RESULTS

The results for the 30 patients with evaluable data, as defined above, are presented herein. There were no significant differences in the demographic and baseline clinical characteristics of the 3 fatty acid and placebo groups (Table 1). Figure 1 depicts a Kaplan-Meier survival analysis of the study cohort. The duration of time remaining in the study was significantly greater in the 3 fatty acid?treated group when compared with placebo (P=.002; Mantel-Cox, log-rank statistic, 21=9.990). The time to a 50% rate of ending the study prematurely ("nonresponse") was 65 days for the placebo group, reflecting the unstable nature of the study population. A post hoc analysis was also performed for the subgroup of 8 subjects who entered the study while receiving no other mood-stabilizing drugs. As was observed in the whole study cohort, the 4 subjects who received 3 monotherapy remained in remission for a significantly longer time than the 4 subjects who received placebo monotherapy (Figure 2; P=.04; Mantel-Cox). Other post hoc analyses showed that sex, the presence or absence of rapid cycling, and the type of bipolar disorder (I vs II) did not predict response to 3 fatty acids, although the number of subjects in each cell was small.

Table 1 displays the comparison of the secondary outcome measures between the 3 and placebo groups. For nearly every outcome measure, the 3 fatty acid group performed better than the placebo group.

Three patients developed side effects of the study drug and were permitted to lower the dosage to a minimum of 5 capsules twice daily. The most common adverse effect in both the 3 and olive oil groups was mild gastrointestinal tract distress, generally characterized by loose stools. Of the patients with adverse effect data at week 4 of the trial, 8 (62%) of 13 3-treated subjects complained of mild gastrointestinal tract side effects, whereas 8 (53%) of 15 placebo-treated subjects experienced gastrointestinal tract side effects (P=.72 by Fisher exact test; 2 subjects with missing data). No other adverse effects appeared with significant frequency or severity, and overall the patients tolerated the trial well. No research subjects were hospitalized or developed marked suicidal ideation or behavior. Demographic and clinical data for each subject are listed in Table 2.

COMMENT

3 Fatty acids used as an adjunctive treatment in bipolar disorder resulted in significant symptom reduction and a better outcome when compared with placebo in this pilot study. Improvement was significantly greater in the 3 fatty acid group than the olive oil control group on almost every assessment measure. The striking difference in relapse rates and response appeared to be highly clinically significant.

These pilot results are intriguing and suggest that the addition of 3 fatty acids improved the subacute course of illness in this cohort of patients with bipolar disorder. The baseline clinical state of the research subjects in this study did not permit an evaluation of the antimanic effects of 3 fatty acids. Although the study was also not designed to provide definitive data on antidepressant effects, most of the patients receiving placebo who were considered treatment failures exhibited depressive exacerbations or recurrence. The suggestion of antidepressant effects of 3 fatty acids in this cohort of patients is noteworthy and warrants further study.

Although this was a double-blind, placebo-controlled study, several methodological factors must be considered. The mixture of bipolar types I and II, varied mood states at study entry, and varying concomitant medications was a less rigorous design than in the ideal clinical trial. The variability in the clinical profiles of the study patients was controlled to some degree by stratifying the randomization for sex, concurrent lithium treatment, and rapid cycling. It would be ideal, although impossible in a small study, also to stratify for other variables. However, the randomization did result in a comparable representation of key variables in the active and control groups, including concomitant medications and baseline mood state.

A further concern is the potential compromise of the blind. A distinct "fishy" aftertaste was episodically reported by subjects in both groups, but more often in the 3 group. When patients were asked to guess their randomization status, 86% of the 3 group guessed correctly, compared with 63% of the placebo group. Although in some cases the guess was based on the presence of a fishy aftertaste, in many cases it was based on the patient's perceived clinical response (or lack thereof in the placebo group). Correctly guessing a putative active treatment in the presence of a good clinical response is probably unavoidable. However, the possibility that the 3 group exhibited a placebo effect must be considered. Future studies to replicate and extend these findings should consider strategies to improve the blind, such as using a lower dose of 3 fatty acids to reduce the frequency of the fishy aftertaste, or alternatively adding a small amount of a fishy-tasting substance to the placebo.

If the results of this study are correct, and 3 fatty acids do possess mood-stabilizing action, then there are tangible implications for our understanding of the pathophysiological mechanisms of bipolar disorder and for the development of future treatments. Biochemical studies of human white blood cells show that high-dose therapy with 3 fatty acids leads to the incorporation of these polyunsaturated compounds into the membrane phospholipids crucial for cell signaling.8, 16 Increased concentrations of 3 fatty acids in membrane phospholipids appears to suppress phosphatidylinositol-associated signal transduction pathways.8, 16 The precise mechanism of this effect remains unclear. However, the incorporation of the polyunsaturated 3 fatty acids into the lipid bilayer of the cell membrane alters the physical and chemical properties of the membrane,17 possibly producing a local environment in which the membrane phospholipids are more resistant to hydrolysis by phospholipases. This could result in reduced generation of the second messenger molecules diacylglycerol and inositol triphosphate, thereby producing less activation of "downstream" intracellular signaling molecules, such as protein kinase C and calcium ion (Figure 3).

As in peripheral tissues, the 3 fatty acids are also highly incorporated into neuronal phospholipids in animal models.18 Thus, it is possible that the 3 fatty acids also inhibit signal transduction mechanisms in the human central nervous system. Recent work by several investigators3-6 strongly suggests that the mechanism of action of typical mood stabilizers, such as lithium and valproate, involves a similar inhibition of postsynaptic signal transduction processes (Figure 3). Our results support other data suggesting that the mechanism of action of mood stabilizers in bipolar disorder is the suppression of aberrant signal transduction pathways. This is consistent with a model of abnormal signal transduction as the pathophysiological basis of bipolar disorder. If further studies confirm their efficacy in bipolar disorder, 3 fatty acids may represent a new class of membrane-active psychotropic compounds, and may herald the advent of a new class of rationally designed mood-stabilizing drugs.

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