Supplementary Material for: Improving Cognition in Bipolar Disorder: A Systematic Review of Current Pharmacological and Nutraceutical Approaches

Introduction: Cognitive impairment is a core feature of bipolar disorder (BD) that impacts functioning and quality of life. This review systematically summarizes the evidence on pharmacological and nutraceutical interventions for cognitive deficits in BD. Methods: A systematic search of MEDLINE, EMBASE, and PsycINFO was conducted to identify studies examining the efficacy of pharmacological or nutraceutical interventions on cognition in individuals aged 18-65 years with euthymic or partially remitted BD from inception to December 29, 2024. This review was registered with PROSPERO (Reference Number: CRD42024618397). Risk of bias assessment was conducted using the National Institutes of Health (NIH) quality assessment tools. The extracted data were summarized using a narrative synthesis approach. Results: Sixteen studies were included, evaluating 13 different agents. Working memory, verbal learning and memory, executive functioning, social cognition, and attention/vigilance were improved by multiple agents. Galantamine showed replicated pro-cognitive effects on verbal learning and memory. Lithium, tianeptine, withania somnifera (ashwagandha), insulin, and lurasidone each demonstrated cognitive benefits in single studies. Erythropoietin and pramipexole showed mixed results across two studies. Methylene blue, JNJ-18038683, docosahexaenoic acid, modafinil, and quetiapine revealed no significant effects. The quality of the studies ranged from good to poor, and the safety and tolerability profiles of the agents were favorable. Discussion: These results suggest possible approaches for improving cognitive functioning in individuals with BD. Nevertheless, the inconsistency in outcomes and differences in study methodologies highlight the need for larger, rigorously controlled trials with uniform cognitive evaluations to confirm these findings and to assess their clinical relevance.