The Emerging Neurobiology of Bipolar Disorder

Bipolar disorder (BD) is a leading cause of global disability. Its biological basis is unknown, and its treatment unsatisfactory. Here, we review two recent areas of progress. First, the discovery of risk genes and their implications, with a focus on voltage-gated calcium channels as part of the disease process and as a drug target. Second, facilitated by new technologies, it is increasingly apparent that the bipolar phenotype is more complex and nuanced than simply one of recurring manic and depressive episodes. One such feature is persistent mood instability, and efforts are underway to understand its mechanisms and its therapeutic potential. BD illustrates how psychiatry is being transformed by contemporary neuroscience, genomics, and digital approaches. BD is highly heritable and mostly attributable to common variants of small effect. Several risk genes and gene networks have been identified. Calcium signalling is prominent among the genetic risk pathways, and currently appears to have the greatest therapeutic traction. Digital technologies and sophisticated mathematical and computational analyses are being used to quantify and understand BD. These new methods reflect, and are promoting, reconceptualisation of BD as a chronic instability of mood and neural circuitry. Stem cells are becoming an integral part of the approaches to understanding BD and its pharmacotherapy. New experimental medicine models are being applied to identify and rapidly test potential mood-stabilising treatments.