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

ABSTRACT: 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 D?/D? receptor agonist pramipexole on cognition in bipolar disorder.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.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.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.clinicaltrials.gov Identifier: NCT00597896.

SUBMITTER: Burdick KE

PROVIDER: S-EPMC4457389 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Burdick Katherine E KE Braga Raphael J RJ Nnadi Charles U CU Shaya Yaniv Y Stearns Walter H WH Malhotra Anil K AK

The Journal of clinical psychiatry 20111129 1

<h4>Objective</h4>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.<h4>Method</h4>Fifty stable outpatients with DSM-IV-diagnosed bipolar I or bipolar II disorder enrolled in an 8-week, double-blind, randomi ...[more]

PMID: 22152405

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Project description:A large proportion of patients with bipolar disorder experience persistent cognitive dysfunction, such as memory, attention and planning difficulties, even during periods of full remission. The aim of this trial is to investigate whether cognitive remediation, a new psychological treatment, improves cognitive function and, in turn, psychosocial function in patients with bipolar disorder in partial or full remission.The trial has an evaluator-blind, randomized, between-groups design. Forty patients with bipolar disorder in full or partial remission, aged 18 to 50 years, who report moderate to severe cognitive difficulties, are recruited. Patients are randomized to receive weekly group-based cognitive remediation treatment over 12 weeks in addition to standard treatment or standard treatment alone. Both groups undergo neurocognitive testing and functional magnetic resonance imaging (fMRI) at baseline, post-treatment (week 12) and follow-up (week 26). The primary outcome is improved verbal memory, as measured with the Rey Auditory Verbal Learning Test (RAVLT) from baseline to post-treatment. With inclusion of 40 patients we obtain 86% power to detect a clinically relevant difference in verbal memory between groups. Secondary outcomes are improved attention, executive function and psychosocial function, as measured with the Rapid Visual Information Processing test, the Trail Making Test part B and the Functional Assessment Short Test (FAST), respectively. Tertiary outcomes are improved scores for additional neuropsychological tests of memory, attention, executive function and facial expression recognition, as well as in questionnaires measuring subjective cognitive difficulties, stress, coping strategies, personality traits, depressive symptoms and quality of life.This is the first randomized controlled trial to evaluate the effects of cognitive remediation on cognitive function in patients with bipolar disorder who experience persistent cognitive difficulties despite being in full or partial remission.ClinicalTrials.gov NCT01457235.

Project description:Depressive episodes are a major cause of morbidity and dysfunction in individuals suffering from bipolar disorder. Currently available treatments for this condition have limited efficacy and new therapeutic options are needed. Extensive research in the pathophysiology of bipolar disorder points to the existence of mitochondrial and bioenergetic dysfunction. We hypothesized that creatine monohydrate, a nutraceutical that works as a mitochondrial modulator, would be effective as an adjunctive therapy for bipolar depression. We conducted a double-blind trial in which 35 patients with bipolar disorder type I or II in a depressive episode by DSM-IV criteria and in use of regular medication for the treatment of this phase of the disease were randomly allocated into two adjunctive treatment groups for 6 weeks: creatine monohydrate 6 g daily (N = 17) or placebo (N = 18). Primary efficacy was assessed by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS). We did not find a statistically significant difference in the comparison between groups for the change in score on the MADRS after 6 weeks in an intention-to-treat (ITT) analysis (p = 0.560; Cohen's d = 0.231). However, we found significant superiority of creatine add-on vs. placebo when we considered the remission criterion of a MADRS score ? 12 at week 6 analyzing the outcome of the 35 randomized patients on ITT (52.9% remission in the creatine group vs. 11.1% remission in the placebo group) and of the 23 completers (66.7% remission in the creatine group vs. 18.2% remission in the placebo group) (p = 0.012; OR = 9.0 and p = 0.036; OR = 9.0, respectively). Two patients who received creatine switched to hypomania/mania early in the trial. No clinically relevant physical side-effects were reported or observed. This proof-of-concept study, aiming to restore brain bioenergetics using an adjunctive mitochondrial modulator, is not conclusive on the efficacy of creatine add-on for bipolar depression, but suggests that this compound may have a role in the adjunctive treatment of this phase of the illness. Further investigation through randomized controlled trials with larger samples should be conducted to verify the efficacy of creatine supplementation for bipolar depression and also for subsyndromal depressive symptoms.

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

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

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