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Original Investigation
December 4, 2019

Prevention of Recurrence After Recovery From a Major Depressive Episode With Antidepressant Medication Alone or in Combination With Cognitive Behavioral Therapy: Phase 2 of a 2-Phase Randomized Clinical Trial

Author Affiliations
  • 1Department of Psychology, University of Pennsylvania, Philadelphia
  • 2Department of Psychiatry, Rush University, Chicago, Illinois
  • 3Department of Psychiatry, Vanderbilt University, Nashville, Tennessee
  • 4Department of Psychiatry, University of Alabama at Birmingham, Birmingham
  • 5Department of Psychiatry, University of Pennsylvania, Philadelphia
  • 6Department of Psychiatry, University of New Mexico, Albuquerque
  • 7Department of Mathematics and Applied Statistics, West Chester University, West Chester, Pennsylvania
  • 8Department of Psychology, Vanderbilt University, Nashville, Tennessee
JAMA Psychiatry. 2020;77(3):237-245. doi:10.1001/jamapsychiatry.2019.3900
Key Points

Question  What are the effects of combining cognitive behavioral therapy with antidepressant medications on the prevention of depressive recurrence when antidepressant medications are withdrawn or maintained after recovery in patients with major depressive disorder?

Findings  In this phase 2 randomized clinical trial of 292 adult patients with major depressive disorder who recovered from a chronic or recurrent major depressive episode, withdrawal of antidepressant medication treatment was associated with higher rates of recurrence compared with maintenance of antidepressant medication treatment regardless of whether patients achieved recovery with or without acute cognitive behavioral therapy treatment.

Meaning  Maintenance of antidepressant medication treatment was associated with a reduced risk of depressive recurrence, but previous treatment with cognitive behavioral therapy was not; whether cognitive behavioral therapy has a similar protective effect or whether adding antidepressant medications to cognitive behavioral therapy treatment interferes with any such protective effect remains unclear.


Importance  Antidepressant medication (ADM) maintenance treatment is associated with the prevention of depressive recurrence in patients with major depressive disorder (MDD), but whether cognitive behavioral therapy (CBT) treatment is associated with recurrence prevention remains unclear.

Objective  To determine the effects of combining CBT with ADM on the prevention of depressive recurrence when ADMs are withdrawn or maintained after recovery in patients with MDD.

Design, Setting, and Participants  A total of 292 adult outpatients with chronic or recurrent MDD who participated in the second phase of a 2-phase trial. Participants had recovered in the first phase of the trial receiving ADM, either alone or in combination with CBT. The trial was conducted in research clinics in 3 university medical centers in the United States. Patients in phase 2 were randomized to receive maintenance of or withdrawal from ADM and were followed up for 3 years. The first and last patients entered phase 2 in August 2003 and October 2009, respectively. The last patient completed phase 2 in August 2012. Data were analyzed from December 2013 to December 2018.

Interventions  Maintenance of or withdrawal from treatment with ADM.

Main Outcomes and Measures  Recurrence of an MDD episode using longitudinal interval follow-up evaluations; sustained recovery across both phases.

Results  A total of 292 participants (171 women, 121 men; mean [SD] age 45.1 [12.9] years) were included in analyses of depressive recurrence. Maintenance ADM yielded lower rates of recurrence compared with ADM withdrawal regardless of whether patients had achieved recovery in phase 1 with ADM alone (48.5% vs 74.8%; z = −3.16; P = .002; number needed to treat [NNT], 2.8; 95% CI, 1.8-7.0) or ADM plus CBT (48.5% vs 76.7%; z = −3.49; P < .001; NNT, 2.7; 95% CI, 1.9-5.9). Sustained recovery rates differed as a function of phase 2 condition, with maintenance ADM superior to ADM withdrawal (z = 2.90; P = .004; OR, 2.54; 95% CI, 1.37-4.84; NNT, 2.3; 95% CI, 1.5-6.4). Phase 1 condition was not associated with differential rates of sustained recovery (ADM alone vs ADM plus CBT; z = 0.22; P = .83; OR, 1.08; 95% CI, 0.52-2.11; NNT, 26.0; 95% CI, number needed to harm 3.2 to NNT 2.8), nor was there a significant interaction of phase 1 condition and phase 2 condition (z = 0.30; P = .77; OR, 1.14; 95% CI, 0.49-2.88).

Conclusions and Relevance  Maintenance ADM treatment, but not previous exposure to CBT, was associated with reduced rates of depressive recurrence. In previous studies, when CBT has been provided without ADM, CBT has shown a preventive effect on depressive relapse. Whether CBT also has a preventive effect on depressive recurrence, or if adding ADM interferes with any such preventive effect, remains unclear.

Trial Registration  ClinicalTrial.gov identifier: NCT00057577

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    1 Comment for this article
    Confounding recurrent MDD episode with ADM withdrawal symptoms
    Justine Lalonde, MD | Private practice
    The tapering schedule in phase 2 for the 3 ADMs +/- lithium was 4 weeks or longer. I could not find the average discontinuation time and % beyond 4 weeks. The modified criteria of 3 weeks, instead of 2 weeks, of meeting LIFE 5 or 6 level for a recurrence of MDD criteria for the first 8 weeks to mitigate withdrawal symptoms for participants who had been on ADM for a min. 9months -2 years appears inadequate.

    I submit that the short tapering schedule and the modified recurrence criteria are surely capturing withdrawal experiences which go beyond physical symptoms,
    and include symptoms of depression, anxiety, insomnia and neurocognitive difficulties. It is also interesting that the KM curves show a differential rate in the first 6 months of the phase 2 but then appear to have similarly recurrence rates thereafter. Such an analysis of curves could be of interest.

    I am convinced that confounding recurrence of MDD episodes instead of ADM withdrawal symptoms is likely, and certainly cannot be ruled-out, and should be stressed in the discussion and conclusion, especially in light of CBT vs ADM trials in the past have shown an advantage for CBT inrecurrence which is duly highlighted in the paper.