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Objectives To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. Methods The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. Results Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. Conclusions This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies. [ABSTRACT FROM AUTHOR]

Objectives Cognitive dysfunction affects a substantial proportion of patients with bipolar disorder ( BD), and genetic-imaging paradigms may aid in the elucidation of mechanisms implicated in this symptomatic domain. The Val allele of the functional Val158Met polymorphism of the catechol-O-methyltransferase ( COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity. This functional magnetic resonance imaging ( fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working memory in BD. Methods Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test Automated Battery ( CANTAB) Spatial Working Memory test outside the scanner. Results During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral prefrontal cortex (dl PFC) ( P=.016). Exploratory whole-brain analysis revealed a bilateral decrease in working memory-related dl PFC activity in the ValVal group vs the ValMet group which was not associated with differences in working memory performance during fMRI. Outside the MRI scanner, Val carriers performed worse in the CANTAB Spatial Working Memory task than Met homozygotes ( P≤.006), with deficits being most pronounced in Val homozygotes. Conclusions The association between Val allelic load, dl PFC activity and WM impairment points to a putative role of aberrant PFC dopamine tonus in the cognitive impairments in BD. [ABSTRACT FROM AUTHOR]