The Emerging Neurobiology of Bipolar Disorder

Abstract

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. Bipolar Disorder and the New Psychiatry Psychiatry still relies largely on 19th-Century diagnostic categories. These are based on clusters of symptoms rather than biological markers, and are treated with drugs discovered serendipitously several decades ago. BD typifies this unsatisfactory state of affairs. Although its name has changed [it was formerly known as manic depression (see Glossary)], its cardinal features, and how it is assessed and treated (Box 1) have barely altered. An important reason for this stagnation has been the lack of any real traction on its causes and underlying biology, beyond its well-established high heritability [1]. Although there is evidence for altered structural and functional brain connectivity [2-4], and changes in markers of oxidative stress [5], mitochondrial function [6], inflammation [7], circadian rhythms [8], and dopamine [9], it remains difficult to integrate these diverse findings, and to disentangle causative changes from those that are secondary to the disorder and its treatment. The situation is belatedly improving. While optimism must be tempered by appreciation of the many complexities, there are realistic prospects for a transformation in our understanding of BD and how it is diagnosed and treated. Here, we highlight two areas of current interest: the discovery of the first BD risk genes and their implications, and the application of novel technologies with the potential to refine, or redefine, the BD phenotype. These developments exemplify how genomics, neuroscience, and digital technologies are heralding a new era for psychiatry. For broader reviews of BD, see [10,11].

Cellular calcium in bipolar disorder: systematic review and meta-analysis

“…The recent resurgence of interest in calcium in bipolar disorder has been fostered by the genomic data showing that VGCCs are part of the genetic risk architecture, implicating a role for Ca 2+ signalling in the disorder [12,16,17]. The question arises as to whether the genetic findings are directly related to the elevated intracellular [Ca 2+ ] observed in platelets and lymphocytes.…”

“…Over the past decade the study of Ca 2+ in bipolar disorder has been received new impetus from the increasingly compelling evidence that voltage-gated calcium channels (VGCCs) are part of the genetic aetiology [12,13]. Interest is enhanced by the therapeutic opportunities which VGCCs provide, given their known druggability by existing calcium channel blockers and the gabapentinoids [14][15][16][17]. However, despite multiple studies and several narrative reviews, there is no consensus as to the specific Ca 2+ abnormality-if any -which characterises bipolar disorder, nor is the robustness of the evidence clear [18][19][20].…”

Affective instability in those with and without mental disorders: A case control study

“…The estimated prevalence of AI in the general population is 14%, with levels being higher in younger people and women (Marwaha et al, 2013c;Patel et al, 2015). We (Broome et al, 2015a), and others (Harrison et al, 2017) have suggested that trans-diagnostic investigation of AI is compatible with the NIMH Research Domain Criteria project (Insel, 2014), a framework for understanding mental disorders by study of dysfunction in individual psychological and biological systems.…”

Case report: manic episode with psychotic symptoms induced by hyponatremia

“…In the literature, dysfunction of voltage-gated ion channels has been implicated in the pathogenesis of bipolar disorder. Most notably, genome-wide analyses have implicated two genes, CACNA1C and ANK3, of which the former encodes a subunit of a voltagegated calcium channel and the latter encodes a protein coupling voltage-gated sodium channels to the axonal cytoskeleton [5].…”