Omega-3 fatty acid treatment, with or without cytidine, fails to show therapeutic properties in bipolar disorder: a double-blind, randomized add-on clinical trial

J Clin Psychopharmacol. 2012 Oct;32(5):699-703. doi: 10.1097/JCP.0b013e318266854c.


Objective: This study aimed to test the effects of omega-3 fatty acids (O3FA), given as fish oil capsules, with and without oral cytidine (CYT), a pyrimidine with reported preclinical and clinical antidepressant-like effects, in patients with bipolar disorder (BD).

Methods: A total of 45 outpatients with diagnosed BD (type I) according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision, were recruited for this 4-month, randomized, double-blind, placebo-controlled, add-on study. Treatment groups were (1) oral CYT + O3FA, (2) placebo + O3FA, and (3) placebo + placebo control. O3FA was given 2 g twice a day and CYT was administered as 1 g twice a day.

Results: There was no statistically significant difference among the groups in the primary outcome: study retention. Clinical measures improved in all treatment groups, and there were no significant differences between groups, including change in probability of symptoms of depression or mania, change in positive ratings of depression or mania, or change in Global Assessment of Functioning scores. Neither CYT + O3FA nor placebo + O3FA treatment was superior to placebo treatment. Rather, there was a statistically nonsignificant trend for both groups treated with O3FA to do worse than the placebo group.

Conclusions: Despite preclinical studies suggesting that the effect of O3FA might be augmented with pyrimidines, add-on CYT did not substantially improve mood symptoms in BD. In addition, although a power analysis indicated that the sample size would be adequate to see beneficial effects similar to those previously reported, O3FA treatment by itself was not superior to placebo for BD.

Trial registration: NCT00854737.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / physiopathology
  • Cytidine / administration & dosage
  • Cytidine / therapeutic use*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Fatty Acids, Omega-3 / administration & dosage
  • Fatty Acids, Omega-3 / therapeutic use*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Treatment Failure


  • Fatty Acids, Omega-3
  • Cytidine

Associated data