• Eric J Lenze, Benoit H Mulsant, Steven P Roose, Helen Lavretsky, Charles F Reynolds, Daniel M Blumberger, Patrick J Brown, Pilar Cristancho, Alastair J Flint, Marie A Gebara, Torie R Gettinger, Emily Lenard, J Philip Miller, Ginger E Nicol, Hanadi A Oughli, Vy T Pham, Bruce L Rollman, Lei Yang, and Jordan F Karp.
• From the Department of Psychiatry (E.J.L., P.C., T.R.G., E.L., G.E.N., V.T.P., L.Y.) and the Division of Biostatistics (J.P.M.), Washington University School of Medicine, St. Louis; the Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto (B.H.M., D.M.B., A.J.F.), the Centre for Addiction and Mental Health (B.H.M., D.M.B.), and the Centre for Mental Health, University Health Network (A.J.F.) - all in Toronto; Columbia University College of Physicians and Surgeons and the Department of Psychiatry, New York State Psychiatric Institute - both in New York (S.P.R., P.J.B.); the Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles (H.L., H.A.O.); University of Pittsburgh School of Medicine, Pittsburgh (C.F.R., M.A.G., B.L.R.); and the Department of Psychiatry, College of Medicine, University of Arizona, Tucson (J.F.K.).
• N. Engl. J. Med. 2023 Mar 23; 388 (12): 106710791067-1079.

BackgroundThe benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied.MethodsWe conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression.ResultsIn step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P = 0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups.ConclusionsIn older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).Copyright © 2023 Massachusetts Medical Society.

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