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Original Research

Variables as Mediators or Moderators in Predicting Relapse to Any Type of Mood Episode in a Bipolar Maintenance Study

Mauricio Tohen, MD, DrPH, MBA; Wei V. Wang, MS; Marion Leboyer, MD; and Kai Yu Jen, PhD

Published: July 15, 2012

Article Abstract

Objective: Post hoc mediator/moderator analyses were designed to identify risk factors and their relationships in predicting relapse in olanzapine- or lithium-treated bipolar patients with an index manic or mixed episode. The aim was to identify moderators that precede and influence other variables to affect relapse and mediators that explain how or why a second variable affects relapse.

Method: We examined DSM-IV-diagnosed bipolar I disorder patients who met symptomatic remission criteria of an index manic or mixed (6.3%) episode after acute (6-12 weeks), open-label, combined therapy with olanzapine (5-20 mg/d; mean dose = 13.5 mg/d) plus lithium (300-1,800 mg/d; mean dose = 1,003.3 mg/d) followed by double-blind randomization to lithium (n = 214) or olanzapine (n = 217) for up to 52 weeks. The study started on August 5, 1999, and finished on June 14, 2002. Mediator/moderator analyses with α cut at .05 were used to understand how variables work together to impact rate of relapse.

Results: For lithium-treated patients, variables identified for relapse were country of residence, smoking status, previous episode history, and previous lithium use. For olanzapine-treated patients, risk factors included smoking status, previous episode history, amount of time patients had a 21-Item Hamilton Depression Rating Scale (HDRS-21) score ≤ 8 at pre-randomization, and HDRS-21 score at randomization. For lithium-treated patients, no mediators/moderators were identified among relapse variables. For olanzapine-treated patients, several baseline variables—such as previous number of mood episodes (manic or depressive)—operate through severity of depressive symptoms prior to remission (mediator) to affect relapse rate. On the other hand, the effect of the patient’s pre-remission depressive symptoms on outcome is moderated by the polarity of the first episode, whether manic, depressive, or mixed.

Conclusions: Mediators and moderators may provide valuable information in the treatment planning of patients with bipolar disorder and potentially influence treatment outcomes.

J Clin Psychiatry 2012;73(7):e913-e917

Submitted: November 23, 2010; accepted March 21, 2012 (doi:10.4088/JCP.10m06737).

Corresponding author: Mauricio Tohen, MD, DrPH, MBA, UT Health Science Center, Division of Mood and Anxiety Disorders, 7526 Louis Pasteur Dr, San Antonio, TX 78229 (

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Volume: 73

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