Arch Gen Psychiatry. 1999;56:407-412

A Preliminary Double-blind, Placebo-Controlled Trial

Andrew L. Stoll, MD; W. Emanuel Severus, MD, PhD; Marlene P. Freeman, MD; Stephanie Rueter; Holly A. Zboyan; Eli Diamond; Kimberly K. Cress, MD; Lauren B. Marangell, MD

Background: 3 Fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether 3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder.

Methods: A 4-month, double-blind, placebo-controlled study, comparing 3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder.

Results: A Kaplan-Meier survival analysis of the cohort found that the 3 fatty acid patient group had a significantly longer period of remission than the placebo group (P=.002; Mantel-Cox). In addition, for nearly every other outcome measure, the 3 fatty acid group performed better than the placebo group. Conclusion 3 Fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder.

BIPOLAR DISORDER (manic-depressive illness) is a common neuropsychiatric illness with a high morbidity and mortality.1 Despite available mood-stabilizing drugs, such as lithium carbonate and valproate, the illness is characterized by high rates of recurrence.1, 2 Recent research suggests that all of the currently available mood-stabilizing drugs have inhibitory effects on neuronal signal transduction systems. These findings have led to the hypothesis that overactive cell-signaling pathways may be involved in the pathophysiological mechanisms underlying bipolar disorder.3-6 By using this model of mood stabilizer action based on suppression of neuronal signal transduction mechanisms, novel mood-stabilizing agents can be rationally developed. One promising group of compounds is the 3 fatty acids, obtained from marine or plant sources.7 Among other effects, the ingestion of large amounts of 3 fatty acids is associated with a general dampening of signal transduction pathways associated with phosphatidylinositol, arachidonic acid, and other systems.8, 9 Thus, 3 fatty acids may be useful in conditions such as bipolar disorder, where the pathophysiological process may involve overactivity of cell signal transduction.

We hypothesized that orally administered 3 fatty acids would exhibit inhibitory effects on signal transduction mechanisms in human neuronal membranes, and that high-dose 3 fatty acids would be an effective mood stabilizer in bipolar disorder. The goal of this preliminary study was to assess the subacute mood-stabilizing effects of 3 fatty acids in patients with unstable bipolar disorder.

PATIENTS AND METHODS

OVERVIEW

This was a 4-month, parallel-group, placebo-controlled, double-blind pilot study in which outpatients with bipolar disorder were randomized to receive either 3 fatty acids or placebo, in addition to their ongoing usual treatment.

PATIENTS

Participating subjects were men and women, 18 to 65 years old, who met DSM-IV10 criteria for bipolar disorder (types I or II), and were free of notable medical and psychiatric comorbidity. The diagnosis of bipolar disorder was established by means of all available clinical information, including the mood disorder module of the Structured Clinical Interview for DSM-IV.11 Patients were required to have had at least 1 manic or hypomanic episode within the past year, because the expected high risk of recurrence in this subgroup1 enhanced the power of the study to detect a difference between the 2 treatment groups within the study period. Forty percent of the study cohort had rapid-cycling symptoms, defined as 4 or more mood episodes in the 1 year before enrollment in the study.12 Patients were permitted to continue with their outpatient psychiatrist or psychotherapist, but no new psychotherapy treatment was started. Subjects receiving other medications at study entry continued to receive these medications at constant dosages, whether or not they were in the therapeutic range.

Table 1 summarizes the demographic and clinical characteristics of the study subjects. This study was approved by the human studies committees of Brigham and Women's Hospital, Boston, Mass, and Baylor College of Medicine, Houston, Tex, and all participating patients gave written informed consent after receiving a full explanation of the study.