Medication Augmentation after the Failure of SSRIs for Depression

Patient Population and Inclusion and Exclusion Criteria

Procedures related to written informed consent and monitoring have been described elsewhere.^4,6,8 All the authors had essential roles in study implementation and supervision, data review, and manuscript development. Medications were supplied to the study at no cost by Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, King Pharmaceuticals, Organon, Pfizer, and Wyeth-Ayerst Laboratories; otherwise these companies had no role in the study design, data accrual, data analysis, or manuscript preparation.

Study Design

Participants were randomly assigned to receive one of the two augmentation medications (sustained-release bupropion or buspirone)^6,12 in a 1:1 ratio, stratified according to the acceptability of treatment and to regional center. Patients who did not have a remission with or who had an intolerance to citalopram alone were eligible for this study, as long as they accepted treatment options that included augmentation with sustained-release bupropion or buspirone. During the trial, the citalopram dose was kept constant (but it could be reduced if side effects occurred). The initial dose of sustained-release bupropion was 200 mg per day during weeks 1 and 2, increasing to 300 mg per day by week 4 and to 400 mg per day (the final dose) during week 6. The starting dose of buspirone was 15 mg per day during week 1, increasing to 30 mg per day during week 2, and then to 45 mg per day during weeks 3 through 5, with a final, maximal dose of 60 mg per day during week 6. Both drugs were taken twice daily.

Protocol Treatment

The aim of augmentation treatment was defined a priori as a remission of symptoms — defined as a score of 5 or less on the 16-item Quick Inventory of Depressive Symptomatology, clinician-rated (QIDS-C-16), which assesses the core symptoms of major depression and on which scores range from 0 to 27, with higher scores indicating greater symptom severity. Clinic visits were recommended at baseline and weeks 2, 4, 6, 9, and 12. Patients with at least a response (defined as a reduction of 50 percent or more in the baseline total QIDS-C-16 score at 12 weeks) and an acceptable level of tolerability could receive treatment for another 2 weeks to determine whether remission would occur with additional time.

Patients could leave the trial before 12 weeks if intolerable side effects occurred, if a remission that was sustained for at least 2 weeks and preferably 4 weeks occurred before 12 weeks (e.g., patients who had a remission by week 4 and remained in remission by week 6 or 9 could move to follow-up), or if substantial symptoms (as determined by a total QIDS-C-16 score of 9 or more) were still present after 9 weeks at maximally tolerated doses. Concomitant treatments were managed as described elsewhere.^6,8 Protocol treatment involved the measurement of symptoms and side effects at each clinic visit to ensure the quality of care (measurement-based care).^8,14

Clinical Measurements

Information with regard to baseline clinical and demographic characteristics, side effects, and adverse events was collected, as described elsewhere.⁸ The primary outcome — remission of symptoms — was defined by a score of 7 or less on the 17-item Hamilton Rating Scale for Depression¹⁵ (HRSD-17). Scores can range from 0 to 52, with higher scores indicating more severe depression. Scores were obtained by independent, trained, and certified assessors of research outcomes who were unaware of patients' treatment assignments and used telephone-based, structured interviews (in English or Spanish) with participants at entry into and at the end of this study. Secondary outcomes included the rates of response to treatment (defined as a reduction of 50 percent or more from the baseline Quick Inventory of Depressive Symptomatology — Self-Report [QIDS-SR-16] score at the end of this study) and remission (defined as a total score of 5 or less at the end of this study), on the basis of the QIDS-SR-16 scores obtained at each treatment visit (range, 0 to 27).^16,17

Statistical Analysis

Summary statistics are presented as described by Rush et al.⁸ Logistic-regression models were used to compare rates of remission (according to HRSD-17 and QIDS-SR-16 scores) and response (according to QIDS-SR-16 scores), after adjustment for the effect of regional center treatment-acceptability strata,⁸ and baseline characteristics that were not balanced among the treatment groups. There were seven possible treatment-acceptability strata, which were collapsed into three categories (medication augmentation only, medication or cognitive-therapy augmentation, and other), owing to small numbers of patients in several strata. If final HRSD-17 scores were missing, it was assumed that there was a lack of remission (as defined in the original analysis plan).⁶ Sensitivity analyses that were performed with the use of two imputation methods yielded results that were consistent with this assumption.⁸ With the use of data regarding clinic visits, the times to first remission (as determined by a QIDS-SR-16 score of less than 6) and first response (a reduction of 50 percent or more from the baseline QIDS-SR-16 score) were defined as the first observed point. Log-rank tests compared the cumulative proportion of patients without remission and response in the two treatment groups.

All effectiveness and safety analyses were conducted according to the intention-to-treat principle (i.e., the analyses included all patients randomly assigned to each treatment group, regardless of adherence to protocol, actual treatment received, or subsequent withdrawal from assessments, treatment, protocol deviations, or all of these).¹⁸

Patients

Overall, 1439 participants enrolled in the second step of treatment (level 2) of the STAR*D trial after intolerance to citalopram developed or they did not have a remission with the use of this agent. The development of the sample of participants is described by Rush et al.⁸ The final sample included 565 patients randomly assigned to receive augmentation of citalopram with sustained-release bupropion (279 patients) or buspirone (286 patients). Most of the patients who were randomly assigned to receive one of these two augmentation medications (430 of 565, or 76.1 percent) had accepted their assignment to receive only the two augmentation medications; 102 patients (18.0 percent) had accepted their assignment to all three augmentation options (two medications plus cognitive therapy); the remaining 33 patients (5.8 percent) had accepted their assignment to other treatment options that included both medication augmentations.⁸

Demographic and Clinical Characteristics

Table 1. Table 1. Clinical and Demographic Characteristics of Patients.

Table 1 shows the characteristics of the participants. The two groups receiving augmentation with sustained-release bupropion or buspirone did not differ significantly with respect to any of the characteristics, including the rates of concurrent coexisting axis I disorders listed in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (data not shown), except that those assigned to receive citalopram plus sustained-release bupropion had a shorter overall length of illness (15 years) than did those receiving citalopram plus buspirone (17 years) (P<0.04).

Treatment Features

Table 2. Table 2. Characteristics of Treatment.

Both augmentation medications were administered in effective doses and were provided for adequate durations of time to detect a benefit. The mean doses at the end of this study were 267.5 mg per day for sustained-release bupropion and 40.9 mg per day for buspirone. Patients receiving citalopram plus sustained-release bupropion had a mean (±SD) of 3.8±1.5 clinic visits (Table 2), as compared with 3.8±1.7 visits among patients receiving citalopram plus busprione (χ²=0.03, P=0.87). Fourteen percent of those receiving citalopram plus sustained-release bupropion received less than four weeks of treatment, as compared with 21.0 percent of those receiving citalopram plus buspirone (χ²=4.79, P=0.03). The mean duration of treatment at the time of the final dose of the augmentation medication was similar for both groups (7.6 weeks for citalopram plus sustained-release bupropion and 7.1 weeks for citalopram plus buspirone). Those treated with citalopram plus sustained-release bupropion adhered to treatment longer (10.2 weeks) than did those receiving citalopram plus buspirone (9.2 weeks, P=0.01).

Symptom Outcomes

Table 3. Table 3. Treatment Outcomes, Side Effects, and Serious Adverse Events.

Figure 1. Figure 1. Time to Remission with Medication.

On the basis of HRSD-17 scores, remission rates did not differ significantly between the group given citalopram plus bupropion (29.7 percent [83 of 279 patients]) and the group given citalopram plus buspirone (30.1 percent [86 of 286 patients]; χ²=0.01; P=0.93). On the basis of QIDS-SR-16 scores, remission rates (39.0 percent for sustained-release bupropion and 32.9 percent for buspirone, P=0.13) and response rates (31.8 percent for sustained-release bupropion and 26.9 percent for buspirone, P=0.21) were not significantly different (Table 3). However, when outcomes were assessed as continuous variables (as is customary in most trials involving the efficacy of antidepressant medication), greater benefit was found with citalopram plus sustained-release bupropion than with citalopram plus buspirone on the basis of percent reductions (from baseline to the end of this study) in QIDS-SR-16 scores (25.3 percent as compared with 17.1 percent, P<0.04). Furthermore, total QIDS-SR-16 scores at the end of this study were significantly lower with citalopram plus sustained-release bupropion treatment than with citalopram plus buspirone (8.0 vs. 9.1, P<0.02). The two groups did not differ significantly with respect to the time to the first QIDS-SR-16 response (log-rank χ²=0.0001, P=0.99) or to first QIDS-SR-16 remission (χ²=0.0024, P=0.96) (Figure 1). For patients who did have a remission, the mean time to a QIDS-SR-16 remission was 6.3 ±4.8 weeks (median, 5.2) for citalopram plus sustained-release bupropion and 5.4±4.4 weeks (median, 4.1) for citalopram plus buspirone. Similarly, the mean time to a QIDS-SR-16 response among patients who had a response was 6.3 ±4.6 weeks (median, 6.0) for citalopram plus sustained-release bupropion and 6.8±3.9 weeks (median, 4.1) for citalopram plus buspirone.

Tolerability and Adverse Events

There were no significant differences between the groups in the maximal frequency, intensity, or burden of side effects (Table 3). Fewer participants taking citalopram plus sustained-release bupropion stopped treatment (i.e., they discontinued the study treatment before four weeks or at or after four weeks, with the reason recorded as due to side effects) because of intolerance than did those taking citalopram plus buspirone (12.5 percent vs. 20.6 percent; χ²=6.86; P<0.001).

The groups did not differ significantly in terms of the number of patients with one or more serious adverse events (3.6 percent for citalopram plus sustained-release bupropion and 4.2 percent for citalopram plus buspirone; χ²=0.14; P=0.71). All together, 24 serious adverse events occurred among 22 patients; of these patients, 3 had at least 1 serious psychiatric adverse event with citalopram plus sustained-release bupropion, whereas 6 had a serious psychiatric adverse event with citalopram plus buspirone. No patient committed suicide during this study. One patient with a preexisting cardiac disease died owing to cardiac arrest.

Among patients with depression who did not have a remission during a vigorous trial of up to 14 weeks of citalopram or who could not tolerate such therapy, augmentation with sustained-release bupropion or buspirone was associated with similar remission rates, as reflected by the primary outcome measure of HRSD-17 scores of 29.7 percent for sustained-release bupropion and 30.1 percent for buspirone. Remission rates were slightly higher according to QIDS-SR-16 scores, but these rates were not significantly different (39.0 percent for sustained-release bupropion and 32.9 percent for buspirone). The QIDS-SR-16 remission rates were slightly higher than the HRSD-17 remission rates, because patients for whom there was no HRSD-17 score at the end of this study (139 patients) were judged, according to the a priori study protocol, not to have had a remission; however, 31 of these patients (22.3 percent) had a remission at the end of this study according to the QIDS-SR-16 scores.

A significantly greater reduction from baseline in QIDS-SR-16 symptoms was found among patients receiving augmentation with sustained-release bupropion (25.3 percent) than with buspirone (17.1 percent), and the mean total QIDS-SR-16 scores at the end of this study were significantly lower with sustained-release bupropion (8.0) than with buspirone (9.1). Additional significant differences between the two groups included longer adherence to treatment with sustained-release bupropion (10.2 weeks) than with buspirone (9.2 weeks), lower rates of discontinuation owing to intolerance with sustained-release bupropion (12.5 percent) than with buspirone (20.6 percent), and a lower rate of treatment cessation before four weeks with sustained-release bupropion (14.0 percent) than with buspirone (21.0 percent, P=0.03). These secondary outcomes (which have traditionally been used as primary outcomes in efficacy studies) favored citalopram plus sustained-release bupropion over citalopram plus buspirone. There were no significant differences between the two groups in terms of the duration of treatment at the time of the final dose; overall attrition rates; proportion of serious adverse events; frequency, intensity, and global burden of side effects; or total number of treatment visits. Overall, these findings reveal a consistently more favorable outcome with sustained-release bupropion than with buspirone augmentation of citalopram.

This study might be considered a “real-world” trial of the augmentation of an SSRI — citalopram — with sustained-release bupropion or buspirone after a consistent, well-implemented trial of citalopram has been performed.¹⁴ To our knowledge, there have been no randomized, controlled trials involving two or more augmentation medications in representative clinical-practice settings with which to compare our results. Remission rates in our trial were similar to those found in most previous uncontrolled trials of augmentation of SSRIs, which have typically been conducted in research clinics and have involved symptomatic volunteers with nonchronic depression and few general medical and psychiatric coexisting illnesses. Remission rates in our trial should be generalizable to most outpatients with nonpsychotic major depressive disorder who are seen in both primary and psychiatric settings and who have not had adequate benefit with the use of an SSRI alone.

Limitations of the study include the lack of a pill placebo and unblinded delivery of treatment, although the data on the primary outcome measure were collected by evaluators who were unaware of patients' treatment assignments, and the HRSD-17 results were concordant with the QIDS-SR-16 results. Although the use of placebo in the second step of treatment could raise concern and may have limited the generalizability of results if patients with severe or chronic depression declined to participate, the lack of a placebo control does not allow us to exclude spontaneous remission, the nonspecific effects of treatment, or the extended use of citalopram alone as the likely explanation for the present findings.

Factors to be considered when selecting augmentation treatments include efficacy, tolerability, burden of side effects, interactions among drugs, dosing convenience, adherence, and cost. Sustained-release bupropion and buspirone, used to augment therapy with the SSRI citalopram, had similar remission rates on the basis of clinician and self-report ratings, but several important secondary measures favored citalopram plus sustained-release bupropion over citalopram plus buspirone. These findings show that augmentation of SSRIs with either agent will result in symptom remission, with some increased benefits with citalopram plus sustained-release bupropion. These results do raise the question of whether to use augmentation agents (or other treatment combinations) as first-line treatment in an attempt to achieve greater remission rates sooner in more patients than with SSRIs alone.

The following investigators participated in the STAR*D trial: National Coordinating Center — A.J. Rush, M. Trivedi, D. Warden, M.M. Biggs, K. Shores-Wilson, D. Stegman, M. Kashner; Data Coordinating Center — S. Wisniewski, G.K. Balasubramani, J. Luther, H. Eng; Regional Centers: University of Alabama, Birmingham, and Tuscaloosa Veterans Affairs Medical Center, Tuscaloosa, Ala. — L. Davis, K. Rice, A. Berry, P. Johnson, S. Ambrose, M. Jewell, B. Thomas, E. Waldrop, T. Allen, E. St. John, R. Williams; University of California, Los Angeles — A. Leuchter, I. Lesser, I. Cook, M. Epstein, S. Rosenberg, S. Zeim, L. Sulkowski, J. Iribarren, R. Armstrong, A. Rosales, M. Abrams; University of California, San Diego, La Jolla — S. Zisook, K. Harless, C. Gonzalez, M. Smith, C. Lawrence, J. Palica, M. Rohrs, M. Capous-Desyllas, K. Ganadjian; Northwestern University Medical School, Chicago — W. McKinney, W. Gilmer, C. Kelley, C. Cooler, A. Bauer, J. Fleck, C. Endick; Psychiatric Research Institute, University of Kansas, Wichita — S. Preskorn, D. Hilger, A. Klick-Davis, R. Lusk, J. Elmore, D. Soetaert; Massachusetts General Hospital, Boston — J. Alpert, M. Fava, A. Nierenberg, A. Farabaugh, T. Petersen, W. Merens, P. Cassano, N. Craven, H. Yang, M. Candrian, R. Fraguas; University of Michigan, Ann Arbor — E. Young, S. Marcus, J. Greden, H. Briggs, K. Bullard, A. Kennedy, A. Benway, E. Rickard; New York State Psychiatric Institute and Columbia College of Physicians and Surgeons, New York — F.M. Quitkin, P. McGrath, J.W. Stewart, H. Sackeim, K. Tate-Brown, S. Rees, C. Smith, A. Couraud, J. Lavelle, K. Broderick; University of North Carolina, Chapel Hill — R. Golden, B. Gaynes, J. DeVeaugh-Geiss, A. Ford, S. Barnett, B. Pearson; Laureate Healthcare System, Tulsa, Okla. — J. Mitchell, W. Yates, J. Kuehnert, L. Jernigan, B. Williams, J. Hilton; University of Pittsburgh Medical Center, Pittsburgh — M. Thase, R.H. Howland, E. Friedman, J. Callan, S. Berman, L. Shutt, C. Spotts; Vanderbilt University Medical Center, Nashville — S. Hollon, R. Shelton, M. Lovett, T. Crutcher, T. Patton, J. Hart, R.M Harris-Turner, D. Lilly, B. Sirles, S. Hicks, N. Harris, S. Addington; University of Texas Southwestern Medical Center, Dallas — M. Husain, M. Downing, D. Stegman, E. Shellhorn, B. O'Neal, D. Turner, MacLeod, M. Henson, T. Hawley, S. Gardner; Virginia Commonwealth University, Richmond — S. Kornstein, R. Schneider, S. Belyea, B. Perry, K. Schmitt, T. Goff, K. Lamoree, M. Britton, C. Glassman.