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Eur Neuropsychopharmacol. 2016 Oct;26(10):1541-61. doi: 10.1016/j.euroneuro.2016.08.011. Epub 2016 Sep 1.

Cognitive enhancement treatments for bipolar disorder: A systematic review and methodological recommendations.

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Copenhagen Psychiatric Centre, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address:
Translational Psychiatry Research Group and Department of Clinical Medicine, Federal University of CearĂ¡, Fortaleza, CE, Brazil. Electronic address:
Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Villarroel 170, Barcelona 08036, Catalonia, Spain. Electronic address:
Copenhagen Psychiatric Centre, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address:


Cognitive dysfunction is an emerging treatment target in bipolar disorder (BD). Several trials have assessed the efficacy of novel pharmacological and psychological treatments on cognition in BD but the findings are contradictory and unclear. A systematic search following the PRISMA guidelines was conducted on PubMed and PsychInfo. Eligible articles reported randomized, controlled or open-label trials investigating pharmacological or psychological treatments targeting cognitive dysfunction in BD. The quality of the identified randomized controlled trials (RCTs) was evaluated with the Cochrane Collaboration's Risk of Bias tool. We identified 19 eligible studies of which 13 were RCTs and six were open-label or non-randomized studies. The findings regarding efficacy on cognition were overall disappointing or preliminary, possibly due to several methodological challenges. For the RCTs, the risk of bias was high in nine cases, unclear in one case and low in three cases. Key reasons for the high risk of bias were lack of details on the randomization process, suboptimal handling of missing data and lack of a priori priority between cognition outcomes. Other challenges were the lack of consensus on whether and how to screen for cognitive impairment and on how to assess efficacy on cognition. In conclusion, methodological problems are likely to impede the success rates of cognition trials in BD. We recommend adherence to the CONSORT guidelines for RCTs, screening for cognitive impairment before inclusion of trial participants and selection of one primary cognition outcome. Future implementation of a 'neurocircuitry-based' biomarker model to evaluate neural target engagement is warranted.


Bipolar disorder; Cognitive dysfunction; Cognitive enhancement; Intervention; Randomized controlled trials; Systematic review

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