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The Efficacy and Safety of Esketamine for the Treatment-Resistant Depression in Older Adults: Comments on TRANSFORM-3 Trial Results

  • Helen Lavretsky
    Correspondence
    Send correspondence and reprint requests to Helen Lavretsky, M.D., M.S., Jane and Terry Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, 37-456, Los Angeles, CA 90095.
    Affiliations
    Late Life Mood, Stress, and Wellness Program, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA (HL), Los Angeles, CA
    Search for articles by this author
  • Steven P. Roose
    Affiliations
    College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute (SPR), New York, NY
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Published:October 18, 2019DOI:https://doi.org/10.1016/j.jagp.2019.10.009
      Treatment-resistant depression in older adults (TRDOA) is common, is associated with increased morbidity and mortality in comorbid medical illness, and most devastatingly a high suicide risk.
      • Unutzer J
      • Park M
      Older adults with severe, treatment-resistant depression.
      ,
      • Cooper C
      • Katona C
      • Lyketsos K
      • et al.
      A systematic review of treatments for refractory depression in older people.
      TRD is commonly defined as nonresponse to two or more antidepressant therapies given at an adequate dose for an adequate duration meaning at least 6 weeks and preferably longer. Between 55% and 81% of older adults with major depressive disorder fail to remit with a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor,
      • Alexopoulos GS
      • Katz IR
      • Reynolds 3rd, CF
      • et al.
      Expert consensus panel for pharmacotherapy of depressive disorders in older patients. The expert consensus guideline series. Pharmacotherapy of depressive disorders in older patients.
      • Allard P
      • Gram L
      • Timdahl K
      • et al.
      Efficacy and tolerability of venlafaxine in geriatric outpatients with major depression: a double-blind, randomised 6-month comparative trial with citalopram.
      • Schatzberg A
      • Roose S
      A double-blind, placebo-controlled study of venlafaxine and fluoxetine in geriatric outpatients with major depression.
      • Raskin J
      • Wiltse CG
      • Siegal A
      • et al.
      Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial.
      • Crossley NA
      • Bauer M
      Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials.
      • Lenze EJ
      • Mulsant BH
      • Blumberger DM
      • et al.
      Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial.
      There are placebo-controlled studies that support the effectiveness of aripiprazole, or lithium in older patients who have failed monotherapy.
      • Crossley NA
      • Bauer M
      Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials.
      ,
      • Lenze EJ
      • Mulsant BH
      • Blumberger DM
      • et al.
      Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial.
      Unlike in younger patients, however, in whom evidence-based strategies for TRD exist, including the 1,500 patient VAST study,
      • Cristancho P
      • Lenard E
      • Lenze EJ
      • et al.
      Optimizing outcomes of treatment-resistant depression in older adults (OPTIMUM): study design and treatment characteristics of the first 396participants randomized.
      the clinician treating TRDOA still does not have evidence-based findings that establish the benefits and risks of different treatment paradigms for this high-risk group of older adults. The OPTIMUM study for TRDOA,
      • Zisook S
      • Johnson GR
      • Tal I
      • et al.
      General predictors and moderators of depression remission: a VAST-D report.
      which will complete recruitment at the end of 2019, will provide evidence on the risk and benefits of different augmentation or switch strategies in TRDOA. These findings promise the clinician new information on the use of aripiprazole and bupropion augmentation and bupropion monotherapy as well as lithium augmentation or switch to nortriptyline in this patient population.
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