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

Importance: Antidepressant medication 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CBT with antidepressant medications on the prevention of depressive recurrence when antidepressant medications are withdrawn or maintained after recovery in patients with MDD.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 had previously participated in phase 1 and had recovered from a chronic or recurrent major depressive episode with antidepressant medication treatment alone or in combination with cognitive behavioral therapy (CBT) in phase 1 participated in a phase 2 trial conducted in research clinics in 3 university medical centers in the United States. Patients in phase 2 were randomized to receive maintenance or withdrawal of treatment with antidepressant medications and were followed for 3 years. The first patient entered phase 2 in August 2003, and the last patient to enter phase 2 began in October 2009. 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 antidepressant medications.

Main Outcomes and Measures: Recurrence of an MDD episode using longitudinal interval follow-up evaluations and sustained recovery.

Results: A total of 292 participants (171 women and 121 men; mean [SD] age, 45.1 [12.9] years) were included in the analyses of depressive recurrence. Antidepressant medication maintenance was associated with lower rates of recurrence compared with medication withdrawal regardless of whether patients had achieved recovery with monotherapy treatment in phase 1 (48.5% with medication maintained vs 74.8% with medication withdrawn; z = -3.16; P = .002; number needed to treat [NNT], 2.8; 95% CI, 1.8-7.0) or combination therapy treatment (48.5% with medication maintained vs 76.7% with medication withdrawn; z = -3.49; P < .001; NNT, 2.7; 95% CI, 1.9-5.9). Maintenance vs withdrawal of medication was associated with sustained recovery rates (z = 2.90; P = .004; odds ratio [OR], 2.54; 95% CI, 1.37-4.84; NNT, 2.3; 95% CI, 1.5-6.4). The interaction of phase 1 and phase 2 treatment conditions also did not have a significant association with sustained recovery (z = 0.30; P = .77; OR, 1.14; 95% CI, 0.49-2.88).

Conclusions and Relevance: In this study, maintenance monotherapy was associated with reduced rates of depressive recurrence. When CBT was provided in the absence of monotherapy treatment, a preventive effect on depressive relapse was noted. Whether CBT treatment has a similar effect on depressive recurrence or if adding monotherapy treatment interferes with any such preventive effect remains unclear.

Trial Registration: ClinicalTrial.gov identifier: NCT00057577.