Preventing depressive relapse and recurrence in higher-risk cognitive therapy responders: a randomized trial of continuation phase cognitive therapy, fluoxetine, or matched pill placebo

Abstract

Importance: Strategies to improve the course of recurrent major depressive disorder have great public health relevance. To reduce the risk of relapse/recurrence after acute phase cognitive therapy (CT), a continuation phase model of therapy may improve outcomes.

Objectives: To test the efficacy of continuation phase CT (C-CT) and fluoxetine for relapse prevention in a pill placebo (PBO)-controlled randomized trial and compare the durability of prophylaxis after discontinuation of treatments.

Design: A sequential, 3-stage design with an acute phase (all patients received 12 weeks of CT); 8-month experimental phase (responders at higher risk were randomized to C-CT, fluoxetine, or PBO); and 24 months of longitudinal, posttreatment follow-up.

Setting: Two university-based specialty clinics.

Patients: A total of 523 adults with recurrent major depressive disorder began acute phase CT, of which 241 higher-risk responders were randomized and 181 subsequently entered the follow-up.

Interventions: Cognitive therapy responders at higher risk for relapse were randomized to receive 8 months of C-CT (n = 86), fluoxetine (n = 86), or PBO (n = 69).

Main outcomes and measures: Survival analyses of relapse/recurrence rates, as determined by blinded evaluators using DSM-IV criteria and the Longitudinal Interval Follow-up Evaluation. RESULTS As predicted, the C-CT or fluoxetine groups were significantly less likely to relapse than the PBO group across 8 months. Relapse/recurrence rates for C-CT and fluoxetine were nearly identical during the 8 months of treatment, although C-CT patients were more likely to accept randomization, stayed in treatment longer, and attended more sessions than those in the fluoxetine and PBO groups. Contrary to prediction, relapse/recurrence rates following the discontinuation of C-CT and fluoxetine did not differ.

Conclusions and relevance: Relapse risk was reduced by both C-CT and fluoxetine in an enriched randomization sampling only CT responders. The preventive effects of C-CT were not significantly more durable than those of fluoxetine after treatment was stopped, suggesting that some higher-risk patients may require alternate longer-term interventions.

Trial registration: clinicaltrials.gov Identifiers: NCT00118404, NCT00183664, and NCT00218764.

Figure 1

Consort Flow Diagram

Figure 2

Kaplan-Meier survival curves estimating time until relapse (DSM-IV major depressive disorder diagnosed by blind evaluator) over the 8 months (35 weeks) post-randomization. Log rank tests revealed that the proportion of relapse in C-CT (18.3%; n = 86) or FLX (18.0%; n = 86) was less than in PBO (32.7%; n = 69) as follows:

1. -

   FLX vs. PBO (χ₁² = 3.92, p-value = .02)

2. -

   C-CT vs. PBO (χ₁² = 3.39, p-value = .03)

3. -

   C-CT vs. FLX (χ₁² = 0.04, p-value = .42)

Figure 3

Kaplan-Meier survival curves estimating time until relapse/recurrence (DSM-IV major depressive disorder diagnosed by blind evaluator) over 20 months (139 weeks) post-randomization. Log rank tests with pairwise comparisons showed no differences among FLX (35.1%; n = 86), (C-CT, 35.0%; n = 86) or PBO (42.7%; n = 69) at α = 0.05. Comparisons at 32 months were also null.