraline, are probably the antidepressants of choice in ambulatory practice. Both SSRIs are well tolerated in elderly depressed patients. Psychotherapy also plays a key role in the acute and longterm treatment of depression in late life, particularly in patients whose depressions appear to be related to adverse life events and severe ongoing psychosocial difficulties. Further randomized, controlled clinical trials involving patients ~75 years of age are greatly needed and are currently under way with paroxetine. Very limited data are available for patients ~‘75 years who have participated in randomized, placebo-controlled clinical trials [49]. Because of their favorable side-effect profiles, the newer SSRIs appear to be promising agents for clinical and investigational use among the old. Finally, it would be particularly useful for clinical December
practice to have a direct, blood-level controlled comparison of the secondary TCAs, such as nortriptyline, and the newer SSRIs, such as paroxetine, with respect to efficacy, side effects, and long-term benefit-to-risk ratio.
REFERENCES 1. Reynolds CF, Zubenko GS, Pollock BG, et al. Depression in late hfe. Curr Opin Psychiatry 1994; 7: 18-21. 2. Zis AP, Grof P, Webster M, Goodwin FK. Prediction of relapse in recurrent affective disorder. Psychopharmacol Bull 1980; 16: 47-9. 3. Caine ED, Lyness JM, King DA. Reconsidering depression in the elderly. Am J Geriatr Psychiatry 1993; 1: 4-20. 4. Kennedy GJ, Kelman HR. Thomas C. Persistence and remission of depressive symptoms in late life. Am J Psychiatry 1991; 148: 174-8. 5. Blazer DG. Affective disorders in late life. In: B&e EW, Blazer DG, eds. Geriatric Psychiatry. Washington, DC: American Psychiatric Press, 1989: 369-401. 6. NIH Consensus Conference. Diagnosis and treatment of depression in late lie. JAMA 1992; 268: 1018-24. 7. Schneider LS, Reynolds CF, Lebowitz BD, Friedhoff AJ, eds. Diagnosis and Treatment of Depression in Late Life: Proceedings of the NIH Consensus Development Conference. Washington, DC: American Psychiatric Press, 1994. 8. Reynolds CF Ill, Frank E, Perel JM, et al. Combined pharmacotherapy and psycho. therapy in the acute and continuatlon’treatment of elderly patients with recurrent major depresslon: a preliminary report. Am J Psychiatry 1992; 149: 1687-92. 9. Reynolds CF III, Frank E, Perel JM, et al. Treatment of consecutive episodes of major depression in the elderly. Am J Psychiatry 1994, in press. 10. Perel JM. Geropharmacokinetics of therapeutics, toxic effects, and compliance. In: Schneider LS, Reynolds CF, Lebowitz BD, Friedhoff Al, eds. Diagnosis and Treatment of Depression in Late Life: Results of the NIH Consensus Development Conference. Washington, DC: American Psychiatric Press, 1994: 245-7. 11. Miller MD, Pollock BG, Rifai AH, et al. Longitudinal analysis of nortriptyline side effects in elderly depressed patients. J Geriatr Psychiatry Neurol 1991; 4: 226-30. 12. Paradis CF, Stack JA, George CJ, et al. Nortriptyline and weight change in depressed patients over 60. J Clin Psychopharmacoll992; 12: 246-50. 13. Dunner DL, Cohn JB, Walshe T Ill, et al. Two combined, multicenter double-bhnd studies of paroxetine and doxepin in geriatrtc patients with major depression. J Clin Psychiatry 1992; 53 (SuppI): 57-60. 14. Cohn CK, Shrivastava R, Mendels J, et al. Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients. J Clin Psychiatry 1990; 51 (Suppl 8): 28-33. 15. Hutchinson DR, Tong S, Moon CAL, Vmce M, Clarke A. A double blind study in general practice to complete the efficacy and tolerability of paroxetine and amitriptyline in depressed elderly patients. Br J Clin Res 1991; 2: 43-57. 16. Boyer WF, Blumhardt CL. The safety profile of paroxetine. J Clin Psychiatry 1992; 53 (SuppI): 61-6. 17. Schdne W, Ludwig M. A double-blind study of paroxetine compared with fluoxetine in geriatric patients with major depression. J Clin Psychopharmacol 1993; 13 (Suppl2): 34s-9s. 18. Baldwin D, Fineberg N, Montgomery S. Fluoxetine, fluvoxamine, and extrapyramidal tract disorders. Int Clin Psychopharmacoll991; 6: 51-8. 19. HoehnSanc R, Lipsey JR, McLeod DR. Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol1990; 10: 343-5. 20. Brymer C, Winograd CH. Fluoxetine in elderly patients: is there cause for concern? J Am Geriatr Sot 1992; 40: 902-5. 21. Kazal LA Jr, Hall DL, Miller LG, Noel ML. Fluoxetine-induced SlADH: a geriatric occurrence? J Fam Pratt 1993; 36: 341-3. 22. Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry 1991; 52 (SuppI): 28-34. 23. Old Age Depression Interest Group. How long should the elderly take antidepressants? A doubleblind, placebwontrolled study of continuation/prophylaxis therapy with dothiepin. Br J Psychiatry 1993; 162: 175-82. 24. Doogan DP, Caillard V. Sertraline in the prevention of depression. Br J Psychiatry 1992; 160: 217-22. 25. Montgomery SA, Dunbar G. Paroxetine is better than placebo in relapse prevention and the prophylaxis of recurrent depression. Int Clin Psychopharmacol 1993; 8: 189-95. 26. Montgomery SA, Dufour H, Brion S, et al. The prophylactic efficacy of fluoxetine in unipolar depression. Br J Psychiatry 1988; 153 (Suppl3): 69-76.
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SYMPOSIUMON THE MANAGEMENTOF DEPRESSION/ REYNOLDS 27. Georgotas A, McCue RE, Cooper TB, Nagachandran N, Chang I. How effective and safe is continuation therapy in elderly depressed patients? Factors affecting relapse rate. Arch Gen Psychiatry 1988; 45: 929-32. 28. Reynolds CF Ill, Perel JM, Frank E, et al. Open-trial maintenance pharmacotherapy in late-life depression: survival analysis. Psychiatry Res 1989; 27: 225-31. 29. Conwell Y, Rotenberg M, Caine ED. Completed suicide at age 50 and over. J Am Gerratr Sot 1990; 38: 640-4. 30. Miller MD, Paradis CF, Houck PR, et al. Medical burden In late life depression: implications for successful treatment. JAMA. Submitted. 31. Coppen A, StandishBarry H, Bailey J, Houston G, Silcocks P, Hermon C. Does lithium reduce the mortality of recurrent mood drsorders? J Affective Disord 1991; 23: l-7. 32. Editorial. Depression and suicide: are they preventable? Lancet 1992; 340: 700-l. 33. Karp JF, Frank E, Anderson B, et al. Time to recovery in late-life depression: analysis of effects of demographic, treatment, and life-events measures. Depression 1993; 1: 250-6. 34. Rifai AH, George CJ, Stack JA, Mann JJ, Reynolds CF Ill. Hopelessness continues to distinguish suicide attempters after acute treatment of major depession in late life. Am J Psychiatry 1994; 151: 1687-1690. 35. Reynolds CF Ill, Frank E, Perel JM, lmber S, Kupfer DJ. Maintenance therapies in late life depression. Neuropsychopharmacology 1994; 10: 61s. 36. Zisook S, Shuchter SR, Sledge PA, Paulus M, Judd LL. The spectrum of depressive phenomena after spousal bereavement. J Clin Psychiatry 1994; 55 (Suppl 4): 29-36. 37. Pasternak RE, Reynolds CF, Frank E, et al. Temporal course of depressive symptoms and grief intensity in late-life spousal bereavement. Depression 1993; 1: 45-9. 38. Wragg RE, Jeste DV. Overview of depression and psychosis in Alzheimer’s disease. Am J Psychiatry 1989; 146: 577-87. 39. Fitz AG, Teri L. Depression, cognition, and functional ability in patients with Alzheimer’s disease. J Am Geriatr Sot 1994; 42: 186-91. 40. Reifler BV, Teri L, Raskind M, et al. Double-blind trial of imipramine in Alzheimer’s disease patients with and without depression. Am J Psychiatr 1989; 146: 45-9. 41. Reynolds CF III, Perel JM, Kupfer DJ, Zimmer B, Stack JA, Hoch CC. Open-trial response to antidepressant treatment in elderly patients with mixed depression and cognitive impairment. Psychiatry Res 1987; 21: 11 l-22. 42. Nyth AL, Goltfries CG, Lyby K, et al. A controlled, multicenter clinrcal study of citalopram and placebo in elderly depressed patients with and without concomitant dementia. Acta Psychiatr Stand 1992; 86: 138-45. 43. Bayer AJ, Roberts NA, Allen EA, et al. The pharmacokinetics of paroxetine in the elderly. Acta Psychiatr Stand Suppll989; 350: 85-6. 44. Barros J, Asnis G. An interaction of sertraline and desipramine. Letter.1 Am J Psychiatry 1993; 150: 1751. 45. Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The effect of selective serotonin reuptake inhibitors on cytochrome P450 llD6 activity in human liver microsomes. Br J Clin Pharmacoll992; 34: 262-5. 46. Lydiard RB, Anton RF, Cunningham T. Interactions between sertraline and tricyclic antidepressants. Letter.1 Am J Psychiatry 1993; 150: 1125-6. 47. Preskorn SH. Recent pharmacologic advances in antidepressant therapy for the elderly. Am J Med 1993; 94 (SuppI 5A1: 2S-12s. 48. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. [Letter.] Am J Psychiatry 1988; 145: 1478. 49. Salzman C, Schneider LS, Lebowitz BD. Antidepressant treatments of very old patients. Am J Geriatr Psychiatry 1993; 1: 21-9.
DISCUSSION Participant:
be prevented
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How can suicide among the elderly by maintenance antidepressant treat-
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ment when there has been no decrease in the rate of suicide over the past 25 years of antidepressant availability? Dr. Reynolds: The long-term incidence data likely reflect suboptimal treatment of recurrent major depression in this population over the past years. Many completed suicides among the elderly are associated with a history of major depression or other affective disorder. I would argue that prevention of major depression with appropriate maintenance therapy gives us the best chance of preventing suicidal behavior that is associated with recurrent depression and breaking the cycle of depression and suicide in the elderly patient. Participant: Does psychotherapy play a role in the treatment of late-life depression? Dr. Reynolds: Psychotherapy is an important adjuvant to antidepressant medication in late-life depression. Interpersonal psychotherapy and cognitive behavioral therapy of acute episodes of major depression have been shown to elicit responses of 60% in late-life depression. I would suggest that psychotherapy is important in terms of educating patients and their families and in achieving better long-term compliance with therapy. Psychotherapy may also play a role in alleviating hopelessness among elderly depressed patients, but this hypothesis requires study. Participant: Do you begin depressed elderly patients with nortriptyline or an SSRI? Dr. Reynolds: Depending on the patient’s history, I often begin treatment with an SSRI, such as paroxetine, because of its well-defined dosage range and efficacy and tolerability without the need for plasma concentration monitoring. The advantage of nortriptyline in some patients with difficultto-treat depression is that therapy can be tailored according to blood levels so that adequate treatment can be assured. Participant: Is therapy with an SSRI a problem in the elderly depressed patient with Parkinson’s disease due to the potential for a decrease in dopaminergic activity when serotonergic effects are increased? Dr. Reynolds: There is the potential for exacerbation of Parkinson’s disease during SSRI therapy. However, this issue requires further study.
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F. REYNOLDS
III,
M.D.,
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Pennsylvania
Depression is a common, but treatable, source of suffering, excess disability, and caregiver strain in late life. It is important to take a long-term view of the treatment of late-life depression because of the high risk for relapse, recurrence, and chronic illness. Elderly patients with medical and neurological illness or bereavement-related depressions also merit greater attention. Recent data highlight several important caveats: (a) the role of medical and psychosocial factors in the course of major depression; (b) variability in etiology, clinical presentation, and treatment response; (c) need for additional studies of syndromal and subsyndromal depression in primary and long-term care facilities, particularly in patients >76 years of age; and (d) importance of continuation and maintenance treatment to maintain quality of life and to lower the risk for chronic illness. Nortriptyline, desipramine, and the newer selective serotonin reuptake inhibitors (SSRIs), paroxetine and sertraline, are preferred pharmacotherapy for short-term and long-term treatment. The newer SSRIs should be further studied in controlled trials of elderly depressed patients, including those >76 years and those with medical or neurological illness. Psychotherapy also appears to be of major importance in successful outcome but, as does pharmacotherapy, merits further controlled investigation in both short- and longterm clinical trials.
From the Departments of Psychiatry and Neurology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania. Rearrests for reprints should be addressed to Charles F. Reynolds Ill, MD, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PennsyC vania 15213.
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D
epression is a common but treatable source of excess disability in the elderly population of ambulatory patients and those who reside in longterm care facilities [l]. It is important to take a long-term view of the treatment of late-life depression, particularly with respect to maintenance therapy, because of the high risk for relapse, recurrence, and chronic illness 123. Special populations of elderly persons, particularly those with medical and neurological illness, and those with bereavementrelated depressions, also merit greater clinical and research attention than they have received to date. Recent studies of depression in late life have highlighted four themes. First, medical and psychosocial factors have great salience in the onset, symptomatic presentation, and offset of major depression in the elderly [3,4]. Secondly, there is considerable variability in etiology, clinical presentation, and treatment response. Third, clinicians need the guidance of additional investigations of both syndromal and subsyndromal depression in primary and long-term care facilities, particularly in the very old and medically and neurologically frail elderly. Finally, studies increasingly emphasize the importance of continuation and maintenance treatment, beyond therapy of the acute episode, to prevent recurrence of symptoms and to maintain quality of life. Epidemiologic studies of major depression in late life have observed a prevalence of ~3% in community-dwelling elders. In contrast, a l&25% prevalence among nursing home residents and a 13% annual incidence of new episodes of major depression among residents of long-term care facilities underscore the importance of major depression in the institutionalized elderly [5,6]. However, the burden of depressive illness in late life is not limited to major depression. Studies estimate an 8-15% prevalence of subsyndromal depression among community samples. Such symptoms represent an important source of excess disability, suffering, caregiver burden, and diminished quality of life. Within the context provided by recent literature, the goals of treating depression in elderly patients should be not only the reduction and resolution of depressive symptoms, but also the prevention of relapse and recurrence, improvement in quality of life, enhancement in the ability to function, and improvement in medical health status, with a reduc-
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tion in mortality and healthcare costs. These treatment goals were articulated by the consensus panel at the NIH Consensus Conference on the Diagnosis and Treatment of Depression in Late Life [7]. Treating depression in elderly patients also needs to be understood within the broader context of their actual lives. Data from Kennedy and associates [4] have suggested, for example, that deterioration in health, persistent sleep disturbance, and lack of formal support services predicted persistence of depressive symptoms in a sample of 1,885 adults 265 years of age participating in the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area study.
SELECTINGAN ANTIDEPRESSANT FORELDERLY PATIENTS:RISKVERSUSBENEFIT Tricyclic Antidepressants Among the tricyclic antidepressants (TCAs), nortriptyline and desipramine are safer for the elderly because they are associated with a more tolerable side-effect profile than the tertiary amines, amitriptyline and imipramine. Therapeutic blood levels of nortriptyline (SO-120 ng/mL) and desipramine (2125 ng/mL) can usually be achieved and sustained in ambulatory elderly patients without orthostasis or excessive sedation, constipation, or dry mouth. The ability to monitor blood levels of these compounds facilitates assessment of both compliance and adequacy of treatment. For example, in an ongoing maintenance study of nortriptyline and interpersonal psychotherapy at the University of Pittsburgh, 78% of 61 patients aged 60-80 years with medically complicated, recurrent, unipolar depression responded to treatment with a HAMD total score of 10. Steady-state therapeutic concentrations of nortriptyline were maintained in the range of 80120 ng/mL during the open, acute, and continuation phases of the study [8]. Moreover, approximately 90% of patients who suffered a recurrence of major depression (after randomization to a maintenance placebo condition) were successfully treated to remission using combined therapy with interpersonal psychotherapy and nortriptyline prescribed at the same dose used to treat the index episode 191. The use of a biological measure-constancy of level-to-dose (L:D) ratios-has been evaluated as a means of providing a more complete assessment of compliance. Measurement of constant L:D ratios has successfully determined patient adherence to therapy. A larger variability in L:D ratio is associated with behavioral measures of noncompliance and poorer clinical outcome [lo]. For example, two succesive L:D values exceeding the group mean by 6A-4OS
1.5 standard deviations provides an indicator of potential noncompliance [lo]. Adequate pharmacotherapy in late-life depression depends not only on steady-state levels of such agents as nortriptyline, but also the duration of treatment. The findings of the University of Pittsburgh study demonstrate that the median time to recovery in the acute treatment of the index episode is 12-13 weeks 181. Thus, patients and their families should be encouraged to comply with pharmacologically adequate treatment for a sufficient period in order to ensure maximal therapeutic response. Evaluation of the University of Pittsburgh database has also shown that three atropinic side effects of nortriptyline (dry mouth, constipation, and modest increases in heart rate of 7-8 beats/min) persisted over an average of approximately 210 days of acute and continuation therapy [ll]. These symptoms are generally experienced by ambulatory depressed patients as minor nuisance symptoms that can be ameliorated by supportive countermeasures, such as stool softeners or bethanechol. In addition, nortriptyline is neither a strong promoter of weight gain in ambulatory depressed patients nor a cause of systolic orthostasis [12]. Thus, the experience of the University of Pittsburgh maintenance therapy trial in late-life depression supports the generally benign side-effect profile of nortriptyline in ambulatory elderly patients with major depression selected with due cognizance of the medical contraindications to nortriptyline (e.g., electrocardiogram conduction disturbances, acute narrow angle glaucoma, and prostatic hypertrophy with urinary retention). It is important to note, however, that the adverse effects of the TCAs, particularly amitriptyline and imipramine, may be exaggerated in the elderly. These adverse effects are principally orthostatic hypotension (which may be associated with falls), sedation, anticholinergic symptoms (including delirium), and cardiac toxicity. Recommendations for a long-term perspective of the treatment of late-life depression also require consideration of the risk-to-benefit ratio of the long-term use of any antidepressant medication. Selective Serotonin Reuptake Inhibitors The tolerable side-effect profile of the newer selective serotonin reuptake inhibitors (SSRIs), paroxetine and sertraline, supports their use in the treatment of depression in elderly patients. The newer SSRIs have been studied in comparative trials with doxepin [13] and amitriptyline [14,151. The efficacy of paroxetine treatment of depression in the elderly has been demonstrated in a 6-week,
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double-blind study, involving doxepin as an active comparator [13]. The mean age of the 271 patients involved in this study was 68 years. The mean daily doses of paroxetine and doxepin were 23.4 mg and 105.2 mg, respectively. Overall, paroxetine and doxepin were equally effective in the relief of depressive symptoms (Figure l), with paroxetine-treated patients showing significantly greater improvement in the Clinical Global Impression measure of severity of illness score, the Hamilton depression retardation factor, and the Hamilton depressed mood item. Paroxetine was also well tolerated, with lower rates of dry mouth (p
vs 28%). December
One study has directly compared two SSRIs in the treatment of late-life depression. &hone and Ludwig [171 compared paroxetine and fluoxetine in 106 elderly depressed patients. There were no significant differences in terms of 6-week endpoint HAMD total score. However, at 3 weeks, the mean HAMD total score was significantly lower (p ~0.05) in the paroxetine group (Figure 2). In addition, there were significant improvements in cognitive function as measured by Mini-Mental State examination and the Sandoz Clinical Assessment Geriatric Scale in the paroxetine-treated patients at week 3 (p ~0.04). There were no significant differences in the incidence or type of adverse effects. In this context, it is appropriate to issue several caveats about the use of SSRIs in elderly patients. Lower starting doses of paroxetine (10 mg), sertraline (25 mg), or fluoxetine (5 mg) and more gradual dosage increases may be necessary in elderly patients. However, just as in a younger population, the dose of SSRI should be increased until the optimal therapeutic response is attained. The elderly, particularly the very old, frail, or medically ill patient, may be less tolerant of long-acting
HAMD TOtal SCOE
104 0
1
2
3
/ 6
4
Week
Figure 1. Efficacy of paroxetine and doxepin In depressed elderly patients. Differences in treatment arms not statistically significant. (Reprinted from 1131, with permission.)
W
Paroxeline (N=54)
C-O
Fluoxetine (N=52)
22. 20 Baseline
Week 1
Figure 2. Paroxetine and fluoxetine pnnted from [171, with permission.)
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Week 6
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SSRIs and may experience extrapyramidal side effects [18], apathy [191, anorexia [20], and inappropriate antidiuretic hormone secretion [211.
CONTINUATION AND MAINTENANCETHERAPY Depression in the elderly is often a chronic illness with a tendency to recur. The risk for recurrence is particularly great among patients with onset of depression after the age of 60 [2]. Hence, most elderly patients will benefit from maintenance therapy that ensures continued remission of depressive symptoms, prevents recurrence of depression, and reduces the likelihood of chronic invalidism and psychosocial dysfunction [6]. The purpose of continuation therapy (i.e., that phase of treatment administered for 4-6 months after symptomatic resolution of the acute or index episode) is to prevent return of depressive symptoms and relapse back into the index episode. Maintenance therapy is the phase of treatment that begins after full remission of the index episode is achieved and sustained for 4-6 months. The objective of maintenance therapy is to preserve recovery and to prevent recurrence of new episodes of major depression [22]. In the ongoing University of Pittsburgh maintenance therapy study, relapse rates following discontinuation of nortriptyline after 16 weeks of continuation therapy of 24% have been reported among placebo-randomized patients. In contrast, none of the patients randomized to continue on full-dose nortriptyline experienced a return of depression [8]. Other data bearing on this point have been reported by the Old Age Depression Interest Group in the United Kingdom [23]. These investigators have observed that elders with major depression are 2.5 times less likely to suffer recurrence on dothiepin maintenance (75 mgiday for 2 years) than on placebo. In addition, although maintenance therapy with the SSRIs in late-life depression has not yet been evaluated, the efficacy and tolerability of these agents in a younger population [24-261 is promising. Elderly patients at risk of recurrence should be treated with the same dose of medication during continuation and maintenance therapy that attained a response during acute therapy. Relapse rates of 17% for nortriptyline and 20% for phenelzine were reported in one series for elderly depressed patients during 4-8 months of continuation therapy [271. Similarly, based on open-trial pilot data in 27 elderly depressives, recurrence rates of 15% occurred during 18 months of nortriptyline maintenance therapy at steady-state levels of 50150 ng mL 1281.
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Obstacles in Treatment of Late-Life Depression to Full Recovery Obstacles to adequate treatment include poor compliance, adverse effects associated with treatment, inadequate family support for proper compliance, comorbid medical illness, occult self-medication, and such psychosocial factors as bereavement and interpersonal isolation. In addition, there is an appreciable clinical risk for suicide among elderly depressed patients [29]. The rate of completed suicides is disproportionately higher in elderly patients than in younger individuals. The suicide rate among 80-&&year olds was 26.5 in 100,000 persons in 1988, which is more than double the rate of 12.4 in 100,000 in the general population. Elderly white males are at greatest risk of suicide [6]. Adverse effects of antidepressant medication treatment can generally be minimized by proper choice of agent and by the use of supportive countermeasures to render such side effects tolerable. Although it is important to consider both the medical burden in the elderly patient and the potential for drug-drug interactions, these factors need not compromise the quality of the ultimate response to antidepressant treatment [30]. Even with appreciable chronic medical burden, it is likely that most depressed elderly patients will benefit from appropriate therapy (either pharmacotherapy, psychotherapy, or a combination of both) as long as concurrent medical conditions are treated appropriately. The most important obstacle to adequate treatment is patient compliance. As many as 70% of elderly patients take only 50-75% of their prescribed dose [6]. Attrition rates due to treatment refusal or noncompliance have been minimized in the ongoing University of Pittsburgh trials. In this database, dropouts are highest during acute treatment (10.2%) but are markedly lower during continuation therapy (3.6%) and maintenance treatment (2.5%). Several factors may promote compliance and retention in treatment among elderly patients with major depression (Table I). First, there must be a consistent focus on compliance during clinic visits by all members of the treatment team, including psychiatrists, therapists, and pharmacists. Patient education about the rationale for compliance, particularly with long-term therapy, in order to increase credibility and acceptance, should be stressed. The message “Getting well is not enough. It is staying well that counts” should be conveyed to all patients and family members. Compliance is enhanced by attention to side effects and to the use of appropriate countermeasures to improve the quality of life (stool softeners, betha-
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nechol). The creation and maintenance of an alliance with family members serves as a means of education about depression in late life and the need for treatment. Educational workshops, monthly telephone calls, and family support groups are useful in this regard. Collaboration with the primary care physician will enhance awareness about the challenge and treatment of depression in late life and will elicit support for participation in long-term treatment. An attitude of caring and enthusiasm among clinicians is very important in eliciting adequate compliance that will ultimately ensure a high response rate. It is reasonable to hypothesize that compliance with long-term treatment will probably reduce suicide rates among patients with chronic mood disorders [31,32]. This point is of particular salience to depression in late life because of high rates of suicide among the elderly. In this context, it is useful to point out that the SSRIs are safer in overdose than the TCAs, with lower potential for lethality. This consideration may persuade many clinicians that the SSRIs are appropriate first-line agents for the treatment of major depression in late life.
Psychosocial Factors and Psychotherapy Stressful life events and ongoing difficulties contribute significantly to delayed response and stabilization during acute therapy of recurrent major depression in late life. Other factors may contribute to delayed treatment response, including perceived lack of social support and eccentric personality features (e.g., schizoid or paranoid types) [33]. Psychotherapy is therefore an important and perhaps critical adjuvant to pharmacotherapy in the treatment of depression in late life. However, psychotherapy should not be considered a substitute for the pharmacotherapy of depression. Interpersonal psychotherapy and cognitive behavior therapy are promising modalities that are particularly useful in depression associated with bereavement, role transitions, interpersonal conflicts, and social isolation. Psychotherapy of late-life depression is also useful for addressing feelings of hopelessness that characterize elderly depressed patients, particularly those with a history of suicide attempts and those who are likely to drop out of treatment 1341. The ongoing maintenance therapies study of recurrent major depression in the elderly at the University of Pittsburgh is designed to test the prophylactic value of nortriptyline and interpersonal psychotherapy. Initial data suggest that both modalities, separately and in combination, may be su-
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TABLEI Factors Associated with Patient Compliance During Therapy for Late-life Depresstion * Teamapproach -Psyc$atrist -Therapst -Pharmaast * Patlenteducation -Explainratlonalefor therapy -“Gethng wellISnotenough.lt is stayingwellthat counts.” * Mlmmueside effectsof TCAs -Stool softeners -8ethanechol * Familymembereducation -Workshops -Telephonefollowup -Support groups * Collaborationbetweenpsychiahistandprrmarycare -Increase awarenessof latelIfedepression -Ellclt support @Caringclinicianattitude
perior to placebo in preventing recurrence during the first year of maintenance treatment [35]. Treatment of Bereavement-Related Depression in Late Life Bereavement can be a significant factor in latelife depression [36]. The temporal course of depressive symptoms and grief intensity in late-life spousal bereavement have recently been described. The findings of a 2-year, naturalistic, follow-up study of the temporal course of depressive symptoms and grief intensity in late-life spousal bereavement suggested that the two processes follow different courses [37]. In addition, although antidepressant medication reduces symptoms of depression, pharmacotherapy appears not to diminish the intensity of bereavement per se. These findings suggest that early intervention with antidepressant medication to reduce the burden of depressive symptoms may better position patients to do the psychological work of bereavement without the additional burden of major depression. A randomized, double-blind, placebo-controlled clinical trial to address these issues further is ongoing at the University of Pittsburgh. Treatment of Depression in Alrheimer’s Dementia Depression and its related functional impairment and behavioral disturbances (including sleep disruption) pose clinically significant problems for patients with Alzheimer’s dementia. Depression in the demented patient is associated with a degrada-
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tion in quality of life, greater burden on patients long-term treatment of depressed patients with Alzheimer’s dementia, with improvement in funcand caregivers, and increased likelihood of early placement in long-term care. Depression and de- tional impairment, diminution in caregiver burden, and perhaps prolongation of community tenure. pressive symptoms are common among patients with Alzheimer’s dementia. Approximately ZO-40% .These hopes need to be investigated, however, in controlled, randomized, clinical trials addressing of cognitively impaired elders exhibit depressive both short- and long-term management. symptoms or depression [38], which are important In open-label, acute treatment studies, nortriptysources of excess functional disability in this populine appears to ameliorate depressive symptoms in lation [39]. depressed patients with Alzheimer’s dementia, The SSRIs may be strong candidates for antidepressant therapy in patients with Alzheimer’s de- thereby improving functional status and allowing mentia, although further controlled studies are many patients to remain in the community [41]. needed. Limited published data suggest that de- There was a reduction in Hamilton depression ratpression in Alzheimer’s dementia may be responings, but no change in Folstein mini-mental state sive to acute therapy with the TCAs such as imiprascores, among patients whose nortriptyline plasma mine [40] and nortriptyline [41] and to the SSRI levels were maintained in the range of 50-150 inhibitor; citalopram 1421, which is not currently ng/mL for 6-8 weeks. Moreover, improvement in available in the United States. The imipramine and Hamilton depression ratings correlated with imcitalopram studies were double-blind and placeboprovement in functional status as measured by the controlled, whereas the nortriptyline work was Blessed dementia rating scale. Improvement in open-label. The study by Reifler and colleagues [40] functional status was particularly evident in showed no significant difference between imipraBlessed items measuring regard for the feelings of mine and placebo with respect to acute antidepresothers, re-engagement in hobbies, and improved sant effect, but did show adverse cognitive effects initiative. Improvement in Hamilton items was of imipramine. most apparent in mood, early-morning awakening, The study by Nyth and colleagues 1421 was a anxiety, and appetite factors. 6-week, double-blind, placebo-controlled trial of In the treatment of depression in patients with citalopram of depressed elderly patients also sufferAlzheimer’s dementia, it is important to consider ing from somatic disorders or “senile dementia.” the possibility that the atropinic side effects of Improvements in cognitive and emotional function TCAs may mask improvement in cognition. In this were significantly greater in the citalopram-treated regard, therefore, it appears that the SSRIs may subgroup of patients with dementia than in the pla- provide a useful contrast to conventional TCA thercebo-treated subgroup. For example, citalopramapy. For example, the comparatively lower antichotreated patients with concomitant dementia and linergic, histaminergic, and adrenergic effects of depression showed more improvement than pla- the SSRIs create a clinically useful contrast to norcebo-treated patients in measures of orientation to triptyline and may make these agents safer, better time, recent memory, ability to increase tempo, and tolerated, and less likely to exacerbate cognitive frequency of fear and panic reactions. By 6 weeks of dysfunction than nortriptyline. treatment, 60% of citalopram-treated patients were In general, paroxetine therapy is well tolerated rated as much improved on the Clinical Global Im- by elderly patients [13,16,1’7]. Moreover, unlike norpression scale versus only 24% of patients in the triptyline, fluoxetine, sertraline, and bupropion, placebo group (p
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function has also been demonstrated in depressed elderly patients [1’71. At a dose of 20-40 mg daily, paroxetine produced significantly greater improvement in cognitive function (p ~0.05; Sandoz Clinical Assessment Geriatric Scale) at week 3 than fluoxetine 20-60 mg daily during a 6-week treatment period in 106 patients ~65 years of age. Finally, but very importantly, in placebo-controlled trials, paroxetine has been shown to be an effective maintenance therapy for preventing recurrence of major depression in mixed-age patients [25]. Thus, based on all of these considerations, paroxetine appears to be a reasonable candidate for further clinical study of acute and maintenance therapy in depressed Alzheimer patients. A final consideration pertaining to pharmacotherapy of depression in Alzheimer’s dementia relates to the concurrent use of tacrine. The specific effect of tacrine on depression has not been assessed in large controlled clinical trials. However, tacrine has the potential to interfere with the activity of anticholinergic medications, including the TCAs. Thus, in theory, the potential for negative effects on the efficacy of tacrine does exist when a TCA is administered concomitantly. Such an interaction would appear to be less likely with an SSRI agent.
CONCLUSION The benefits of treating depression in elderly patients clearly outweigh the risks of not treating or of inadequate treatment. The risks of no treatment include chronic depression, cognitive impairment, medical illness, poor compliance with medical treatment, social dysfunction, and suicide. Thus, patients should be vigorously treated, and complete remission of symptoms should be the therapeutic goal. Secondary TCAs, such as nortriptyline or desipramine, and the newer SSRIs, paroxetine and sertraline, are probably the antidepressants of choice in ambulatory practice. Both SSRIs are well tolerated in elderly depressed patients. Psychotherapy also plays a key role in the acute and longterm treatment of depression in late life, particularly in patients whose depressions appear to be related to adverse life events and severe ongoing psychosocial difficulties. Further randomized, controlled clinical trials involving patients ~75 years of age are greatly needed and are currently under way with paroxetine. Very limited data are available for patients ~‘75 years who have participated in randomized, placebo-controlled clinical trials [49]. Because of their favorable side-effect profiles, the newer SSRIs appear to be promising agents for clinical and investigational use among the old. Finally, it would be particularly useful for clinical December
practice to have a direct, blood-level controlled comparison of the secondary TCAs, such as nortriptyline, and the newer SSRIs, such as paroxetine, with respect to efficacy, side effects, and long-term benefit-to-risk ratio.
REFERENCES 1. Reynolds CF, Zubenko GS, Pollock BG, et al. Depression in late hfe. Curr Opin Psychiatry 1994; 7: 18-21. 2. Zis AP, Grof P, Webster M, Goodwin FK. Prediction of relapse in recurrent affective disorder. Psychopharmacol Bull 1980; 16: 47-9. 3. Caine ED, Lyness JM, King DA. Reconsidering depression in the elderly. Am J Geriatr Psychiatry 1993; 1: 4-20. 4. Kennedy GJ, Kelman HR. Thomas C. Persistence and remission of depressive symptoms in late life. Am J Psychiatry 1991; 148: 174-8. 5. Blazer DG. Affective disorders in late life. In: B&e EW, Blazer DG, eds. Geriatric Psychiatry. Washington, DC: American Psychiatric Press, 1989: 369-401. 6. NIH Consensus Conference. Diagnosis and treatment of depression in late lie. JAMA 1992; 268: 1018-24. 7. Schneider LS, Reynolds CF, Lebowitz BD, Friedhoff AJ, eds. Diagnosis and Treatment of Depression in Late Life: Proceedings of the NIH Consensus Development Conference. Washington, DC: American Psychiatric Press, 1994. 8. Reynolds CF Ill, Frank E, Perel JM, et al. Combined pharmacotherapy and psycho. therapy in the acute and continuatlon’treatment of elderly patients with recurrent major depresslon: a preliminary report. Am J Psychiatry 1992; 149: 1687-92. 9. Reynolds CF III, Frank E, Perel JM, et al. Treatment of consecutive episodes of major depression in the elderly. Am J Psychiatry 1994, in press. 10. Perel JM. Geropharmacokinetics of therapeutics, toxic effects, and compliance. In: Schneider LS, Reynolds CF, Lebowitz BD, Friedhoff Al, eds. Diagnosis and Treatment of Depression in Late Life: Results of the NIH Consensus Development Conference. Washington, DC: American Psychiatric Press, 1994: 245-7. 11. Miller MD, Pollock BG, Rifai AH, et al. Longitudinal analysis of nortriptyline side effects in elderly depressed patients. J Geriatr Psychiatry Neurol 1991; 4: 226-30. 12. Paradis CF, Stack JA, George CJ, et al. Nortriptyline and weight change in depressed patients over 60. J Clin Psychopharmacoll992; 12: 246-50. 13. Dunner DL, Cohn JB, Walshe T Ill, et al. Two combined, multicenter double-bhnd studies of paroxetine and doxepin in geriatrtc patients with major depression. J Clin Psychiatry 1992; 53 (SuppI): 57-60. 14. Cohn CK, Shrivastava R, Mendels J, et al. Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients. J Clin Psychiatry 1990; 51 (Suppl 8): 28-33. 15. Hutchinson DR, Tong S, Moon CAL, Vmce M, Clarke A. A double blind study in general practice to complete the efficacy and tolerability of paroxetine and amitriptyline in depressed elderly patients. Br J Clin Res 1991; 2: 43-57. 16. Boyer WF, Blumhardt CL. The safety profile of paroxetine. J Clin Psychiatry 1992; 53 (SuppI): 61-6. 17. Schdne W, Ludwig M. A double-blind study of paroxetine compared with fluoxetine in geriatric patients with major depression. J Clin Psychopharmacol 1993; 13 (Suppl2): 34s-9s. 18. Baldwin D, Fineberg N, Montgomery S. Fluoxetine, fluvoxamine, and extrapyramidal tract disorders. Int Clin Psychopharmacoll991; 6: 51-8. 19. HoehnSanc R, Lipsey JR, McLeod DR. Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol1990; 10: 343-5. 20. Brymer C, Winograd CH. Fluoxetine in elderly patients: is there cause for concern? J Am Geriatr Sot 1992; 40: 902-5. 21. Kazal LA Jr, Hall DL, Miller LG, Noel ML. Fluoxetine-induced SlADH: a geriatric occurrence? J Fam Pratt 1993; 36: 341-3. 22. Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry 1991; 52 (SuppI): 28-34. 23. Old Age Depression Interest Group. How long should the elderly take antidepressants? A doubleblind, placebwontrolled study of continuation/prophylaxis therapy with dothiepin. Br J Psychiatry 1993; 162: 175-82. 24. Doogan DP, Caillard V. Sertraline in the prevention of depression. Br J Psychiatry 1992; 160: 217-22. 25. Montgomery SA, Dunbar G. Paroxetine is better than placebo in relapse prevention and the prophylaxis of recurrent depression. Int Clin Psychopharmacol 1993; 8: 189-95. 26. Montgomery SA, Dufour H, Brion S, et al. The prophylactic efficacy of fluoxetine in unipolar depression. Br J Psychiatry 1988; 153 (Suppl3): 69-76.
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SYMPOSIUMON THE MANAGEMENTOF DEPRESSION/ REYNOLDS 27. Georgotas A, McCue RE, Cooper TB, Nagachandran N, Chang I. How effective and safe is continuation therapy in elderly depressed patients? Factors affecting relapse rate. Arch Gen Psychiatry 1988; 45: 929-32. 28. Reynolds CF Ill, Perel JM, Frank E, et al. Open-trial maintenance pharmacotherapy in late-life depression: survival analysis. Psychiatry Res 1989; 27: 225-31. 29. Conwell Y, Rotenberg M, Caine ED. Completed suicide at age 50 and over. J Am Gerratr Sot 1990; 38: 640-4. 30. Miller MD, Paradis CF, Houck PR, et al. Medical burden In late life depression: implications for successful treatment. JAMA. Submitted. 31. Coppen A, StandishBarry H, Bailey J, Houston G, Silcocks P, Hermon C. Does lithium reduce the mortality of recurrent mood drsorders? J Affective Disord 1991; 23: l-7. 32. Editorial. Depression and suicide: are they preventable? Lancet 1992; 340: 700-l. 33. Karp JF, Frank E, Anderson B, et al. Time to recovery in late-life depression: analysis of effects of demographic, treatment, and life-events measures. Depression 1993; 1: 250-6. 34. Rifai AH, George CJ, Stack JA, Mann JJ, Reynolds CF Ill. Hopelessness continues to distinguish suicide attempters after acute treatment of major depession in late life. Am J Psychiatry 1994; 151: 1687-1690. 35. Reynolds CF Ill, Frank E, Perel JM, lmber S, Kupfer DJ. Maintenance therapies in late life depression. Neuropsychopharmacology 1994; 10: 61s. 36. Zisook S, Shuchter SR, Sledge PA, Paulus M, Judd LL. The spectrum of depressive phenomena after spousal bereavement. J Clin Psychiatry 1994; 55 (Suppl 4): 29-36. 37. Pasternak RE, Reynolds CF, Frank E, et al. Temporal course of depressive symptoms and grief intensity in late-life spousal bereavement. Depression 1993; 1: 45-9. 38. Wragg RE, Jeste DV. Overview of depression and psychosis in Alzheimer’s disease. Am J Psychiatry 1989; 146: 577-87. 39. Fitz AG, Teri L. Depression, cognition, and functional ability in patients with Alzheimer’s disease. J Am Geriatr Sot 1994; 42: 186-91. 40. Reifler BV, Teri L, Raskind M, et al. Double-blind trial of imipramine in Alzheimer’s disease patients with and without depression. Am J Psychiatr 1989; 146: 45-9. 41. Reynolds CF III, Perel JM, Kupfer DJ, Zimmer B, Stack JA, Hoch CC. Open-trial response to antidepressant treatment in elderly patients with mixed depression and cognitive impairment. Psychiatry Res 1987; 21: 11 l-22. 42. Nyth AL, Goltfries CG, Lyby K, et al. A controlled, multicenter clinrcal study of citalopram and placebo in elderly depressed patients with and without concomitant dementia. Acta Psychiatr Stand 1992; 86: 138-45. 43. Bayer AJ, Roberts NA, Allen EA, et al. The pharmacokinetics of paroxetine in the elderly. Acta Psychiatr Stand Suppll989; 350: 85-6. 44. Barros J, Asnis G. An interaction of sertraline and desipramine. Letter.1 Am J Psychiatry 1993; 150: 1751. 45. Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The effect of selective serotonin reuptake inhibitors on cytochrome P450 llD6 activity in human liver microsomes. Br J Clin Pharmacoll992; 34: 262-5. 46. Lydiard RB, Anton RF, Cunningham T. Interactions between sertraline and tricyclic antidepressants. Letter.1 Am J Psychiatry 1993; 150: 1125-6. 47. Preskorn SH. Recent pharmacologic advances in antidepressant therapy for the elderly. Am J Med 1993; 94 (SuppI 5A1: 2S-12s. 48. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. [Letter.] Am J Psychiatry 1988; 145: 1478. 49. Salzman C, Schneider LS, Lebowitz BD. Antidepressant treatments of very old patients. Am J Geriatr Psychiatry 1993; 1: 21-9.
DISCUSSION Participant:
be prevented
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How can suicide among the elderly by maintenance antidepressant treat-
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ment when there has been no decrease in the rate of suicide over the past 25 years of antidepressant availability? Dr. Reynolds: The long-term incidence data likely reflect suboptimal treatment of recurrent major depression in this population over the past years. Many completed suicides among the elderly are associated with a history of major depression or other affective disorder. I would argue that prevention of major depression with appropriate maintenance therapy gives us the best chance of preventing suicidal behavior that is associated with recurrent depression and breaking the cycle of depression and suicide in the elderly patient. Participant: Does psychotherapy play a role in the treatment of late-life depression? Dr. Reynolds: Psychotherapy is an important adjuvant to antidepressant medication in late-life depression. Interpersonal psychotherapy and cognitive behavioral therapy of acute episodes of major depression have been shown to elicit responses of 60% in late-life depression. I would suggest that psychotherapy is important in terms of educating patients and their families and in achieving better long-term compliance with therapy. Psychotherapy may also play a role in alleviating hopelessness among elderly depressed patients, but this hypothesis requires study. Participant: Do you begin depressed elderly patients with nortriptyline or an SSRI? Dr. Reynolds: Depending on the patient’s history, I often begin treatment with an SSRI, such as paroxetine, because of its well-defined dosage range and efficacy and tolerability without the need for plasma concentration monitoring. The advantage of nortriptyline in some patients with difficultto-treat depression is that therapy can be tailored according to blood levels so that adequate treatment can be assured. Participant: Is therapy with an SSRI a problem in the elderly depressed patient with Parkinson’s disease due to the potential for a decrease in dopaminergic activity when serotonergic effects are increased? Dr. Reynolds: There is the potential for exacerbation of Parkinson’s disease during SSRI therapy. However, this issue requires further study.
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