The goal of the proposed clinical trial is to assess the effect of oral cytidine and omega-3 fatty acids (O3FA) on bipolar disorder symptoms. This study is a 4-month, randomized, parallel-group, double-blind, placebo-controlled pilot study of a combination of cytidine and omega-3 fatty acids in 90 recently ill subjects with bipolar disorder. During the 16 week period of the study, subjects are assigned to one of three groups: 1) omega-3 fatty acids + cytidine supplementation, 2) omega-3 fatty acids supplementation alone, and 3) placebo supplementation.

Previous studies examining the effect of omega-3 fatty acids on bipolar depression have had mixed results. Some studies have found that omega-3 fatty acids have a positive effect on bipolar depression symptoms, while other studies have found no difference between placebo and omega-3 fatty acid treatment.

The variable effects noted with omega-3 fatty acids may be due in part to a real effect with limited potency. Larger effects might be achieved by combining agents with synergistic effects.

Cytidine is necessary to form key intermediates in the biosynthesis of the phospholipids phosphatidylcholine and phosphatidylethanolamine, which are major components of eukaryotic cell membranes. Recent human studies by our group have shown that CDP-choline (a compound composed of cytidine and choline) can modify brain phospholipid synthesis in healthy adults and may have antidepressant effects (Babb et al., 1996; Babb et al., 2002; Carlezon et al., 2002; Renshaw et al., 1999). The combination of omega-fatty acids and the related pyrimidine, uridine, was associated with enhanced antidepressant-like activity in rats (Carlezon et al., 2005). Thus, the combination of omega-3 fatty acid and cytidine, which is interconverted with uridine in the body, may provide a safe and powerful way to treat bipolar disorder, especially bipolar depression.

This study is a 4-month, randomized, parallel-group, double-blind, placebo-controlled pilot study of a combination of cytidine and omega-3 fatty acids in 90 recently ill subjects with bipolar disorder. During the 16 week period of the study, subjects are assigned to one of three groups: 1) omega-3 fatty acids + cytidine supplementation, 2) omega-3 fatty acids supplementation alone, and 3) placebo supplementation.

Inclusion Criteria:

• bipolar disorder
• mood episode within past year
• stable medication regimen

Exclusion Criteria:

• primary psychiatric disorder other than bipolar disorder
• significant suicide or homicide risk
• unstable medical conditions
• current or planned pregnancy
• lactose intolerance
• medications affecting lipid absorption or metabolism
• clozapine treatment