title: Placebo-controlled adjunctive trial of pramipexole in patients with bipolar disorder: targeting cognitive dysfunction.
abstract: 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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00597896.
authors.affiliation: Mount Sinai School of Medicine, New York, NY 10029, USA. katherine.burdick@mssm.edu
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Burdick
authors.forename: Raphael J
authors.initials: RJ
authors.lastname: Braga
authors.forename: Charles U
authors.initials: CU
authors.lastname: Nnadi
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Shaya
authors.forename: Walter H
authors.initials: WH
authors.lastname: Stearns
authors.forename: Anil K
authors.initials: AK
authors.lastname: Malhotra
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D052160:Benzothiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000150:complications / Q000188:drug therapy* / Q000523:psychology*; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy* / Q000523:psychology; D018491:Dopamine Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods / Q000523:psychology / Q000706:statistics & numerical data; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D000077487:Pramipexole; D011619:Psychotropic Drugs / Q000627:therapeutic use
chemical_list: D052160:Benzothiazoles; D018491:Dopamine Agonists; D011619:Psychotropic Drugs; D000077487:Pramipexole