Research reportDivalproex in the treatment of bipolar depression: a placebo-controlled study
Introduction
The lifetime prevalence of bipolar disorder ranges from 3% to 6.5%, depending on the specific diagnostic definition of bipolar used (Hirschfeld et al., 2002a, Akiskal et al., 2000, Lewinsohn et al., 1995, Weissman et al., 1996). As part of the natural course of illness, patients with bipolar disorder often suffer from episodes of depression more frequently and for longer durations than mania (Judd et al., 2002, Judd et al., 2003). Although, perhaps, less overtly disruptive than the manic phase of the illness, bipolar depression is a significant cause of psychiatric morbidity and mortality, and thus a major public health concern. A major challenge in the treatment of bipolar depression is the tendency for antidepressant medications, particularly tricyclic antidepressants, to precipitate episodes of mania, or to increase cycle frequency or symptom intensity (Boerlin et al., 1998, Bottlender et al., 1998, Peet, 1994). Thus, exploring the utility of mood stabilizers as monotherapy for bipolar depression is important. Divalproex (Depakote®) has become the most widely prescribed mood stabilizer in the United States but has not been extensively tested for its potential antidepressant characteristics (Davis et al., 2000).
We have previously reported an open label treatment trial of divalproex in unipolar major depressive disorder with positive results (Davis et al., 1996). Also, data from the double-blind study of treatment for acute mania in bipolar disorder, which compared divalproex, lithium, and placebo (Bowden et al., 1994), suggests that those patient with pretreatment depressive symptoms responded preferentially to divalproex compared to lithium or placebo (Swann et al., 1997). These promising results encouraged us to perform a double-blind, randomized, placebo-controlled clinical trial to test the efficacy of divalproex in the treatment of patients with bipolar depression.
Section snippets
Subjects
Subjects were recruited from the Mental Heath Clinic at the Dallas Veterans Affairs Medical Center. The study was approved by the Dallas VA Subcommittee on Human Studies (Institutional Review Board). After providing signed informed consent, patients received a standard laboratory, medical, and psychiatric examination. Diagnoses were confirmed by the Structured Clinical Interview for DSM-IV (SCID) and the borderline and antisocial personality disorder modules of the Structured Clinical Interview
Descriptive
Twenty-five patients were enrolled in the study, with 12 assigned to placebo and 13 to divalproex. Most were male (89%) and of Caucasian origin (81%), with a mean age of 41 years (S.D.±8, range 25–54). There were no significant differences in demographics between the two groups. The mean±S.D. serum valproic acid levels were 80±9.3 mcg/mL at week 4 and 81±19.2 mcg/mL at week 8.
Of the 25 patients who were randomized, 20 (80%) completed at least 4 weeks of the study, and 12 participants (48%, 6 in
Discussion
To our knowledge, this is one of two, small, double-blind, placebo-controlled, clinical trials of divalproex in the treatment of bipolar depression. The major finding of this work is that patients suffering from bipolar I depression that were treated with divalproex showed greater improvement in symptoms of depression and anxiety than those treated with placebo. The rate of improvement over time in patients treated with divalproex was about twice as great for symptoms of depression and about
Acknowledgements
The authors would like to acknowledge the support of the Department of Veterans Affairs Research and Development and the Stanley Foundation. We also thank Michelle Bollig, Alexandria Nugent, Gerald Kramer, Praveen P. Fernandes, MD, S. Pizada Sattar, MD, Prasad R. Padala, MD, and Thomas Carmody, PhD, for technical support.
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