Incidence and Time Course of Subsyndromal Symptoms in Patients With Bipolar I Disorder: An Evaluation of 2 Placebo-Controlled Maintenance Trials

Mark A. Frye, M.D.; Lakshmi N. Yatham, M.D.; Joseph R. Calabrese, M.D.; Charles L. Bowden, M.D.; Terence A. Ketter, M.D.; Trisha Suppes, M.D., Ph.D.; Bryan E. Adams, Ph.D.; and Thomas R. Thompson, M.D.

Background: Subsyndromal symptoms in bipolar disorder can cause significant functional impairment and are associated with relapse.

Method: In this post hoc analysis from 2 randomized, double-blind, 18-month, placebo-controlled maintenance trials for bipolar I disorder (both trials were conducted between August 1997 and August 2001 and used DSM-IV criteria), the incidence, time course, and impact of pharmacotherapy on subsyndromal symptoms were examined.

Results: Subsyndromal symptoms occurred in approximately 25% of all visits. Compared with placebo (54.8%), a significantly higher mean percentage of visits in remission were observed with lamotrigine treatment (63.0%, p = .020) but not with lithium treatment (60.0%, p = .165). The median time to onset of subsyndromal symptoms for lamotrigine (N = 223), lithium (N = 164), and placebo (N = 188) was 15, 15, and 9 days, respectively. Compared with placebo, both lamotrigine and lithium significantly delayed the time from randomization to onset of subsyndromal symptoms (p = .046, lamotrigine vs. placebo; p = .033, lithium vs. placebo; p = .763, lamotrigine vs. lithium) and the time from onset of subsyndromal symptoms to subsequent mood episode (p = .037, lamotrigine vs. placebo; p = .023, lithium vs. placebo; p = .845, lamotrigine vs. lithium). Agreement between the polarities of the first-observed subsyndromal symptom and subsequent intervention for mood episode was statistically significant (p < .001).

Conclusion: Subsyndromal symptoms are common during maintenance treatment and appear to be associated with relapse into an episode of the same polarity. Both lithium and lamotrigine delayed the onset of subsyndromal symptoms and the time from onset of subsyndromal symptoms to subsequent relapse. Further study to assess whether treatment intervention can minimize subsyndromal symptoms or prevent relapse is encouraged.

(J Clin Psychiatry 2006;67:1721-1728)

Received Jan. 23, 2006; accepted April 11, 2006. From the Mood Disorders Research Program, University of California at Los Angeles (Dr. Frye); the Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada (Dr. Yatham); the Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio (Dr. Calabrese); the Department of Psychiatry, University of Texas Health Science Center at San Antonio (Dr. Bowden); the Stanford University School of Medicine, Stanford, Calif. (Dr. Ketter); the University of Texas Southwestern Medical Center, Dallas (Dr. Suppes); GlaxoSmithKline, Research Triangle Park, N.C. (Dr. Thompson); and Clinforce, Research Triangle Park, N.C. (Dr. Adams). Dr. Adams is now with GlaxoSmithKline, Research Triangle Park, N.C.

GlaxoSmithKline funded the studies described in this article.

Financial disclosure for all authors appears at the end of this article.

Corresponding author and reprints: Mark A. Frye, M.D., Department of Psychiatry and Psychology, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905 (e-mail: mfrye@mayo.edu).