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 D-2/D-3 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.

Background: There is an increased interest in early intervention strategies for severe mental disorders with hopes of mitigating the emergence and impact of the illness. Individuals at clinical high-risk (CHR) for schizophrenia have been primarily identified by the presence of attenuated positive symptoms. Although bipolar disorder and schizophrenia may have overlapping etiologies, few studies have investigated the potential prodrome in bipolar disorder. We sought to determine if there is a prodrome to bipolar disorder and if clinical or neurocognitive measures could distinguish between the bipolar and schizophrenia prodromes.Methods: We examined subjects who were initially identified as CHR for schizophrenia during the prodrornal phase of the illness and followed them prospectively. Unexpectedly, eight subjects developed bipolar disorder. Baseline data from subjects who eventually developed bipolar disorder (pre-BP; N = 8), schizophrenia or a psychotic disorder (pre-SZ; N = 24) and a non-converter comparison group (NCC; N = 115) were compared.Results: The pre-BP and pre-SZ groups did not differ on attenuated positive symptom severity, global measures of functioning or on the global neurocognitive score. Compared to NCC individuals, both pre-BP and pre-SZ patients reported more severe attenuated positive symptoms and were more likely to be on antipsychotic medication at baseline. The pre-SZ group had a significantly lower current IQ and was significantly more impaired than the NCC group on the overall neurocognitive score.Conclusions: This study provides preliminary support for a bipolar prodrome, which may be indistinguishable from the schizophrenia prodrome based on clinical and neurocognitive measures currently used in high-risk schizophrenia programs. (C) 2010 Elsevier B.V. All rights reserved.