Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial

Abstract

Importance: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant.

Objective: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD.

Design, setting, and participants: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks.

Interventions: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase).

Main outcomes and measures: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects.

Results: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain.

Conclusions and relevance: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.

Trial registration: clinicaltrials.gov Identifier: NCT01421342.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Mr Johnson reports his spouse being an employee of and owning stock in Bristol-Myers Squibb. Dr Davis reports receiving grant funding from Tonix and personal fees from Otsuka, Tonix, Lundbeck, and Bracket. Dr Rao reports being in the speaker’s bureau for Janssen, Otsuka, and Alkermes. Dr Thase reports consulting for Alkermes, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Gerson Lehman Group, GlaxoSmithKline, Guidepoint Global, Lundbeck, MedAvante, Merck, Neuronetics, Ortho-McNeil Pharmaceuticals, Otsuka, Pfizer, Roche, Shire US, Sunovion, Takeda, American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Peloton Advantage, Cerecor, Moksha8, Pamlab, Allergan, Trius Therapeutical, Fabre-Kramer Pharmaceuticals; and receiving grant funding from Eli Lilly, Forest Laboratories, Otsuka. Dr Suppes reports receiving grant funding from Merck, Sunovion, Stanley Medical Research Institute, Palo Alto Health Sciences Services and Elan Pharma International Limited; personal fees from AstraZeneca, Lundbeck, Merck, Sunovion, Global Medication Education, CMEology, and Medscape Education; and royalties from Jones and Bartlett and UpToDate. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients Through the VAST-D Trial of Antidepressant Switching vs Augmentation

DSM-IV indicates Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; MDD, major depressive disorder; QIDS-C16, 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. Patients followed up to week 12 completed the acute treatment phase. All 1522 patients were included in the primary analysis, following the intention-to-treat principle. aOnly the most frequent reasons for not enrolling screened individuals are shown. Individuals could have more than 1 reason for exclusion. bOther includes patients who moved away or withdrew for other illness. cLost to follow-up includes patients who did not return to the clinic and could not be located for contact.

Figure 2.. Cumulative Probability of Remission and Response Among Patients With Antidepressant-Resistant Major Depressive Disorder, Acute Treatment Phase

HR, hazard ratio. Remission was defined as a 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) score (range, 0-27; 0 indicates better symptoms, 27 indicates worse symptoms) of 5 or less for 2 consecutive weeks after baseline during the acute treatment phase. Response was defined as reduction in QIDS-C16 score of 50% or more from baseline at any scheduled visit after baseline through week 12 or improvement in Clinical Global Impression Severity score (range, 1-7; 1 indicates less severe, 7 indicates more severe) of “much improved” or “very much improved” at any scheduled visit after baseline through week 12. Time to first remission or first response was determined by 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) assessments at scheduled visits. In this analysis, follow-up was censored if the patient withdrew from the study. A, HRs from stratified life-table regressions: augment-aripiprazole group vs switch group, 1.28 (95% CI, 1.00-1.64); augment-bupropion group vs switch group, 1.15 (95% CI, 0.89-1.48); augment-aripiprazole group vs augment-bupropion group, 1.06 (95% CI, 0.84-1.35). Median follow-up time to remission or censoring was 81 days (interquartile range [IQR], 41-90) for the switch group, 83 days (IQR, 42-90) for both the augment-bupropion group and augment-aripiprazole group. Plot is truncated at 91 days; 32 observations for week 12 occurred after 91 days. B, HRs from stratified life-table regressions: augment-aripiprazole group vs switch group, 1.32 (95% CI, 1.13-1.54); augment-bupropion group vs switch group, 1.05 (95% CI, 0.89-1.23); augment-aripiprazole group vs augment-bupropion group, 1.23 (95% CI, 1.05-1.43). Median follow-up time to response or censoring was 30 days (IQR, 14-70) for the switch group, 30 days (IQR, 14-69) for the augment-bupropion group and 28 days (IQR, 12-65) for the augment-aripiprazole group. Plot is truncated at 91 days; 25 observations for week 12 occurred after 91 days.

Figure 3.. Cumulative Probability of Relapse After Remission Among Patients With Antidepressant-Resistant Major Depressive Disorder, Acute Treatment Phase

HR, hazard ratio. Time to first relapse was determined by first occurrence of QIDS-C16 score of 11 or more after remission in the acute treatment phase through the week 36 visit. Follow-up time 0 indicates the day that remission was determined. The proportions relapsing within each treatment group were 26 of 114 patients (22.8%) for the switch group, 35 of 136 patients (25.7%) for the augment-bupropion group, and 37 of 146 patients (25.3%) for the augment-aripiprazole group. Follow-up time was censored in this analysis if the patient withdrew from the study. HRs for stratified life-table regressions for relapse: augment-bupropion group vs switch group, 1.36 (95% CI, 0.78-2.39); augment-aripiprazole group vs switch group, 1.12 (95% CI, 0.65-1.94); augment-aripiprazole group vs augment-bupropion group, 0.96 (95% CI, 0.58-1.59). Median follow-up time to relapse or censoring was 163 days (interquartile range [IQR], 70-201) for the switch group, 163 days (IQR, 68.5-197) for the augment-bupropion group and 160.5 days (IQR, 59-203) for the augment-aripiprazole group. Maximum follow-up time was 245 days.