Despite advances in the treatment of bipolar disorder, most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction. These persistent features of the illness represent critical treatment targets, as they do not adequately improve with standard mood stabilizing medications and they are strongly associated with functional disability and poor quality of life. In prior work by our group (Burdick et al. 2012), we reported preliminary evidence of a significant efficacy signal in a subset of bipolar patients who participated in a controlled cognitive enhancement trial of the D2/D3 agonist, pramipexole (Mirapex(c)). In conducting this previous study, we noted several important methodological limitations and illness-related confounds that require follow-up using a modified approach in order to adequately test the safety and efficacy of this agent in treating cognitive dysfunction in bipolar disorder. Thus, we propose a 2-site, collaborative, 24-week, randomized, placebo-controlled, adjunctive study to evaluate the safety and efficacy of pramipexole on neurocognitive functioning in 100 affectively-stable bipolar patients. We have modified the design from the prior trial to optimize the likelihood of detecting a positive signalby addressing several of the identified previous limitations by: 1) increasing the maximum daily dose~ 2) including patients who are affectively-stable with objective evidence of cognitive impairment~ 3) stratifying randomization based upon concomitant antipsychotic treatment~ and 4) increasing the duration of the trial to 6 months in an effort to address longer term safety and efficacy as well as potential improvement in everyday functioning. Pramipexole is approved by the US FDA for Parkinson's disease and Restless Leg Syndrome. In an off-label application, we will administer flexibly-dosed pramipexole (1-3 mg/day) vs. placebo to 100 stable patients with bipolar I disorder for 24 weeks. We will measure patients' performance on tasks of attention, memory and higher order cognition, using several paper-pencil and computerized tests, before pramipexole is administered, at week 4, week 8, week 16, and again at the end of the 24-week study. In addition, we will include several novel affective-neuroscience-based measures to gain insight into pramipexole's effect on the neural networks associated with DA-based reward processing. Finally, we will also investigate the effects of pramipexole on measures of functional capacity and community functions. We will closely monitor patients for unforeseen changes in mood symptoms that are deemed to place them at risk for developing mania or depression and will discontinue the trial as deemed necessary. We expect that findings from this study will provide a definitive go/no-go decision regarding the pursuit of this agent as a cognitive enhancer in bipolar disorder. Regardless of primary outcome, we expect that this trial will provide additional important data related to D2/D3-based reward processing in affective disorders.
Converging evidence suggests that patients with bipolar disorder suffer from deficits in neurocognitive functioning that persist, despite remission of acut affective symptoms. These impairments contribute directly to functional disability, highlighting the need for interventions above and beyond standard treatments in order to achieve a full inter-episode recovery. The current study aims to expand upon our initial promising findings to investigate the safety and efficacy of a dopamine agonist (pramipexole), on these persistent cognitive abnormalities in euthymic bipolar patients using a placebo-controlled, adjunctive, 24-week trial design.
|Van Rheenen, Tamsyn E; Lewandowski, Kathryn E; Lipschitz, Jessica M et al. (2018) Conducting clinical studies targeting cognition in psychiatry: guiding principles and design. CNS Spectr :1-6|
|Ospina, L H; Nitzburg, G C; Shanahan, M et al. (2018) Social cognition moderates the relationship between neurocognition and community functioning in bipolar disorder. J Affect Disord 235:7-14|
|Ospina, Luz H; Russo, Manuela; Nitzburg, George M et al. (2016) The effects of cigarette smoking behavior and psychosis history on general and social cognition in bipolar disorder. Bipolar Disord 18:528-538|
|Russo, Manuela; Mahon, Katie; Burdick, Katherine E (2015) Measuring cognitive function in MDD: emerging assessment tools. Depress Anxiety 32:262-9|
|Burdick, Katherine E; Ketter, Terence A; Goldberg, Joseph F et al. (2015) Assessing cognitive function in bipolar disorder: challenges and recommendations for clinical trial design. J Clin Psychiatry 76:e342-50|