Skip to main content
×
Home
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 10
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Yoshimizu, T Pan, J Q Mungenast, A E Madison, J M Su, S Ketterman, J Ongur, D McPhie, D Cohen, B Perlis, R and Tsai, L-H 2015. Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. Molecular Psychiatry, Vol. 20, Issue. 2, p. 162.


    Berger, Stefan M. and Bartsch, Dusan 2014. The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function. Cell and Tissue Research, Vol. 357, Issue. 2, p. 463.


    Erk, Susanne Meyer-Lindenberg, Andreas Linden, David E.J. Lancaster, Thomas Mohnke, Sebastian Grimm, Oliver Degenhardt, Franziska Holmans, Peter Pocklington, Andrew Schmierer, Phöbe Haddad, Leila Mühleisen, Thomas W. Mattheisen, Manuel Witt, Stephanie H. Romanczuk-Seiferth, Nina Tost, Heike Schott, Björn H. Cichon, Sven Nöthen, Markus M. Rietschel, Marcella Heinz, Andreas and Walter, Henrik 2014. Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects. NeuroImage, Vol. 94, p. 147.


    Gonzalez, Suzanne Camarillo, Cynthia Rodriguez, Marco Ramirez, Mercedes Zavala, Juan Armas, Regina Contreras, Salvador A. Contreras, Javier Dassori, Albana Almasy, Laura Flores, Deborah Jerez, Alvaro Raventós, Henriette Ontiveros, Alfonso Nicolini, Humberto and Escamilla, Michael 2014. A genome-wide linkage scan of bipolar disorder in Latino families identifies susceptibility loci at 8q24 and 14q32. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, Vol. 165, Issue. 6, p. 479.


    Gonzalez, Suzanne Xu, Chun Ramirez, Mercedes Zavala, Juan Armas, Regina Contreras, Salvador A Contreras, Javier Dassori, Albana Leach, Robin J Flores, Deborah Jerez, Alvaro Raventós, Henriette Ontiveros, Alfonso Nicolini, Humberto and Escamilla, Michael 2013. Suggestive evidence for association between L-type voltage-gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family-based association study. Bipolar Disorders, Vol. 15, Issue. 2, p. 206.


    Keshavan, Matcheri S. Clementz, Brett A. Pearlson, Godfrey D. Sweeney, John A. and Tamminga, Carol A. 2013. Reimagining psychoses: An agnostic approach to diagnosis. Schizophrenia Research, Vol. 146, Issue. 1-3, p. 10.


    Bhat, Shambhu Dao, David T. Terrillion, Chantelle E. Arad, Michal Smith, Robert J. Soldatov, Nikolai M. and Gould, Todd D. 2012. CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Progress in Neurobiology, Vol. 99, Issue. 1, p. 1.


    De León, Ovidio A. 2012. Response to Nimodipine in Ultradian Bipolar Cycling After Amygdalohippocampectomy. Journal of Clinical Psychopharmacology, Vol. 32, Issue. 1, p. 146.


    Maigaard, Katrine Hageman, Ida Jørgensen, Anders Jørgensen, Martin B. and Wörtwein, Gitta 2012. Electroconvulsive stimulations prevent chronic stress-induced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdala. Neuroscience Letters, Vol. 516, Issue. 1, p. 24.


    Weber, Heike Kittel-Schneider, Sarah Gessner, Alexandra Domschke, Katharina Neuner, Maria Jacob, Christian P Buttenschon, Henriette N Boreatti-Hümmer, Andrea Volkert, Julia Herterich, Sabine Baune, Bernhard T Gross-Lesch, Silke Kopf, Juliane Kreiker, Susanne Nguyen, Thuy Trang Weissflog, Lena Arolt, Volker Mors, Ole Deckert, Jürgen Lesch, Klaus-Peter and Reif, Andreas 2011. Cross-Disorder Analysis of Bipolar Risk Genes: Further Evidence of DGKH as a Risk Gene for Bipolar Disorder, but also Unipolar Depression and Adult ADHD. Neuropsychopharmacology, Vol. 36, Issue. 10, p. 2076.


    ×

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)
  • DOI: http://dx.doi.org/10.1017/S0033291708005084
  • Published online: 01 February 2009
Abstract

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.

Copyright
Corresponding author
*Address for correspondence: R. Keers, MRC SGDP Centre, Institute of Psychiatry, 16 De Crespigny Park, Denmark Hill, LondonSE5 8AF, UK. (Email: robert.keers@iop.kcl.ac.uk)
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

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.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords: