White matter alterations in bipolar disorder: potential for drug discovery and development

Objectives: Brain white matter (WM) alterations have recently emerged as potentially relevant in bipolar disorder. New techniques such as diffusion tensor imaging allow precise exploration of these WM microstructural alterations in bipolar disorder. Our objective was to critically review WM alterations in bipolar disorder, using neuroimaging and neuropathological studies, in the context of neural models and the potential for drug discovery and development.

Methods: We conducted a systematic PubMed and Google Scholar search of the WM and bipolar disorder literature up to and including January 2013.

Results: Findings relating to WM alterations are consistent in neuroimaging and neuropathology studies of bipolar disorder, especially in regions involved in emotional processing such as the anterior frontal lobe, corpus callosum, cingulate cortex, and in fronto-limbic connections. Some of the structural alterations are related to genetic risk factors for bipolar disorder and may underlie the dysfunctional emotional processing described in recent neurobiological models of bipolar disorder. Medication effects in bipolar disorder, from lithium and other mood stabilizers, might impact myelinating processes, particularly by inhibition of glycogen synthase kinase-3 beta.

Conclusions: Pathways leading to WM alterations in bipolar disorder represent potential targets for the development and discovery of new drugs. Myelin damage in bipolar disorder suggests that the effects of existing pro-myelinating drugs should also be evaluated to improve our understanding and treatment of this disease.