Placebo-controlled adjunctive trial of pramipexole in patients with bipolar disorder: targeting cognitive dysfunction

J Clin Psychiatry. 2012 Jan;73(1):103-12. doi: 10.4088/JCP.11m07299. Epub 2011 Nov 29.


Objective: Patients with bipolar disorder suffer from significant cognitive impairment that contributes directly to functional disability, yet few studies have targeted these symptoms for treatment, and the optimal study design remains unclear. We evaluated the effects of the dopamine D₂/D₃ receptor agonist pramipexole on cognition in bipolar disorder.

Method: Fifty stable outpatients with DSM-IV-diagnosed bipolar I or bipolar II disorder enrolled in an 8-week, double-blind, randomized, placebo-controlled cognitive enhancement trial between July 2006 and April 2010. Patients completed neurocognitive testing at baseline and at week 8, and the primary outcome measures were change scores calculated for each of the 11 tasks. Symptoms and side effects were monitored weekly.

Results: Forty-five patients completed the study (placebo, n = 24; pramipexole, n = 21), and groups were well matched on demographic and clinical features. Primary cognitive analyses indicated no compelling cognitive benefit of pramipexole versus placebo; however, secondary analyses highlight several important methodological issues for future trials and identify a subgroup of patients who might benefit more readily from cognitive enhancement strategies. This outcome suggests that the study design played a very important role in the results-implying a failed rather than altogether negative trial. Specifically, we found that even very subtle, subsyndromal mood symptoms at baseline had a significant influence on the degree of improvement due to active drug, with strictly euthymic patients faring best (multivariate analysis of variance, P = .03 in euthymic subgroup). In addition, the extent of baseline cognitive impairment also contributed to the likelihood of treatment response. Finally, concomitant medications may weaken, or in some cases enhance, response to cognitive treatment and should be accounted for in study design.

Conclusions: Although our results point toward a lack of clear effect of pramipexole on cognition in bipolar patients, our data revealed a potentially beneficial effect of pramipexole in a subgroup, providing some enthusiasm for pursuing this line of research in the future. Moreover, this study emphasizes the importance of rigorous subject selection for cognitive trials in bipolar illness. Future studies will be necessary to determine the possible clinical and functional implications of these results.

Trial registration: Identifier: NCT00597896.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Benzothiazoles / administration & dosage
  • Benzothiazoles / adverse effects
  • Benzothiazoles / therapeutic use*
  • Bipolar Disorder / complications
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / psychology*
  • Cognition Disorders / complications
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / psychology
  • Dopamine Agonists / adverse effects
  • Dopamine Agonists / therapeutic use*
  • Double-Blind Method
  • Drug Therapy, Combination / methods
  • Drug Therapy, Combination / psychology
  • Drug Therapy, Combination / statistics & numerical data
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neuropsychological Tests / statistics & numerical data
  • Pramipexole
  • Psychotropic Drugs / therapeutic use


  • Benzothiazoles
  • Dopamine Agonists
  • Psychotropic Drugs
  • Pramipexole

Associated data