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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-C 16 ] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C 16 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

This review of the literature indicates that the incidence of psychiatric reactions to prescription and nonprescription respiratory drugs, such as decongestants, bronchodilators, expectorants, cough suppressants, and related agents, is low. When these reactions do occur they are most likely to appear in patients who are chronic users of these preparations, are overmedicated, or are chronic drug abusers in general. The authors found reports of toxicity to be in general scarce and poorly defined. A careful drug history with inquiry specifically directed at use of these agents is recommended when searching for possible causes of psychiatric reactions, in particular CNS stimulation, anxiety, and a nervous aspect to behavior.