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Extracting a needle from a haystack: reanalysis of whole genome data reveals a readily translatable finding

  • R. Keers (a1), A. E. Farmer (a1) and K. J. Aitchison (a1)

There is significant unmet need for more effective treatments for bipolar disorder. The drug discovery process is becoming prohibitively expensive. Hence, biomarker clues to assist or shortcut this process are now widely sought. Using the publicly available data from the whole genome association study conducted by the Wellcome Trust Case Control Consortium, we sought to identify groups of genetic markers (single nucleotide polymorphisms) in which each marker was independently associated with bipolar disorder, with a less stringent threshold than that set by the original investigators (p⩽1×10−4). We identified a group of markers occurring within the CACNA1C gene (encoding the alpha subunit of the calcium channel Cav1.2). We then ascertained that this locus had been previously associated with the disorder in both a smaller and a whole genome study, and that a number of drugs blocking this channel (including verapamil and diltiazem) had been trialled in the treatment of bipolar disorder. The dihydropyridine-based blockers such as nimodipine that bind specifically to Cav1.2 and are more penetrant to the central nervous system have shown some promising early results; however, further trials are indicated. In addition, migraine is commonly seen in affective disorder, and calcium channel antagonists are successfully used in the treatment of migraine. One such agent, flunarizine, is structurally related to other first-generation derivatives of antihistamines such as antipsychotics. This implies that flunarizine could be useful in the treatment of bipolar disorder, and, furthermore, that other currently licensed drugs should be investigated for antagonism of Cav1.2.

Corresponding author
*Address for correspondence: R. Keers, MRC SGDP Centre, Institute of Psychiatry, 16 De Crespigny Park, Denmark Hill, London SE5 8AF, UK. (Email:
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WK Amery (1983). Flunarizine, a calcium channel blocker: a new prophylactic drug in migraine. Headache 23, 7074.

AE Baum , N Akula , M Cabanero , I Cardona , W Corona , B Klemens , TG Schulze , S Cichon , M Rietschel , MM Nothen , A Georgi , J Schumacher , M Schwarz , JR Abou , S Hofels , P Propping , J Satagopan , SD tera-Wadleigh , J Hardy , FJ McMahon (2008). A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Molecular Psychiatry 13, 197207.

G Brunet , B Cerlich , P Robert , S Dumas , E Souetre , G Darcourt (1990). Open trial of a calcium-antagonist, nimodipine, in acute mania. Clinical Neuropharmacology 13, 224228.

SD Detera-Wadleigh , N Barden , N Craddock , H Ewald , T Foroud , J Kelsoe , A McQuillin (1999). Chromosomes 12 and 16 workshop. American Journal of Medical Genetics 88, 255259.

JA DiMasi , RW Hansen , HG Grabowski (2003). The price of innovation: new estimates of drug development costs. Journal of Health Economics 22, 151185.

SL Dubovsky , M Thomas , A Hijazi , J Murphy (1994). Intracellular calcium signaling in peripheral cells of patients with bipolar affective-disorder. European Archives of Psychiatry and Clinical Neuroscience 243, 229234.

AB Ettinger , ML Reed , JF Goldberg , RMA Hirschfeld (2005). Prevalence of bipolar symptoms in epilepsy vs other chronic health disorders. Neurology 65, 535540.

JJ Gargus (2006). Ion channel functional candidate genes in multigenic neuropsychiatric disease. Biological Psychiatry 60, 177185.

LL Judd , HS Akiskal , PJ Schettler , J Endicott , J Maser , DA Solomon , AC Leon , JA Rice , MB Keller (2002). The long-term natural history of the weekly symptomatic status of bipolar I disorder. Archives of General Psychiatry 59, 530537.

T Kato (2007). Molecular genetics of bipolar disorder and depression. Psychiatry and Clinical Neuroscience 61, 319.

NA Levy , PG Janicak (2000). Calcium channel antagonists for the treatment of bipolar disorder. Bipolar Disorders 2, 108119.

RW Licht (1998). Drug treatment of mania: a critical review. Acta Psychiatrica Scandinavica 97, 387397.

P McGuffin , F Rijsdijk , M Andrew , P Sham , R Katz , A Cardno (2003). The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Archives of General Psychiatry 60, 497502.

E Mogilnicka , A Czyrak , J Maj (1988). Bay-K-8644 enhances immobility in the mouse behavioral despair test, an effect blocked by nifedipine. European Journal of Pharmacology 151, 307311.

JC Mulley , IE Scheffer , S Petrou , SF Berkovic (2003). Channelopathies as a genetic cause of epilepsy. Current Opinion in Neurology 16, 171176.

RA Ophoff , GM Terwindt , MN Vergouwe , R van Eijk , PJ Oefner , SMG Hoffman , JE Lamerdin , HW Mohrenweiser , DE Bulman , M Ferrari , J Haan , D Lindhout , GJB van Ommen , MH Hofker , MD Ferrari , RR Frants (1996). Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87, 543552.

PJ Pazzaglia , RM Post , TA Ketter , AM Callahan , LB Marangell , MA Frye , MS George , TA Kimbrell , GS Leverich , G Cora-Locatelli , D Luckenbaugh (1998). Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness. Journal of Clinical Psychopharmacology 18, 404413.

PJ Pazzaglia , RM Post , TA Ketter , MS George , LB Marangell (1993). Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation. Psychiatry Research 49, 257272.

F Radat , J Swendsen (2005). Psychiatric comorbidity in migraine: a review. Cephalalgia 25, 165178.

FD Sheftell , SJ Atlas (2002). Migraine and psychiatric comorbidity: from theory and hypotheses to clinical application. Headache 42, 934944.

D Silberstein , PJ Goadsby (2002). Migraine: preventive treatment. Cephalalgia 22, 491512.

MJ Sinnegger-Brauns , A Hetzenauer , IG Huber , E Renstrom , G Wietzorrek , S Berjukov , M Cavalli , D Walter , A Koschak , R Waldschutz , S Hering , S Bova , P Rorsman , O Pongs , N Singewald , J Striessnig (2004). Isoform-specific regulation of mood behavior and pancreatic beta cell and cardiovascular function by L-type Ca2+ channels. Journal of Clinical Investigation 113, 14301439.

P Sklar , JW Smoller , J Fan , MAR Ferreira , RH Perlis , K Chambert , VL Nimgaonkar , MB McQueen , SV Faraone , A Kirby , PIW de Bakker , MN Ogdie , ME Thase , GS Sachs , K Todd-Brown , SB Gabriel , C Sougnez , C Gates , B Blumenstiel , M Defelice , KG Ardlie , J Franklin , WJ Muir , KA McGhee , DJ MacIntyre , A McLean , M VanBeck , A McQuillin , NJ Bass , M Robinson , J Lawrence , A Anjorin , D Curtis , EM Scolnick , MJ Daly , DH Blackwood , HM Gurling , SM Purcell (2008). Whole-genome association study of bipolar disorder. Molecular Psychiatry 13, 558569.

J Wei , GP Hemmings (2006). A further study of a possible locus for schizophrenia on the X chromosome. Biochemical and Biophysical Research Communications 344, 12411245.

Wellcome Trust Case Control Consortium (2007). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661678.

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Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
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