Comparison of Desipramine and Cognitive/Behavioral Therapy in the Treatment of Elderly Outpatients With Mild-to-Moderate Depression Larry W. Thompson, Ph.D., David W. Coon, Ph.D. Dolores Gallagher-Thompson, Ph.D., Barbara R. Sommer, M.D. Diana Koin, M.D. The authors evaluated the efficacy of desipramine-alone, vs. cognitive/behavioral therapy-alone (CBT) vs. a combination of the two, for the treatment of depression in older adult outpatients. Patients (N )201סmeeting criteria for major depressive disorder were randomly assigned to one of these three treatments for 16 to 20 therapy sessions. All treatments resulted in substantial improvement. In general, the CBT-Alone and Combined groups had similar levels of improvement. In most analyses, the Combined group showed greater improvement than the Desipramine-Alone group, whereas the CBT-Alone group showed only marginally better improvement. The combined therapies were most effective in patients who were more severely depressed, particularly when desipramine was at or above recommended stable dosage levels. The results indicate that psychotherapy can be an effective treatment for older adult outpatients with moderate levels of depression. (Am J Geriatr Psychiatry 2001; 9:225–240) D epression is one of the most common psychiatric disorders among older adults,1–3 with estimates of at least 15%–20% of community elderly persons suffering from a type and degree of depression that needs clinical and public health attention.4 Although pharmacotherapy is known to be effective in the treatment of depression, various forms of psychotherapy also have an essential role, in that they address the psychosocial and functional antecedents and consequences of this disorder.5–10 Controlled trials evaluating psychotherapeutic interventions for the treatment of late-life depression have most often featured brief approaches, including timelimited psychodynamic therapy, interpersonal psychotherapy (IPT), or cognitive/behavioral therapy (CBT). A meta-analysis of 17 psychosocial treatment studies involving 765 depressed elderly patients demonstrated that these interventions were more effective than notreatment or placebo-control conditions, yielding an overall effect size of 0.78.11 Furthermore, effect sizes Received September 13, 1999; revised July 6, 2000; accepted August 21, 2000. From the Geriatric Research, Education and Clinical Center (GRECC), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, and the Dept. of Medicine, Stanford University School of Medicine, Stanford, CA. Address correspondence to Dr. Thompson, Pacific Graduate School of Psychology, 935 East Meadow, Palo Alto, CA 94304. e-mail: larrywt@leland.stanford.edu Copyright ᭧ 2001 American Association for Geriatric Psychiatry Am J Geriatr Psychiatry 9:3, Summer 2001 225 Desipramine vs. Psychotherapy varied negligibly between self-rated and clinician-rated outcome measures, as well as across studies with only major depressive disorder or with subclinical varieties of depression. Correspondingly, only a handful of studies to date have directly compared psychotherapies to pharmacotherapies in treatment of late-life depression, and thus an insufficient amount of data precludes researchers and clinicians from drawing firm conclusions. Sloane and colleagues12 found that IPT was comparable to nortriptyline in the acute treatment of depressed elderly subjects and was associated with lower dropout rates. Likewise, Beutler and his fellow researchers,13 in their comparison of group cognitive therapy-plus-alprazolam, group cognitive therapy-plus-placebo support, alprazolam-plus-support, and placebo-plus-support, found that patients assigned to group cognitive therapy improved more on self-reported depressive symptoms and objective sleep efficiency than patients not assigned to group cognitive therapy. No differences between alprazolam and placebo were found, regardless of whether or not patients received group cognitive therapy. Finally, Reynolds and colleagues14,15 have demonstrated in several reports that a combination treatment of IPT with nortriptyline can be quite efficacious in both the acute and maintenance treatment of elderly patients with recurrent depression. Although not targeted toward elderly patients, the highly publicized results of the Treatment of Depression Collaborative Research Program (TDCRP), sponsored by the National Institute of Mental Health,16 produced significant implications for clinicians and clinical researchers treating depressed elderly patients. The TDCRP compared imipramine-plus-clinical management (IMI-CM), IPT, CBT, and placebo-plus-clinical management (PLA-CM) for the treatment of major depressive disorder in adult outpatients. Initial findings reported a significant reduction in depressive symptoms and functional improvement over time across all four conditions. At the time, the authors also pointed out a consistent ordering of treatments at termination, with IMI-CM generally doing the best and demonstrating a more rapid effect, PLA-CM the worst, and the two psychotherapies in between.16–18 More recent post-hoc analyses of TDCRP data have used random regression models to investigate the role of initial severity in treatment outcome, as measured by scores on the Hamilton Rating Scale for Depression (Ham-D),19 the Beck Depression Inventory (BDI),20 or the Global Assessment 226 Scale (GAS).21 Results have suggested significantly better outcomes on depressive symptoms in IMI-CM for patients who were severely depressed at baseline, when compared with similar patients in each of the other treatments. However, treatment differences were less evident in patients who were less severely depressed on study entry.22 Even though the TDCRP project has sparked considerable debate about site differences, therapeutic allegiances, placebo-control conditions, and treatment fidelity issues,11,23–28 the project’s results were still instrumental in shaping treatment guidelines prepared for both the American Psychiatric Association (APA)29 and the Agency For Health Care Policy and Research (AHCPR).30 For example, the resultant APA guidelines suggest that CBT may not be any more effective than pill-placebo coupled with clinical management. Similarly, AHCPR guidelines state that there is strong evidence for the efficacy of medication in the treatment of severe depressions and little or none for the efficacy of psychotherapy alone. Contrary to these positions, a recent meta-analysis reported in 1999 on four randomized clinical trials investigating the acute outcomes of antidepressant medication and CBT in severely depressed outpatients does not support the position that antidepressant medication is superior to CBT in these patients.31 Thus, the question of the relative efficacy of pharmacotherapy, psychotherapy, and their combination remains unanswered. Researchers summarizing points from the 1991 Consensus Conference pointed out that “both antidepressant medications and brief structured psychotherapies have efficacy in the acute treatment of older adult depressed outpatients with major unipolar, nondelusional depression, but the relative efficacy of specific medications and psychotherapies is unclear (p 485).”32 Similarly, as part of the Consensus Update, Niederehe noted, in a review of randomized trials of psychotherapy conditions, that the “weaknesses lie not so much with the quality of specific studies, but with the cumulative body of evidence (p S76).”10 Furthermore, he makes the point that “combination-treatment studies deserve much greater emphasis, and [an] integration of psychopharmacological and psychotherapy research should prove beneficial to both areas (p S75).”10 Previous research in patients with late-life depression has shown the efficacy of CBT and brief psychodynamic treatments alone.24 The present study was de- Am J Geriatr Psychiatry 9:3, Summer 2001 Thompson et al. signed to evaluate the efficacy of a specific medication, desipramine, and a specific structured psychotherapy, CBT, or a combination of both in the treatment of older adult outpatients with major depressive disorder. At the time that this study was first conceived, tricyclic antidepressants were the pharmacologic treatments of choice for both young adult and elderly patients with severe depression. Although newer selective serotonin reuptake inhibitors (SSRIs) are now the preferred firstline treatments, tricyclics continue to play a role as both primary and augmenting treatments of this disorder.33,34 Tricyclics may even be treatments of first choice for medically stable patients with very severe depression33,35 or for patients with both depression and chronic neuropathic pain syndromes. This project therefore remains timely in its attempt to evaluate these specific treatments for depression in elderly patients. METHODS Subjects The study was conducted at the Veterans Affairs Palo Alto Health Care System and Stanford University School of Medicine, in a clinic specializing in the treatment of older adults with affective disorders. Study subjects were required to meet the following criteria: 1) age 60 years or older; 2) a current diagnosis of major depressive disorder (MDD) as determined by the Research Diagnostic Criteria (RDC)36 applied to the Schedule for Affective Disorders and Schizophrenia (SADS)37; 3) a score of 14 or greater on the Ham-D; 4) a score of 16 or greater on the BDI; 5) a score of 26 or greater on the Mini-Mental State Exam38; 6) no medical or psychiatric contraindications; 7) no evidence of serious alcohol abuse; 8) no evidence of a psychotic disorder; 9) no evidence of bipolar disorder; 10) no immediate suicide risk; 11) not taking another medication for the treatment of depression; and 12) adequate transportation to reach the outpatient clinic. Potential patients were either self-referred in response to media advertisements or were referred directly to the project by community physicians, mental health organizations, and social service agencies. Patients diagnosed as being in an episode of MDD according to RDC upon initial screening (N )712סwere then seen by a staff psychiatrist in order to confirm the diagnosis. A few prospective participants were already re- Am J Geriatr Psychiatry 9:3, Summer 2001 ceiving medication for depression. In these instances, the medication was withdrawn after consultation and approval from their primary care physician, and rescreening occurred after a 2-week washout. Those with a confirmed diagnosis by the project psychiatrist were scheduled for admission to the hospital overnight for medical screening to determine whether there were any contraindications for using desipramine. Patients were then re-screened to see if they still met criteria for the study. Because of scheduling issues, the time interval for this entire screening process ranged from 2 to 6 weeks. Approximately half of these subjects (n)511ס were not entered into the study because they no longer met criteria for MDD or they were below the cutoff score on the Ham-D or BDI at the time of re-screening. Ultimately, 102 patients met inclusion and exclusion requirements and were enrolled in the study. Two of these subjects dropped out after randomization but before receiving any treatment. They are included in the initial descriptive analyses, but not in the outcome analyses of the 100 patients presented here. Ineligible or uninterested subjects were offered referrals to local clinics, physicians, psychiatrists, psychotherapists, and other research studies to help address their needs. Although this was not a placebo-controlled study, the length of time from initial rating scales to study entry was about 1 month, on average. It was our expectation that this waiting period would exclude patients who might improve as a result of the inquiry itself. Procedures Patients were assigned randomly to receive treatment with either Desipramine-Alone, CBT-Alone, or a Combination of the two (Desipramine םCBT). Patients in all three treatment conditions were seen for 16 to 20 sessions over a 3- to 4-month period. During the first 4 weeks, they were seen twice per week, and then once per week for the next 8 to 12 weeks. Medication treatment. Six psychiatrists (3 women, 3 men) with a primary interest in geriatrics and geropsychiatry participated as therapists in this research program. All had received specialized training in geriatrics and geriatric psychiatry. Desipramine was chosen in consultation with project psychiatrists because of its low side-effect profile, including low sedative effect and lower anticholinergic effect when compared with other tricyclic and hetero- 227 Desipramine vs. Psychotherapy cyclic agents.39,40 In the Desipramine-Alone condition, the psychiatrists followed the drug condition protocol developed for the NIMH-TDCRP,41 with some minor modifications to make the protocol more suitable for elderly patients. (The manual for this modified protocol is available upon request from the first author.) Patients were seen individually for approximately 30 minutes per session on the frequency schedule described previously. Each session began with a brief inquiry about the patient’s current level of distress. Psychiatrists maintained a supportive attitude in talking with patients about their feelings and problems and continued to emphasize the importance of the medication in improving patients’ depression. A review of other symptoms and side effects currently experienced by the patient followed this discussion and included a count of the number of desipramine pills the patient had remaining. Blood pressure (sitting and standing) and weight were also monitored during every session. Sessions ended with a brief discussion about the medication regimen to be followed until the next session, a brief summarization of treatments prescribed to counteract any disquieting side effects, and words of continued encouragement by the psychiatrist regarding the efficacy of desipramine in treating patients’ depression. The general strategy for prescribing medication was to start with very low doses (10 mg) of desipramine and increase this amount gradually, depending on the magnitude of side effects and the patients’ general willingness to tolerate them. A physician, board-certified in Internal Medicine and Geriatrics, was available as needed for consultation in managing these side effects. Desipramine plasma levels were obtained at 1 month after initiation of treatment or at any point in the course of treatment that the psychiatrist felt this information would be helpful in determining appropriate daily dosage. In some patients, repeated levels were measured to assist in establishing preferred dosage levels or check on compliance. The mean stable daily dose of desipramine in this study was 90.0 00.36עmg, which is below the dosage level recommended by Potter42 for use with young patients, but slightly above the daily dosage range (10 mg–75mg) recommended by Salzman for use with geriatric patients.43 The mean plasma level of desipramine was 123 ng/mL which approximates the recommended therapeutic blood level of 125 ng/mL or greater,44 but values ranged from barely detectable to 466 331עng/mL. The design of this study did not call for plasma levels to be obtained consistently at stable 228 dose levels; therefore it is not known whether patients were in the recommended steady-state therapeutic level of 125 ng/ml. Actual plasma levels were not related to outcome in therapy, but it should be noted that plasma determinations were not obtained according to a suitable protocol specifically designed to address this question. Moreover, although appropriately designed studies have generally found a significant relationship between serum levels of desipramine and outcome, this has not always been the case.42 Cognitive/behavioral therapy. Eight clinical psychologists (4 men, 4 women) were therapists in the CBTAlone condition. All therapists had at least 1 year of experience in working with geriatric patients who evidenced psychiatric symptoms. The CBT-Alone condition essentially followed the conceptual model and treatment program developed by Aaron Beck and his colleagues,45 with specific modifications for older individuals.46 These involved strategies to facilitate learning, such as repeated presentation of information using different modalities, slower rates of presentation, greater use of practice, and so forth, along with greater use of structure and modeling behavior. Briefly, patients were taught to identify, monitor, and ultimately challenge negative cognitions about themselves or their situations and then to develop more adaptive and flexible cognitions in their stead. Where appropriate, emphasis was also placed on teaching patients to monitor and increase daily pleasant events in their lives by use of behavioral treatment procedures.47,48 Each session lasted for 50 to 60 minutes and followed a structured manual developed specifically for this research program.49 Drug and CBT combined. In the Combined condition, patients saw both a psychiatrist and a cognitive– behavioral therapist in two separate contacts for each of the 16–20 therapeutic sessions. Typically, these drug and CBT contacts were conducted back-to-back, although, occasionally, scheduling difficulties would require that one contact be held on the next day. In the drug administration component of this condition, the psychiatrist completed a brief (approximately 15 minutes) review of symptoms and a check on medication usage. Any issues besides concerns about side effects or questions about medication that arose during this time were deferred until the next CBT contact. In the CBT component, the therapist followed the protocol de- Am J Geriatr Psychiatry 9:3, Summer 2001 Thompson et al. scribed in the CBT-Alone condition. Any questions regarding side effects or medication usage were either deferred until the next meeting with the psychiatrist or, if there were indications of possible serious complications, referred immediately to the treating psychiatrist. Measures During project screening and enrollment, SADS interviews were used to formulate a diagnosis of major depressive disorder, and Ham-D ratings were made. Also, all patients completed self-report scales before treatment to assess their level of symptoms and general functioning, their characteristic ways of dealing with stressful situations, and their personality. At the conclusion of treatment, these measures were repeated. A posttreatment RDC diagnosis was also made, using the SADS-Change interview,50 along with the Ham-D. Information about pre–post diagnostic status and mean levels on measures of symptoms and functioning have been previously reported at professional conferences (Gerontological Society of America Convention, November 1991, San Francisco, CA; American Psychological Association Convention, August 1994, Los Angeles, CA), and also reviewed at the 1991 Consensus Conference51 (papers are available upon request). The primary focus of this report is on the application of a recently developed method for the analysis of change over time, described in the Statistical Measures section, below. We selected, a priori, two measures of depressive symptoms for these outcome analyses. They are the BDI (a self-report measure) and the 17-item version of the (interviewer-rated) Ham-D; both were used to evaluate the intensity of depression. We used the long form of the BDI during initial screening reported here and for the pre–post-treatment comparisons reported in earlier data referred to above. During the actual treatment, patients completed the short form of the BDI (BDI-SF) at every session.52,53 We selected the BDI-SF rather than the long form (LF), as well as the Ham-D, for the growth model analyses reported in this paper. Both measures were obtained immediately before patients entered the first treatment session. The BDI-SF was collected at each subsequent treatment session, including termination, whereas Ham-D observer ratings were collected at every other session. When patients discontinued treatment, BDI and Ham-D ratings were obtained within 10 days of termination. On the rare occasions when patients were unable to complete Ham-D ratings at a Am J Geriatr Psychiatry 9:3, Summer 2001 scheduled visit, these ratings were obtained at the patient’s next appointment. Ham-D interviews were audiotaped, and over 50% were randomly selected for review by a project psychiatrist or the principal investigator for quality-control purposes. All independent interviewers were trained to proficiency by the principal investigator, and interviewer training ratings were cross-compared with training proficiency standards applied in an independent clinical research laboratory at Stanford University School of Medicine. Dual ratings were obtained on approximately 50% of Ham-D interviews, yielding a mean interrater reliability for the Ham-D across the study of 0.97, with a range of 0.91 to 0.99. Statistical Methods Growth modeling54,55 was used to investigate the differential treatment effects on the reduction of patient depression as measured by patient responses on the BDI and the Ham-D. This method is similar to random-regression model methods applied to analyses of the TDCRP data set.17,22 Also, our interest in both intraindividual as well as interindividual and group change in depression over the course of treatment lent itself to the use of this particular methodology. Moreover, in contrast to traditional analytic methods, such as endpoint analysis and multivariate repeated-measures analysis, growth modeling permits the number and spacing of assessments to vary across subjects. Patients who missed some evaluation points or who discontinued treatment are still considered in the analyses. This is of particular importance, given illness, transportation, and other concerns that can interfere with older adults’ being able to keep scheduled appointments. Since all 100 study subjects who entered treatment had completed some outcome measurements both before and during treatment, we were able (with this statistical method) to include all data collected on these patients whether or not they completed the full trial. In this growth modeling framework, a linear mixedeffects (random coefficients) model56 was fitted to the data. The basic functional form of the model specifies two linear growth parameters of interest: the intercept, or pre-treatment level of depression, and the slope, or the per-session rate of improvement (the current study’s dependent variable as measured by the reduction of depression levels in the Ham-D and BDI). These two parameters are estimated as random effects that are allowed to vary across individuals, where a straight line 229 Desipramine vs. Psychotherapy with an initial depression level and the improvement rate specific to the individual then describes each patient. Each subject’s treatment trajectory is thus captured by the linear regression of the dependent variable on time. In this study, time is indexed by the progression of therapy sessions. Treatment efficacy in the reduction of depression levels is estimated by introducing the treatment-group variable as a fixed effect into the linear mixed model, where the distribution of each parameter across study participants is described by its mean and variance. Systematic differences among participants due to different treatments can then be estimated by examining the distributions of the growth parameters across the three different treatment groups. Restricted maximum-likelihood technique, as implemented in the SAS MIXED procedure, was used to obtain estimates of the model parameters and their standard errors (see Verbeke and Molenberghs57 for technical details). All other data analyses were completed using the Systat for Windows, Release 5.0 program.58 A brief summary of pre– post-treatment means of the Ham-D and the BDI-Long Form for the full sample (N )001סhas also been included. Because there is concern that our Ham-D cutoff score for exclusion was too low, we also have included a post-hoc analysis on only those subjects with initial Ham-D scores above 16. These analyses were completed using a 3 (treatment) ( 2 ןpre–post-treatment) multivariate analysis of variance design for repeated measures. RESULTS Sociodemographic Characteristics Table 1 lists the sociodemographic characteristics for the total number of patients who received treatment (N ,)001סgrouped according to treatment condition. There were no significant differences among the groups for age, education, occupation, gender, or marital status either at the start or at the endpoint of treatment. Subjects were mostly in their mid- to late-sixties. Most were white; almost one-third of them still had some form of employment; and all were reasonably well-educated for this age cohort. The female-to-male ratio was 2:1. As evidenced in previous work with depressed elderly patients,59 the mean duration of the current depressive episode for this age group was greater than 2 years. 230 Pretreatment Ham-D mean scores ranged between 18.6 and 18.8 for the three groups and were not significantly different. Thus, the sample was generally in the low end of the geriatric age range, was relatively high-functioning, and was experiencing mild-to-moderate major depression. Treatment Discontinuation vs. Completion After randomization and across the course of treatment, 31 of 102 patients (30%) discontinued. This rate is slightly lower than the dropout rate of 32% reported in the TDCRP.16 There were no significant differences in discontinuation due to treatment condition (v2[2] ;92.1סN ;201סP .)25.0סTwelve patients (34%) dropped from the Desipramine-Alone condition, and 12 (33%) from the Combined condition, whereas 7 patients (23%) discontinued from the CBT-Alone condition. There was no significant difference in discontinuation due to treatment dissatisfaction across the three treatments (v2[2] ;99.2סN ;201סP .)22.0סNo significant gender, age, education, occupation, or maritalstatus differences were found between project Completers and Dropouts across the three treatment groups. Thus, the rate of discontinuation does not appear to be associated with sociodemographic characteristics or with the type of therapy. A comparison of Dropouts and Completers was also made on the pretreatment measures of depressive symptoms. There were no significant differences between the two groups on either the BDI-LF (t[100];77.0ס P )544.0סor the Ham-D (t[100] ;89.0סP .)823.0סAlso, initial severity of depressive symptoms was explored by use of the pretreatment Ham-D ratings split into Low (scores Յ18) and High (scores Ն19) categories. This split is slightly different from the Ham-D severity groups of Յ19 and Ն20 chosen by the TDCRP. Although we considered using the TDCRP’s Ham-D cut-off, the distribution of initial scores in the current study supported our choice. Moreover, there appears to be no empirical basis for the TDCRP cut-off. A log-linear analysis yielded no significant differences in Completers and Dropouts across treatment conditions on the basis of initial severity of depressive symptoms (LR v2[7] ;97.5סP.)565.0ס Thus, the rate of discontinuation does not appear to be associated with overall depressive symptoms or with initial severity of those symptoms before patients entered treatment. Am J Geriatr Psychiatry 9:3, Summer 2001 Thompson et al. Treatment Outcomes Growth-curve analysis. In contrast to the pretreatment BDI scores just discussed, all BDI scores used in the analysis of treatment outcomes are based on the BDI-SF. Table 2 summarizes the results for the Ham-D and BDI-SF change per session. Overall, results investigating the treatment effects indicated significant persession improvement in depressive symptoms as measured by the Ham-D in all three conditions. Improvement in symptoms as measured by the BDI-SF was also evident, as reflected in negative per-session rates of change or slopes, but only the slopes for the CBT-Alone and Combined conditions were statistically significant at the 0.05 level. A significant differential treatment effect was also found in a comparison of rates of change among the three groups. Looking first at Ham-D (Table 2) the persession rate of change for the Combined condition was significantly greater than for the Desipramine-Alone TABLE 1. condition. There was no significant difference between the Combined and CBT-Alone conditions. Although CBT-Alone showed a larger per-session rate of decline than the Desipramine-Alone condition, this difference was not significant. For the BDI-SF, both the Combined and the CBT-Alone conditions showed a significantly greater per-session rate of change than the DesipramineAlone condition. There was no significant difference between the Combined and the CBT-Alone conditions. Post-hoc analyses regarding initial level of severity and treatment outcome. One concern with this study has been the low cutoff score of 14 on the Ham-D for inclusion. Although we think this cutoff was justified, given the long delay in the screening process and the careful re-screening that was done to ensure that patients were still clinically depressed, the argument could be made that our patients were not sufficiently depressed to provide a fair evaluation of treatments for MDD. We addressed this issue first by comparing Highand Low-Severity groups in the growth-curve analysis. Sociodemographic characteristics and initial depression levels for patients entering treatment, by treatment condition Desipramine (n33) Variable Age, years Education, years Occupation, category Sex, n Men Women Marital status, n Married Not married CBT-Alone (n31) Combined (n36) Total (N100) F or v2[df] P 66.82.6ע 14.64.2ע 3.67.1ע 66.51.5ע 14.34.2ע 3.24.1ע 67.24.6ע 14.80.2ע 3.48.1ע 66.89.5ע 14.63.2ע 3.46.1ע 0.138[2,97] 0.485[2,97] 0.510[2,97] 0.878 0.617 0.602 12 21 10 21 11 25 33 67 0.274[2] 0.872 16 17 14 17 14 22 44 56 0.668[2] 0.716 Note: Values are meanעstandard deviation, unless otherwise specified. CBTסcognitive–behavioral therapy. For occupational category: 1סexecutive/professional; 2סbusiness/managerial; 3סadministrative; 4סclerical/sales; 5סskilled labor; 6סsemiskilled labor; 7סunskilled labor. TABLE 2. Comparison of change in Ham-D and BDI-SF scores across therapy sessions for the three treatment conditions: rate of change per session Ham-D BDI-SF Estimate (SE) Desipramine CBT Combined Desipramine vs. CBT Desipramine vs. Combined CBT vs. Combined Variance Residual t Estimate (SE) t –0.20 (0.06) –0.36 (0.06) –0.41 (0.06) 0.16 (0.09) 0.21 (0.09) 0.05 (0.09) 0.07 (0.02) 11.67 (0.69) –3.10** –5.81*** –6.54*** 1.82 2.39* 0.59 –0.10 (0.07) –0.31 (0.07) –0.44 (0.07) 0.21 (1.10) 0.34 (1.10) 0.13 (1.10) 0.13 (0.02) 8.56 (0.32) –1.32 –4.26*** –6.15*** 2.08* 3.39*** 1.30 Note: Ham-DסHamilton Rating Scale for Depression; BDI-SFסBeck Depression Inventory–Short Form; SEסstandard error; CBTסcognitive– behavioral therapy; t values test the null hypotheses that parameter.0ס *PϽ0.05; **PϽ0.01; ***PϽ0.001. Am J Geriatr Psychiatry 9:3, Summer 2001 231 Desipramine vs. Psychotherapy In the TDCRP, analyses that considered initial level of severity found that patients with severe depression responded more favorably to medication than to psychotherapy, but this effect was not evident in patients with mild-to-moderate depression.16,22 The recent interest and controversy on this issue23,25–27,60,61 has further encouraged us to conduct a post-hoc exploratory evaluation of the effect of initial severity on treatment outcome. As described previously, the current study assigned patients with initial Ham-D scores of Յ18 to the Low Severity group and those with Ham-D scores of Ն19 to the High Severity group. Pretreatment Ham-D means for these two groups are included in Table 3. The range for the Low group was 14–18; for the High group, 19–34. Growth-curve analyses revealed an interaction between initial level of severity and type of treatment for both the Ham-D (F[6, 647] ;90.41סP )100.0סand the BDI-SF (F[6, 1486] ;64.01סP )100.0סmeasures. Comparisons between treatments for the High- and Low-Severity groups are summarized in Table 3. Looking first at the Ham-D, there was little difference in improvement between High- and Low-Severity groups, as reflected in slope measures, for either the Desipramine-Alone or the CBT-Alone treatments. In the Combined condition, the slope of change was noticeably greater for the HighSeverity group than for the Low-Severity group. As shown in Table 3, post-hoc comparisons, however, did not reveal significant differences between High and TABLE 3. Low groups for any of these treatments. In contrast to the Ham-D results, post-hoc comparisons for the BDI-SF in the Combined treatment indicated that the expected per-session reduction in BDI-SF for subjects with high initial severity of depression was significantly greater (0.58 per session) than the rate of improvement (0.29 per session) reported for subjects with low initial severity of depression (t[1486] ;91.2סPϽ0.05). Again, there was little difference in improvement between the High- and Low-Severity patient groups in the Desipramine-Alone and CBT-Alone treatment conditions. The overall pattern of results for both the Ham-D and the BDI-SF are quite similar, suggesting that the lack of statistical significance of the post-hoc tests on the Ham-D is likely due to lower power, since these ratings were obtained at every other intervention session. Further analyses investigating treatment effects within High- and Low-Severity groups conveyed results similar to those described in the investigation of main treatment outcomes. Table 4 reports comparisons of the mean rate of change in Ham-D and BDI-SF across treatment conditions, grouped according to initial severity level. In the High group, depressive symptoms as measured by the Ham-D improved –0.50 per session for the Combined condition. This is significantly greater than the –0.19 per-session improvement reported in the Desipramine-Alone condition (t[234] ;59.1סPϽ0.05). Similarly, depressive symptoms in the High group as captured by the BDI-SF improved at a significantly greater Difference in mean rate of change in Ham-D and BDI-SF between Low- and High-Initial-Severity groups by treatment condition Effect Pretreatment Ham-D, meanעSD Rate of change per session for Ham-D Desipramine CBT-Alone Combined Variance Residual Rate of change per session for BDI-SF Desipramine CBT-Alone Combined Variance Residual Low (n53) High (n47) Low vs. High 16.05.1ע 21.93.3ע t[647] –0.20 –0.36 –0.41 0.07 11.67 –0.20 –0.35 –0.31 0.05 9.62 –0.19 –0.36 –0.50 0.10 14.06 0.12 0.28 1.22 –0.10 –0.31 –0.44 0.13 8.56 –0.09 –0.30 –0.29 0.06 6.99 –0.10 –0.33 –0.58 0.12 12.55 0.06 0.11 2.19* Total Note: For differences in mean rate of Ham-D and BDI-SF change between Low- and High-Initial-Severity groups across treatment conditions: F[6, 647] ;90.41סPϽ0.001 and F[6, 1486] ;64.01סPϽ0.001, respectively. Ham-DסHamilton Rating Scale for Depression; BDI-SFסBeck Depression Inventory–Short Form; SDסstandard deviation; CBTסcognitive– behavioral therapy. *PϽ0.05. 232 Am J Geriatr Psychiatry 9:3, Summer 2001 Thompson et al. rate, –0.58 per session, as opposed to –0.10 per session for the Desipramine-Alone condition (t[643];21.3ס PϽ0.01). There were no significant differences between the CBT-Alone and the Combined, nor between the CBT and Desipramine-Alone treatments for the High-Severity groups. In contrast, no significant differences in the rate of change in depressive symptoms as measured with HamD were found across treatments within the Low-Severity group. However, the estimated reduction in depressive symptoms in this group as measured by the BDI-SF was significantly greater in separate comparisons of Desipramine-Alone with CBT-Alone (t[844] ;54.2סPϽ0.05) and with the Combined treatment (t[844] ;31.2סPϽ0.05). In the Low group, the estimated per-session changes of –0.30 in the CBT-Alone and –0.29 in Combined treatment are over three times the –0.09 rate of change reported in the Desipramine-Alone condition. No significant differences were found between the CBT-Alone and Combined conditions for the Low-Severity groups. Intent-to-treat analysis: pre–post change in mean Ham-D and BDI-Long Form scores. Mean scores before and after treatment are also being presented to provide a clearer description of absolute levels of depression. Table 5 contains the means and standard deviations (SD) of the BDI and the Ham-D from pretest to endpoint for subjects in the three treatment groups who received some treatment (N .)001סBoth Dropouts TABLE 4. and Completers were included in these analyses. “Post-” evaluations were completed within 10 days of the final treatment session for all dropouts. The multivariate analysis of variance (MANOVA) for repeated measures is reported in Table 6. An estimate of Wilks’ lambda yielded an F ratio indicating that the improvement in level of depression across time was highly significant (F[2,96] ;37.74סPϽ0.000. A comparison of all three groups for the Treatment ןTime interaction yielded an estimate of Wilks’ lambda of borderline significance (F[2,96] ;70.2סP .)680.0סTurning to the univariate analyses, the F ratio was significant for the BDI (P,)120.0ס but not for the Ham-D (P .)001.0סTable 6 also reports post-hoc comparisons of the three treatment-group pairs. Looking at the CBT-Alone treatment compared with Desipramine-Alone, the MANOVA for repeated measures was highly significant for change across time (F[2,61] ;15.23סPϽ0.000, and not significant (F[2,61] ;35.2סP 880.0סfor the Treatment ןTime interaction. The univariate analyses for the BDI and HamD yielded a significant interaction for the BDI (P )040.0סand a marginal value for the Ham-D (P .)350.0סThere was clearly no significant Treatment ןTime interaction in the comparison of the CBT-Alone and Combined treatment conditions, but, as expected, the improvement across time was highly significant. A comparison of the Combined treatment and the Desipramine-Alone again showed the improvement across time to be highly significant (F[2,66] ;78.82סPϽ0.000). Comparison (t values) between treatment conditions in the mean rate of change per session by Low- and High-InitialSeverity level for both Ham-D and BDI-SF scores Ham-D BDI-SF Low Severity (df322) Desipramine vs. CBT Desipramine vs. Combined Combined vs. CBT Low Severity (df844) High Severity (df643) 1.51 1.01 –0.37 Effect High Severity (df234) 1.01 1.95* 0.86 2.45* 2.13* –0.11 1.33 3.12** 1.61 Note: Ham-DסHamilton Rating Scale for Depression; BDI-SFסBeck Depression Inventory–Short Form; CBTסcognitive–behavioral therapy. *PϽ0.05; **PϽ0.01. TABLE 5. Pre- and endpoint meansؓstandard deviations for the Beck Depression Inventory–Long Form (BDI–LF) and the Hamilton Rating Scale for Depression (Ham-D), grouped by treatment condition (N100) BDI–LF Condition n Pre- Desipramine-Alone Cognitive–Behavioral Combined treatmenta 33 31 36 22.88.4ע 24.35.7ע 25.54.7ע Ham-D Post18.62.7ע 16.47.9ע 15.76.8ע Pre18.87.4ע 18.97.3ע 18.73.3ע Post15.02.6ע 12.50.7ע 12.09.6ע a Combined treatment includes both cognitive–behavioral therapy and desipramine. Am J Geriatr Psychiatry 9:3, Summer 2001 233 Desipramine vs. Psychotherapy The Treatment ןTime interaction for these two groups was also significant (F[2,66] ;67.3סP .)920.0סUnivariate analyses showed that the Treatment ןTime interaction effect for the BDI and the Ham-D were both significant (P 700.0סand 0.048, respectively). In summary, the intent-to-treat analyses, in which both Dropouts and Completer subjects are included, indicated that all three treatments resulted in substantial improvement. The Combined treatment resulted in significantly greater improvement than the DesipramineAlone condition. Although the univariate analyses suggested that the CBT-Alone condition showed greater improvement than the Desipramine-Alone condition, the multivariate analysis did not support this interpretation. As noted earlier, in order to adjust for the patients with mild depression, consideration of initial severity was introduced by comparing High- and Low-Severity groups by using a cutoff of 19. However, the numbers in the two severity groups were relatively small, and this may have resulted in an absence of clear effects. For the endpoint analysis, we selected 16 as the cutoff point and analyzed only those data above this point. In doing so, we had a larger group (n )87סwith descriptive statistics more in line with other samples. The resulting Ham-D mean and SD scores for the three treatment groups were 19.8 ,5.2ע3.02 ,3.3עand 20.0 5.4עfor the CBT-Alone, Combined, and the Desipramine-Alone groups, respectively. TABLE 6. A MANOVA for repeated measures revealed a significant overall Treatment ןTime interaction (F[4, 148] ;528.2סP .)720.0סUnivariate analyses indicated that both the BDI-LF and the Ham-D were significant (P 600.0סand 0.031, respectively). Post-hoc comparison of the treatment pairs indicated that greater improvement occurred in the Combined than in the Desipramine-Alone condition (F[2,49] ;922.5סP.)900.0ס Both the BDI-LF and the Ham-D were significant (PϽ0.002 and 0.014, respectively). The improvement for the CBT-Alone was marginally greater than for the Desipramine-Alone (F[2,49] ;920.3סP .)850.0סUnivariate analysis yielded significant differences for the BDILF (PϽ0.031) and the Ham-D (PϽ0.026). There was no difference between the Combined and the CBT-Alone conditions. Interaction of stable dose level with treatment outcome. Although the mean stable dose of desipramine in this study was consistent with dose levels recommended in past psychopharmacologic reviews,43,44 the argument could be made that the stable dose for some of our subjects was not at a therapeutic level. Unfortunately, plasma serum levels at stable dose levels are not available to address this issue. To allay concerns about the treatment regimen, we grouped the subjects according to those who were receiving a stable dose of 100 mg or more and those receiving less than 100 mg, and then compared their outcomes for the Multivariate and univariate analyses of variance with repeated measures comparing three treatment groups on the BDI-LF and the Ham-D: endpoint analysis (N100) Treatment Time Interaction Change Over Time Comparison: Analysis Type All three treatments Wilks’ lambda (F statistic) BDI-SF Ham-D CBT vs. Desipramine-Alone Wilks’ lambda (F statistic) BDI-SF Ham-D CBT vs. Combined Wilks’ lambda (F statistic) BDI-SF Ham-D Combined vs. Desipramine-Alone Wilks’ lambda (F statistic) BDI-SF Ham-D F[df] P F[df] P 47.73[2,96] 77.61[1,97] 86.31[1,97] 0.000 0.000 0.000 2.07[4,192] 4.03[2,97] 2.36[2,97] 0.086 0.021 0.100 35.51[2,61] 45.78[1,62] 59.69[1,62] 0.000 0.000 0.000 2.53[2,61] 4.39[1,62] 3.90[1,62] 0.088 0.040 0.053 35.49[2,64] 63.22[1,65] 63.15[1,65] 0.000 0.000 0.000 0.52[2,64] 0.67[1,65] 0.04[1,65] 0.597 0.418 0.840 28.87[2,66] 47.68[1,67] 55.25[1,67] 0.000 0.000 0.000 3.76[2,66] 7.62[1,67] 4.07[1,67] 0.029 0.007 0.048 Note: N includes both Dropouts and Completers. Wilks’ lambda is multivariate F statistic. BDI-SFסBeck Depression Inventory–Long Form; Ham-DסHamilton Rating Scale for Depression; CBTסcognitive–behavioral therapy. 234 Am J Geriatr Psychiatry 9:3, Summer 2001 Thompson et al. three Treatment conditions. Table 7 shows the mean BDI-LF and Ham-D scores for subjects with pretreatment Ham-D levels at Ն16, grouped according to stable dose level. A MANOVA for repeated measures for subjects in the High-Dose group revealed that the overall Treatment ןImprovement interaction was highly significant (F[4,98] ;310.4סP .)500.0סThe effect was apparent for both the BDI-LF (P )100.0סand the HamD (P .)820.0סPost-hoc comparison of treatment pairs indicated that patients in the Combined treatment showed greater improvement than the CBT-Alone (F[2,35] ;715.3סP )140.0סor the Desipramine-Alone condition (F[2,24] ;434.01סP .)100.0סThere was no significant difference between the CBT-Alone and the Desipramine-Alone conditions (F[2,38] ;818.1סP,)671.0ס although mean changes for both measures were greater in the CBT-Alone condition than in the DesipramineAlone condition (P 950.0סfor the Ham-D). The overall comparison of the Treatment ןImprovement interaction for subjects who were receiving 100 mg or less was not significant (F[4,94];519.0ס P .)954.0סThe pre–post-treatment change was highly significant for all comparisons made in all three treatment conditions (PϽ0.001 for all). This analysis was repeated on the full sample, and all results were similar, except that the difference in rate of improvement between the Combined and CBT-Alone conditions was marginally significant (F[2,43] ;846.2סP.)280.0ס In summary, the data indicated that all three treatTABLE 7. ment conditions resulted in significant improvement in depressive symptoms. Comparisons among the treatments showed that the Combined treatment consistently resulted in greater improvement than the Desipramine-Alone condition. In most analyses, the difference between the CBT-Alone and the combined conditions was negligible. The difference between the CBTAlone and the Desipramine-Alone conditions was less clear. Some analyses suggested that CBT resulted in greater improvement than desipramine, particularly as reflected in the self-report measure, rather than the clinical rating. Controlling for initial level of depression and stable medication level did not noticeably affect the rate of improvement in the medication condition. Posthoc analyses did suggest that the consistently more positive effect of the combined treatment, when compared with desipramine alone, was due in large measure to the interaction of severity of depression and size of the stable medication dose. Thus, more severely depressed patients in the Combined treatment condition showed greater improvement than those in either the CBT or Desipramine-Alone condition when they were on a stable dose of desipramine that was equal to or greater than 100 mg. Also, the suggested differences between Desipramine-Alone and CBT-Alone were not apparent in this select group of high-stable-dose patients. When patients were on a lower stable dose of medication, there were no significant differences between the three conditions. Change in depression symptoms in the three treatments for subjects with pretreatment Ham-D scores Ն16, grouped by level of stable medication dosage High Medication Dose Ն100 mg Desipramine (n15) CBT (n26) Combined (n12) P PreMANOVA Ham-D BDI-LF Post- Pre- Post- Pre- Post- Time Group Time 19.67.3ע 23.91.4ע 15.54.5ע 20.42.5ע 19.83.3ע 24.89.7ע 12.91.7ע 16.85.9ע 20.70.3ע 28.19.7ע 10.06.7ע 12.20.01ע 0.000 0.000 0.000 0.005a 0.028b 0.001b 0.000 0.000 0.000 0.459a 0.187b 0.360b Low Medication Dose Ͻ100 mg (n11) MANOVA Ham-D BDI-LF 20.67.5ע 23.59.5ע 17.59.8ע 20.10.9ע (n26) 19.83.3ע 24.89.7ע 12.91.7ע 16.80.01ע (n14) 20.00.2ע 25.64.6ע 14.31.7ע 18.01.7ע Note: Values are meanעstandard deviation. Ham-DסHamilton Rating Scale for Depression; CBTסcognitive–behavioral therapy; MANOVAסmultivariate analysis of variance; BDI-LFסBeck Depression Inventory–Long Form. a Multivariate analysis of variance was used, and P levels reflect an F ratio estimate of Wilks’ lambda. All treatments showed improvement at PϽ0.005 or better in both multivariate and univariate tests. Group ןTime significance in the High Medication group is due to greater improvement in the Combined than in either treatment alone. b Univariate tests. Am J Geriatr Psychiatry 9:3, Summer 2001 235 Desipramine vs. Psychotherapy DISCUSSION Our findings indicate that over 16–20 weeks of individual treatment, the total sample of older adult outpatients in a current episode of MDD showed substantial improvement in all three treatment conditions. CBT combined with desipramine resulted in greater improvement in depression than desipramine administered alone. There was little difference between CBT alone and CBT combined with desipramine. Looking just at the self-report measure, the data suggest that patients receiving only cognitive–behavioral therapy improved more than those receiving only desipramine. However, this effect was not apparent in the Ham-D ratings. The low cutoff point for inclusion on the initial Ham-D might suggest that our sample comprised primarily mildly depressed patients, which may have contributed to the lack of effect between CBT and Desipramine-Alone. To address this question, we completed post-hoc analyses to control for initial level of depression. Looking first at the growth-curve analysis, the Ham-D ratings indicate that the Combined treatment is superior to Desipramine-Alone, but not CBT-Alone in the High-Severity group (Ham-DϾ18). The trend was similar for the Low-Severity patients (Ham-DϽ19), but not statistically significant. For the self-report measure, the Combined group was again superior to Desipramine-Alone, and not CBT-Alone in the High-Severity group. In the Low-Severity group, both the CBT-Alone and the Combined groups were favored over the Desipramine-Alone. The intent-to-treat analysis showed a similar picture using this severity cutoff, but the data are not presented here, as explained below. A question concerning the adequacy of the treatment with desipramine could also be raised. The high proportion of patients who were on relatively low stable medication levels, in combination with the highly variable plasma levels of desipramine, suggested that many of the patients may not have been at therapeutic level. In attempting to address this question, we first compared patients with plasma levels Ͼ125 ng/ml with those who were below this level. We found no significant differences. These data were not reported here because most subjects were not at steady-state medication levels when the samples were obtained. We decided to address the question by grouping the patients according to High stable-dose level (Ն100 mg) or Low stable-dose 236 level (Ͻ100 mg). We assumed that patients in the High stable medication group were more likely to be at therapeutic level than those in the Low stable medication group. We evaluated this effect in the intent-to-treat analysis, using the same severity cutoff mentioned above, but the cell sizes were small and variable. We decided to decrease the severity cutoff to 16, which would give us larger cell sizes in the High-dose group and yet still have depression levels similar to those reported in other studies. We analyzed the data in the High-dose and Low-dose group separately. Patients in the Combined treatment, who were receiving a high stable dose, clearly showed greater improvement than patients in either treatment alone. Patients receiving a high stable dose of desipramine-only were not favored over those receiving CBT-Alone. In the Low-stable-dose group, there was no significant difference among the three groups. To our knowledge, there are no randomized trials of depressed older adult outpatients involving pharmacotherapy and individual CBT with which we could compare our findings. However, Hollon et al.62 have reviewed a number of such studies involving younger patients. They reported that pharmacotherapy-alone did not prove to be clearly superior to cognitive therapyalone in any of these studies and, further, that a combined treatment, although never inferior, was not clearly superior to either single modality. Results of the TDCRP also showed minimal differences over a 16week time-span between pharmacotherapy-plus-clinical management and either cognitive–behavioral or interpersonal therapy if the effects of initial level of severity were excluded from the analyses.16,17 When initial severity was considered, TDCRP results suggested better outcomes on depressive symptoms in the imipramineplus-clinical management condition for patients who were both severely depressed and functionally impaired. In contrast, DeRubeis and colleagues’ recent meta-analysis,31 which also included TDCRP data, found no statistically significant advantage for either antidepressant medication or CBT in the treatment of severely depressed outpatients. On the other hand, Thase and his colleagues,63 in their meta-analysis of several studies comparing psychotherapy and a psychotherapy–pharmacotherapy combination in younger patients, found the combined condition to be superior to psychotherapy in patients with high severity levels, but not in those with low severity. Our results are consistent with the finding that a com- Am J Geriatr Psychiatry 9:3, Summer 2001 Thompson et al. bination of psychotherapy–pharmacotherapy is superior to either alone when treating severely depressed patients. Our data also suggest, however, that if, for some reason, the dosage is below therapeutic level, this may not be the case. These findings, in combination with results from the TDCRP,22 argue that initial level of severity should be considered as a primary variable in the design of future studies to evaluate treatment effects in the older adult. Furthermore, particular attention should be given to plasma levels of medication at steadystate dose levels. The discussion of initial severity warrants mention of our general clinical impression that patients who participated in the current study seemed to have more complications than patients did in our previous projects and did not show as much improvement as seen in earlier studies.59,64 A possible contributing factor may be the delay from initial clinic contact to treatment start date mentioned earlier. The delay was a direct result of the extensive pretreatment work-up implemented to ensure that patients were suitable treatment risks for desipramine. As we reported earlier, over 40% of the potential subjects were not enrolled in the study because they no longer met MDD diagnosis or Ham-D and BDI criteria at re-screening. Therefore, these delays may have greatly reduced the number of spontaneous responders and rapid responders who entered the treatment program—two groups that often may be included in clinical trial reports. A number of questions in addition to this clinical impression need to be raised regarding the generalizability of these results. For example, the argument could be raised that the present study does not provide an adequate appraisal of “pharmacotherapy” as practiced in clinical settings. Clinical lore supports the importance of individual differences in response to different antidepressants, and a clinician might reasonably try several antidepressants before finding one that results in a positive patient response. Although desipramine is still useful in practice and is associated with fewer adverse side effects for elderly patients than other TCAs (e.g., amitriptyline and imipramine), a number of selective serotonin reuptake inhibitors (SSRIs) and other non-tricyclic agents with even fewer side effects have been introduced since the study began. The effectiveness of SSRIs (as indicated by their lower dropout rates among older patients) may ultimately prove somewhat better than TCAs. Still, there are too few clinical trials involving older adults that compare SSRIs directly with Am J Geriatr Psychiatry 9:3, Summer 2001 TCAS to confirm this assumption.9 Furthermore, this study has been limited to outpatients, most of whom are in a moderate range of depression, and similar results may not be obtained with more severely depressed inpatients. Nevertheless, these data do support the feasibility of alternatives to the use of medication in the treatment of MDD in older adult outpatients. This may be particularly helpful in instances where the use of antidepressants is contraindicated because of medical problems or in situations where older adult patients are reluctant to comply with a drug treatment regimen because of disturbing side effects. Our results also may not apply to more socially, ethnically, and clinically diverse groups of depressed older adults. The majority of patients recruited into the study were well-educated, middle-class, self-identified white, older adults in their 60s, who were without serious cognitive or physical impairment. Thus, our results may apply only to psychologically-minded older adults with milder forms of depression, seen in outpatient settings. Future studies, as emphasized in the recent Consensus Update Conference,6,7 need to investigate more heterogeneous study populations encompassing ethnic and racial diversity, persons with disabilities, and a variety of medical illnesses and comorbidities, to help ensure clinical generalizability. The Conference also stressed the need for studies of patients 70 years or older, and the need to broaden outcomes beyond depressive symptoms alone to quality-of-life components, healthcare utilization, social and occupational functioning, interpersonal relationships, and coping skills. Studies examining these various issues will help clinical research and practice move toward systematic treatment selection by identifying critical individual-difference variables that influence treatment adherence, course, and outcome, and help determine which techniques work best with which patients. Finally, caution is needed in interpreting the efficacy of desipramine on the basis of these data, since determination of plasma levels of desipramine at stable medication levels were not available for all patients. The plasma level at 1 month was obtained before most patients were receiving a stable dose. Many individuals had dose levels below the recommended range, and it may be that they were not at the recommended therapeutic level. However, in this particular sample, the psychiatrists met resistance from many of the patients in attempting to increase dose levels above those attained, despite frequent consultations with the internist for 237 Desipramine vs. Psychotherapy remedies to counteract side effects. Therefore, the psychiatrists proceeded, using their best clinical judgment as to what would be the most likely regimen to achieve maximal benefit without raising side effects to a level such that patients would discontinue treatment. Ironically, this issue may reflect an important confound pertaining to individual differences that is often neglected in drug outcome studies. Individuals who refuse to comply with a medication regimen, and therefore may not attain therapeutic plasma levels, are more likely to be the kind of patients who benefit minimally from any type of therapy. On the other hand, patients who are willing and able to cope with the uncomfortable symptoms of side effects of medication are more likely to be the more resilient individuals, who with proper guidance and support, can overcome immense difficulties and disruptions in their lives. In summary, our study has found that CBT in combination with desipramine is more efficacious than desipramine-alone in reducing symptoms of depression in older adults, but the efficacy of CBT-alone over desipramine-alone is less consistently demonstrated in the various analyses completed. These results are in contrast to the comments of the 1991 Consensus Conference regarding the usefulness of psychotherapy. As Niederehe10 noted, the Consensus Conference “appeared to emphasize [psychotherapy’s] adjunctive role” or its use “as a second-line choice when antidepressant medications are not suitable (e.g., because of medical complications or medication intolerance) or simply not preferred,” and “suggested that antidepressant medications are useful across the range of severity in depression and are required in its more severe forms, but that the use- fulness of psychotherapy may be limited primarily to cases of mild-to-moderate depression (p S69).” Our results provide additional evidence for the assertion that psychosocial treatments have an essential role in the treatment of late-life depression, without relegating these interventions to adjunctive positions. Although the combination treatment appeared most efficacious in our findings, on both the Ham-D and the BDI-SF, the only instance where the combined treatment was significantly different from the CBT-alone occurred in the more severely depressed group, who were receiving higher levels of medication. Some researchers have suggested that combined treatments may well be considered the standard of care in clinical practice.9,10 Reynolds and his colleagues14,15 have found that a combination of IPT and nortriptyline was efficacious in both the acute and the maintenance treatment of elderly patients experiencing recurrent depression. However, more studies are needed to reach a definitive conclusion on this matter. Nevertheless, the current study adds to the growing body of evidence suggesting that CBT, either alone or in combination with appropriate psychotropic medication, deserves greater attention in the treatment of late-life depression. The authors acknowledge the generous assistance of Leo Hollister, M.D., in the planning of this research, as well as Jerome Yesavage, M.D., Richard Vieth, M.D., and Lissy Jarvik, M.D., Ph.D., for their helpful consultation on issues pertaining to the medication regimen. The desipramine was provided by Merrill-Dow Chemical. This work was supported principally by Grant #MH37196 from the National Institute of Mental Health. References 1. Parmelee PA, Katz IR, Lawton P: Depression among institutionalized aged: assessment and prevalence estimation. J Gerontol 1989; 44:22–29 2. Myers JK, Weissman MM, Tischler GL: Six-month prevalence of psychiatric disorders in three communities, 1980–1982. Arch Gen Psychiatry 1984; 41:959–967 3. Blazer DG, Hughes DC, George LK: The epidemiology of depression in an elderly community population. Gerontologist 1987; 27:281–287 4. Gurland GJ, Cross PS, Katz S: Epidemiological perspectives on opportunities for treatment of depression. 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