Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression

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, Jordan F. Karp

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Background: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. Methods: We 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. Results: In 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. Conclusions: In 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.

Original languageEnglish (US)
Pages (from-to)1067-1079
Number of pages13
JournalNew England Journal of Medicine
Issue number12
StatePublished - 2023


  • Clinical Medicine
  • Clinical Medicine General
  • Depression
  • Geriatrics/Aging
  • Geriatrics/Aging General
  • Neurology/Neurosurgery
  • Neurology/Neurosurgery General
  • Psychiatry

ASJC Scopus subject areas

  • General Medicine


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