Neurocognitive functioning in bipolar disorder: What we know and what we don't.

Introduction: This narrative review of systematic reviews and meta-analyses aims at compiling available evidence in various aspects of neurocognitive functioning in Bipolar Disorder (BD). Methods: We conducted a MEDLINE literature search and identified 38 relevant systematic reviews and metaanalyses. Results: Current evidence suggests that BD is associated with cognitive impairment across multiple domains and during all clinical states. However, there is a considerable cognitive heterogeneity within BD, which cannot be explained by clinical subtypes, and the pattern of neurocognitive impairment in BD overlaps with other psychiatric conditions such as major depression and schizophrenia. Residual depressive symptoms, poor clinical course and higher number of manic episodes may negatively impact cognitive performance, which is a major predictor of general functioning in BD. Evidence from available prospective studies does not support the notion of progressive cognitive decline in BD while some evidence exists to suggest patients may show some improvements in cognitive functioning following the first manic episode. Furthermore, a subset of patients may show premorbid cognitive abnormalities that could signal an early neurodevelopmental aetiology. Preliminary findings from small studies identify potential pro-cognitive effects of Cognitive Remediation, erythropoietin, intranasal insulin, lurasidone, mifepristone, repetitive Transcranial Magnetic Stimulation and transcranial Direct Current Stimulation in BD. Discussion: Longitudinal studies in high-risk individuals can provide a better understanding of the development and progression of neurocognitive impairment in BD. Largescale randomised control trials are needed to compare the pro-cognitive efficacy of various pharmacological and non-pharmacological interventions in different cognitive subgroups of patients at different stages of BD.