The Emerging Neurobiology of Bipolar Disorder
Authors: Paul J. Harrison, John R. Geddes, Elizabeth M. Tunbridge
Journal: Trends in Neurosciences (2017)

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. 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 (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. 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 [1Craddock N. Sklar P. Genetics of bipolar disorder.Lancet. 2013; 381: 1654-1662Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar]. Although there is evidence for altered structural and functional brain connectivity [2Phillips M.L. Swartz H.A. A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research.Am. J. Psychiatry. 2014; 171: 829-843Crossref PubMed Scopus (140) Google Scholar, 3Wise T. et al.Voxel-based meta-analytical evidence of structural disconnectivity in major depression and bipolar disorder.Biol. Psychiatry. 2016; 79: 293-302Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 4Hibar D.P. et al.Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group.Mol. Psychiatry. 2017; (Published online May 2, 2017)https://doi.org/10.1038/mp.2017.73Crossref Scopus (0) Google Scholar], and changes in markers of oxidative stress [5Brown N.C. et al.An updated meta-analysis of oxidative stress markers in bipolar disorder.Psychiatry Res. 2014; 218: 61-68Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar], mitochondrial function [6Andreazza A.C. et al.Bipolar disorder as a mitochondrial disease.Biol. Psychiatry. 2017; (Published online September 28, 2017)https://doi.org/10.1016/j.biopsych.2017.09.018Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar], inflammation [7Goldsmith D.R. et al.A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression.Mol. Psychiatry. 2016; 21: 1696-1709Crossref PubMed Scopus (97) Google Scholar], circadian rhythms [8Melo M.C.A. et al.Chronotype and circadian rhythm in bipolar disorder: a systematic review.Sleep Med. Rev. 2017; 34: 46-58Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar], and dopamine [9Ashok A.H. et al.The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment.Mol. Psychiatry. 2017; 22: 666-679Crossref PubMed Scopus (1) Google Scholar], it remains difficult to integrate these diverse findings, and to disentangle causative changes from those that are secondary to the disorder and its treatment.Box 1Bipolar Disorder: A Clinical PrimerThe classic picture of BD is like a modified sine wave, with mood fluctuating between episodes of mood elevation (mania) and depression, interspersed with periods of euthymia. The number of episodes in each mood phase, and their duration, varies markedly between individuals, but for most patients the depressive episodes are more prolonged and are responsible for much of the morbidity of the disorder.The depressive episodes of BD are broadly similar in nature and severity to those of 'ordinary' depression. A manic episode includes not only significant elevation of mood, but also related changes in behaviour, such as a reduced need for sleep, increased energy, grandiose thoughts and beliefs, rapid speech, increased libido, and reckless behaviour (e.g., spending excessively). In severe episodes, psychotic symptoms (delusions and hallucinations) may also be present; for example, the person may believe, or hear voices telling them, that they have superpowers (and they may then act accordingly). 'Hypomania' refers to a milder and less prolonged form of mania. The exact criteria depend upon the classificatory system used (ICD-10 or DSM-5); the latter subdivides BD into bipolar I and bipolar II. Although not part of the diagnostic criteria, cognitive impairment is a notable aspect of BD; it is present at first episode and persists during euthymia. Attention, processing speed, and verbal learning and fluency are the domains most affected. At least half of patients with BD also have an anxiety disorder or substance use disorder. Patients are typically diagnosed during their 20s, following a long prodrome, and actual onset is often in adolescence. The lifetime prevalence of BD is approximately 1%, rising to 4% if a broader definition of bipolar spectrum disorder is used. The major risk factors are genetic (see the main text), but environmental factors, including childhood adversity, also have a role. Of patients with BD, 10% die by suicide and this, coupled with an excess mortality from natural causes, shortens average life expectancy by approximately 15 years.The mainstay of BD treatment is pharmacological, with lithium salts or the antiepileptic drug sodium valproate used for prophylaxis. Antipsychotics, antidepressants, and antiepileptic drugs are given to treat the mood episodes. Psychoeducation and psychological treatments also have an important supporting role. All current treatments have limited efficacy, and the drugs can have serious adverse effects.For an introduction to clinical aspects of BD, see [10Grande I. et al.Bipolar disorder.Lancet. 2016; 387: 1561-1572Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 95Harrison P.J. et al.Bipolar disorder.in: Harrison P.J. Shorter Oxford Textbook of Psychiatry. 7th edn. Oxford University Press, 2017: 233-252Google Scholar]. The classic picture of BD is like a modified sine wave, with mood fluctuating between episodes of mood elevation (mania) and depression, interspersed with periods of euthymia. The number of episodes in each mood phase, and their duration, varies markedly between individuals, but for most patients the depressive episodes are more prolonged and are responsible for much of the morbidity of the disorder. The depressive episodes of BD are broadly similar in nature and severity to those of 'ordinary' depression. A manic episode includes not only significant elevation of mood, but also related changes in behaviour, such as a reduced need for sleep, increased energy, grandiose thoughts and beliefs, rapid speech, increased libido, and reckless behaviour (e.g., spending excessively). In severe episodes, psychotic symptoms (delusions and hallucinations) may also be present; for example, the person may believe, or hear voices telling them, that they have superpowers (and they may then act accordingly). 'Hypomania' refers to a milder and less prolonged form of mania. The exact criteria depend upon the classificatory system used (ICD-10 or DSM-5); the latter subdivides BD into bipolar I and bipolar II. Although not part of the diagnostic criteria, cognitive impairment is a notable aspect of BD; it is present at first episode and persists during euthymia. Attention, processing speed, and verbal learning and fluency are the domains most affected. At least half of patients with BD also have an anxiety disorder or substance use disorder. Patients are typically diagnosed during their 20s, following a long prodrome, and actual onset is often in adolescence. The lifetime prevalence of BD is approximately 1%, rising to 4% if a broader definition of bipolar spectrum disorder is used. The major risk factors are genetic (see the main text), but environmental factors, including childhood adversity, also have a role. Of patients with BD, 10% die by suicide and this, coupled with an excess mortality from natural causes, shortens average life expectancy by approximately 15 years. The mainstay of BD treatment is pharmacological, with lithium salts or the antiepileptic drug sodium valproate used for prophylaxis. Antipsychotics, antidepressants, and antiepileptic drugs are given to treat the mood episodes. Psychoeducation and psychological treatments also have an important supporting role. All current treatments have limited efficacy, and the drugs can have serious adverse effects. For an introduction to clinical aspects of BD, see [10Grande I. et al.Bipolar disorder.Lancet. 2016; 387: 1561-1572Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 95Harrison P.J. et al.Bipolar disorder.in: Harrison P.J. Shorter Oxford Textbook of Psychiatry. 7th edn. Oxford University Press, 2017: 233-252Google Scholar]. 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 [10Grande I. et al.Bipolar disorder.Lancet. 2016; 387: 1561-1572Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 11Harrison P.J. et al.Innovative approaches to bipolar disorder and its treatment.Ann. N.Y. Acad. Sci. 2016; 1366: 76-89Crossref PubMed Scopus (11) Google Scholar]. A child of an affected parent has about a tenfold increased risk of developing BD, and twin studies estimate a heritability of 0.7–0.8 [1Craddock N. Sklar P. Genetics of bipolar disorder.Lancet. 2013; 381: 1654-1662Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar]. There is no evidence for Mendelian inheritance or for genes of major effect. Instead, as with most psychiatric disorders, there are multiple susceptibility loci, each of small effect, which genome-wide association studies (GWAS) are beginning to identify. Several GWAS, and meta-analyses thereof, have been carried out since 2007; Table 1 lists the loci and implicated genes that have emerged to date. The combined sample sizes remain small by GWAS standards, and more loci remain to be identified; indeed, the forthcoming Psychiatric Genomics Consortium analysis, comprising over 20 000 BD cases and 30 000 controls, identifies 19 significant loci, including 12 novel ones. Initial exome and genome sequencing data suggest that rare deleterious variants also have a role in some BD cases, but their identity and overall contribution to the disorder remain unclear [12Goes F.S. et al.Exome sequencing of familial bipolar disorder.JAMA Psychiatry. 2016; 73: 590-597Crossref PubMed Google Scholar, 13Ament S.A. et al.Rare variants in neuronal excitability genes influence risk for bipolar disorder.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 3576-3581Crossref PubMed Scopus (0) Google Scholar, 14Kataoka M. et al.Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations.Mol. Psychiatry. 2016; 21: 885-893Crossref PubMed Google Scholar]. Within BD, there is modest clinicogenetic heterogeneity, for example, based on the predominant symptoms, or between bipolar I and bipolar II subtypes [15Charney A.W. et al.Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.Transl. Psychiatry. 2017; 7: e993Crossref PubMed Google Scholar]. However, there is little evidence for BD-specific genes; joint GWAS analyses show substantial commonalities in risk loci for BD and schizophrenia [16O'Donovan M.C. Owen M.J. The implications of the shared genetics of psychiatric disorders.Nat. Med. 2016; 22: 1214-1219Crossref PubMed Scopus (17) Google Scholar], as well as significant overlap with other major psychiatric disorders [17Cross-Disorder Group of the Psychiatric Genomics Consortium Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.Nat. Genet. 2013; 45: 984-994Crossref PubMed Scopus (755) Google Scholar] and with intermediate phenotypes, including circadian traits [18Fears S.C. et al.Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees.JAMA Psychiatry. 2014; 71: 375-387Crossref PubMed Scopus (38) Google Scholar, 19Pagani L. et al.Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: E754-E761Crossref PubMed Scopus (0) Google Scholar]. One distinction between schizophrenia and BD is that copy number variation is much less prominent in the latter [20Green E.K. et al.Copy number variation in bipolar disorder.Mol. Psychiatry. 2016; 21: 89-93Crossref PubMed Scopus (34) Google Scholar].Table 1GWAS Hits for BDaData from [98,117].LocusImplicated gene(s)2q11.2LMAN2L2q32.1ZNF804A3p22.2TRANK1 (LBA1)5p15.31ADCY26q16.1MIR2113, POU3F2 (OTF7)6q25.2SYNE17p22.3MAD1L19p21.3Intergenic10q21.2ANK311q14.1TENM4 (ODZ4)12p13.3CACNA1C12q13.1DDN17q12ERBB2a Data from 98Hofmann F. et al.L-type CaV1.2 channels: from in vitro findings to in vivo function.Physiol. Rev. 2014; 94: 303-326Crossref PubMed Scopus (0) Google Scholar, 117Hou L.P. et al.Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.Hum. Mol. Genet. 2016; 25: 3383-3394Crossref PubMed Scopus (13) Google Scholar. Open table in a new tab Although the genomics of BD are in their infancy, efforts have begun to understand the biological basis for the associations identified to date. Interest has centred on two genes (CACNA1C and ANK3) because of what was already known of their functions. CACNA1C is discussed in detail below. ANK3 encodes ankyrin G, which couples axonal voltage-gated sodium channels to the cytoskeleton and also has roles in dendrites and glia; another risk gene, TRANK1, contains multiple ankyrin repeat domains, suggesting some shared functions. Complementing the focus on specific risk genes, the first attempts have been made to identify the pathways that they influence. Using data from four of the GWAS, Nurnberger et al. [21Nurnberger J.I. et al.Identification of pathways for bipolar disorder: a meta-analysis.JAMA Psychiatry. 2014; 71: 657-664Crossref PubMed Scopus (78) Google Scholar] reported six pathways that showed replicable association with BD, involving glutamate and calcium signalling, second messengers, and hormones. Together, these findings support the possibility that BD is, at least in part, an ion channelopathy [22Gargus J.J. Ion channel functional candidate genes in multigenic neuropsychiatric disease.Biol. Psychiatry. 2006; 60: 177-185Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], in which aberrant calcium signalling is important [23Berridge M.J. Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia.Cell Tissue Res. 2014; 357: 477-492Crossref PubMed Scopus (38) Google Scholar]. Calcium dysregulation has long been implicated in BD, based primarily on ex vivo studies in cells taken from patients and controls. The findings are disparate, but on balance indicate that measures of intracellular calcium signalling are increased in BD, especially after stimulation (reviewed in [23Berridge M.J. Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia.Cell Tissue Res. 2014; 357: 477-492Crossref PubMed Scopus (38) Google Scholar, 24Warsh J.J. Role of intracellular calcium signalling in the pathophysiology and pharmacotherapy of bipolar disorder: current status.Clin. Neurosci. Res. 2004; 4: 201-213Crossref Scopus (0) Google Scholar]). The abnormalities appear largely independent of current mood state (i.e., they are trait rather than state related). Moreover, they are attenuated by lithium, which is used in the treatment of the disorder (Box 1). Despite the many uncertainties, these findings led to L-type voltage-gated calcium channel (VGCC) antagonists, with existing indications in angina and hypertension, being evaluated for the treatment of BD [25Cipriani A. et al.A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.Mol. Psychiatry. 2016; 21: 1324-1332Crossref PubMed Scopus (4) Google Scholar]. Antiepileptic drugs, such as pregabalin, which act via VGCC α2δ subunits (Box 2) have also been tested [26Houghton K.T. et al.Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis.BMJ Open. 2017; 7e013433Crossref PubMed Scopus (0) Google Scholar], and lamotrigine, another antiepileptic drug that may block calcium channels, among its various actions [27Ketter T.A. et al.Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders.J. Clin. Psychopharmacol. 2003; 23: 484-495Crossref PubMed Scopus (88) Google Scholar], is an effective treatment for bipolar depression [28Geddes J.R. et al.Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 x 2 factorial randomised trial.Lancet Psychiatry. 2016; 3: 31-39Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar].Box 2VGCC Genes, Their Isoforms, and Relevance in Bipolar DisorderIdentifying the specific VGCCs most relevant for BD is a significant challenge, because their genes give rise to a vast diversity of functional channels (named Cav channels) [96Dolphin A.C. Voltage-gated calcium channels and their auxiliary subunits: physiology and pathophysiology and pharmacology.J. Physiol. 2016; 594: 5369-5390Crossref PubMed Scopus (20) Google Scholar, 97Striessnig J. et al.L-type Ca2+ channels in heart and brain.WIREs Membr. Transp. Signal. 2014; 3: 15-38Crossref Scopus (47) Google Scholar]. VGCCs comprise multiple subunits, each encoded by one of a subfamily of separate genes. The properties of the ten distinct α1 subunits (encoded by the CACNA1- gene family) depend on the accessory subunits to which it is bound (Figure I). The main accessory subunits are the β (encoded by CACNB1–4) and α2δ (encoded by CACNA2D1–4) subunits, which are obligate in most cases [98Hofmann F. et al.L-type CaV1.2 channels: from in vitro findings to in vivo function.Physiol. Rev. 2014; 94: 303-326Crossref PubMed Scopus (0) Google Scholar]. Current VGCC antagonists block the L-type channels; the anticonvulsant/analgesic drugs pregabalin and gabapentin are α2δ ligands [30Zamponi G.W. et al.The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential.Pharmacol. Rev. 2015; 67: 821-870Crossref PubMed Scopus (127) Google Scholar].Further channel diversity arises because each gene gives rise to multiple isoforms. The human CACNA1C mRNA has at least 50 exons and over 40 predicted isoforms (arising from transcriptional and splicing mechanisms). CACNA1C splicing gives rise to channel isoforms that are differentially expressed in brain compared with heart, and which differ in their biophysical properties, including voltage-gating characteristics [97Striessnig J. et al.L-type Ca2+ channels in heart and brain.WIREs Membr. Transp. Signal. 2014; 3: 15-38Crossref Scopus (47) Google Scholar]. Another feature affected by splicing is the isoform sensitivity to existing VGCC antagonists [98Hofmann F. et al.L-type CaV1.2 channels: from in vitro findings to in vivo function.Physiol. Rev. 2014; 94: 303-326Crossref PubMed Scopus (0) Google Scholar]. This suggests that it might be possible to selectively target splice variants that mediate disease risk and/or are preferentially expressed in the brain, compared with peripheral tissues (particularly the cardiovascular system, where VGCCs are also abundant), thereby maximising their therapeutic potential and tolerability in BD [25Cipriani A. et al.A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.Mol. Psychiatry. 2016; 21: 1324-1332Crossref PubMed Scopus (4) Google Scholar].Given these considerations, defining the repertoire of VGCCs present in different human tissues is important, as is identifying which ones are impacted by the BD-associated risk variants or by BD itself. However, information on the transcript diversity of human VGCC subunits is sparse, particularly in brain. Furthermore, because VGCC subunit genes are large (full-length CACNA1C mRNA, for instance, is over 10 kb long), the transcript structure of most isoforms remains unclear. Characterising the profile of full-length VGCCs isoforms in the human brain, compared with other tissues, and assessing which are altered in association with genetic risk for BD, are critical first steps in translating the VGCC genomic findings into pathophysiological insights and novel treatment targets. The availability of large, high-quality human postmortem brain series and technological advances in the field of RNA sequencing make this goal achievable. Identifying the specific VGCCs most relevant for BD is a significant challenge, because their genes give rise to a vast diversity of functional channels (named Cav channels) [96Dolphin A.C. Voltage-gated calcium channels and their auxiliary subunits: physiology and pathophysiology and pharmacology.J. Physiol. 2016; 594: 5369-5390Crossref PubMed Scopus (20) Google Scholar, 97Striessnig J. et al.L-type Ca2+ channels in heart and brain.WIREs Membr. Transp. Signal. 2014; 3: 15-38Crossref Scopus (47) Google Scholar]. VGCCs comprise multiple subunits, each encoded by one of a subfamily of separate genes. The properties of the ten distinct α1 subunits (encoded by the CACNA1- gene family) depend on the accessory subunits to which it is bound (Figure I). The main accessory subunits are the β (encoded by CACNB1–4) and α2δ (encoded by CACNA2D1–4) subunits, which are obligate in most cases [98Hofmann F. et al.L-type CaV1.2 channels: from in vitro findings to in vivo function.Physiol. Rev. 2014; 94: 303-326Crossref PubMed Scopus (0) Google Scholar]. Current VGCC antagonists block the L-type channels; the anticonvulsant/analgesic drugs pregabalin and gabapentin are α2δ ligands [30Zamponi G.W. et al.The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential.Pharmacol. Rev. 2015; 67: 821-870Crossref PubMed Scopus (127) Google Scholar]. Further channel diversity arises because each gene gives rise to multiple isoforms. The human CACNA1C mRNA has at least 50 exons and over 40 predicted isoforms (arising from transcriptional and splicing mechanisms). CACNA1C splicing gives rise to channel isoforms that are differentially expressed in brain compared with heart, and which differ in their biophysical properties, including voltage-gating characteristics [97Striessnig J. et al.L-type Ca2+ channels in heart and brain.WIREs Membr. Transp. Signal. 2014; 3: 15-38Crossref Scopus (47) Google Scholar]. Another feature affected by splicing is the isoform sensitivity to existing VGCC antagonists [98Hofmann F. et al.L-type CaV1.2 channels: from in vitro findings to in vivo function.Physiol. Rev. 2014; 94: 303-326Crossref PubMed Scopus (0) Google Scholar]. This suggests that it might be possible to selectively target splice variants that mediate disease risk and/or are preferentially expressed in the brain, compared with peripheral tissues (particularly the cardiovascular system, where VGCCs are also abundant), thereby maximising their therapeutic potential and tolerability in BD [25Cipriani A. et al.A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.Mol. Psychiatry. 2016; 21: 1324-1332Crossref PubMed Scopus (4) Google Scholar]. Given these considerations, defining the repertoire of VGCCs present in different human tissues is important, as is identifying which ones are impacted by the BD-associated risk variants or by BD itself. However, information on the transcript diversity of human VGCC subunits is sparse, particularly in brain. Furthermore, because VGCC subunit genes are large (full-length CACNA1C mRNA, for instance, is over 10 kb long), the transcript structure of most isoforms remains unclear. Characterising the profile of full-length VGCCs isoforms in the human brain, compared with other tissues, and assessing which are altered in association with genetic risk for BD, are critical first steps in translating the VGCC genomic findings into pathophysiological insights and novel treatment targets. The availability of large, high-quality human postmortem brain series and technological advances in the field of RNA sequencing make this goal achievable. The results of the recent genomic studies strongly suggest that the involvement of calcium signalling in BD is at least partly causal [29Heyes S. et al.Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders.Prog. Neurobiol. 2015; 134: 36-54Crossref PubMed Scopus (21) Google Scholar], and have rekindled attempts to explain more precisely the nature of the alterations, not least because this may provide clues to more-effective and tolerable drug strategies to normalise them [30Zamponi G.W. et al.The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential.Pharmacol. Rev. 2015; 67: 821-870Crossref PubMed Scopus (127) Google Scholar]. However, the discovery of genetic variants is only the first step, and provides many more questions than answers. Calcium signalling offers an informative exemplar to highlight the opportunities and complexities associated with moving from psychiatric genomic discoveries to pathophysiological insights and therapeutic advances [31Harrison P.J. Recent genetic findings in schizophrenia and their therapeutic relevance.J. Psychopharmacol. 2015; 29: 85-96Crossref PubMed Google Scholar, 32Breen G. et al.Translating genome-wide association findings into new therapies for psychiatry.Nat. Rev. Neurosci. 2016; 19: 1392-1396Crossref Scopus (7) Google Scholar]. Genomic data provide a starting point to identify the molecules involved in the core 'calcium pathophysiology' of BD. They focus attention on the VGCCs, especially of the L-type, and their accessory subunits (encoded by the CACNx genes; Box 2). As indicated above, the best evidence is for CACNA1C (encoding the α1 subunit of Cav 1.2), but pathway analysis also suggests a role for CACNA1D and CACNB3 [29Heyes S. et al.Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders.Prog. Neurobiol. 2015; 134: 36-54Crossref PubMed Scopus (21) Google Scholar, 33Psychiatric GWAS Consortium Bipolar Disorder Working Group Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.Nat. Genet. 2011; 43: 977-983Crossref PubMed Scopus (622) Google Scholar], and other VGCC genes are implicated in BD by rare variant studies [13Ament S.A. et al.Rare variants in neuronal excitability genes influence risk for bipolar disorder.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 3576-3581Crossref PubMed Scopus (0) Google Scholar]. Of note, apart from BD, CACNA1C is associated with schizophrenia [34Schizophrenia Working Group of the Psychiatric Genomics Consortium Biological insights from 108 schiz