Are Migraine and Bipolar Disorders Comorbid Phenomena? Findings From a Pharmacoepidemiological Study Using the Norwegian Prescription Database Ketil J. Oedegaard, MD,*Þ Steven C. Dilsaver, MD,þ Øivind Hundal, PhD,*§ Trond Riise, PhD,|| Anders Lund, MD,*Þ Hagop S. Akiskal, MD, ¶ # and Ole B. Fasmer, MD*Þ Objectives: Clinical, epidemiological, and, recently, genome-wide link- age and genome-wide association studies suggest migraine and bipolar dis- order are comorbid phenomena. The objective of this study was to determine whether there is also evidence that this comorbidity exists by virtue of there being a positive relationship between the prescription of medications used to treat migraine and mood-stabilizing agents using the National Norwegian Prescription Database. Methods: Data allowing ascertainment of the concurrence of prescrip- tions for migraine and mood-stabilizing agents were gleaned from the Norwegian Prescription Database for calendar year 2006, covering the total population (N = 4,640,219). Results were obtained using logistic regression analyses and were expressed by odds ratios (ORs). Results: A total of 81,225 persons (1.8% of the population) received medications for migraine and 19,517 (0.45%) received a mood-stabilizing agent for a bipolar disorder; 843 persons received both types of medi- cations. The OR expressing the relationship between the concurrent use of both categories of medications was 2.55 (95% confidence interval [CI], 2.38Y2.73, P G 0.001, z score = 26.44), significant for all mood stabilizers (lithium: OR = 1.82 [95% CI, 1.58Y2.10], P G 0.001, z score = 8.31; carbamazepine: OR = 2.48 [95% CI, 2.01Y3.06], P G 0.001, z score = 8.42; valproic acid: OR = 2.26 [95% CI, 1.89Y2.70], P G 0.001, z score = 8.96; and lamotrigine: OR = 3.50 [95% CI, 3.14Y3.90], P G 0.001, z score = 22.68). The association was significantly higher for men (OR = 3.16 [95% CI, 2.74Y3.66], P G 0.001, z score = 15.53) than for women (OR = 2.21 [95% CI, 2.04Y2.39], P G 0.001, z score = 19.61) and was most pronounced in younger age groups and for lamotrigine. Conclusions: There was a strong positive association between the prescription of medications used to treat migraine and mood-stabilizing agents. This is compatible with the hypothesis that migraine and bipolar disorders are associated with one another. Key Words: migraine, bipolar disorder, comorbidity, epidemiology, mood stabilizers, Norwegian prescription registry (J Clin Psychopharmacol 2011;31: 734Y739) T he comorbidity of migraine and bipolar disorders is well documented in both clinical and epidemiological studies. 1Y10 Recently, data from both a genome-wide linkage study 11 and a genome-wide association study 12 suggest that these disorders may, at least in some instances, have a shared genetic vulnerabil- ity and that patients with comorbid migraine and bipolar disorder may comprise a group providing investigators with a viable en- dophenotype for utilization in genetic studies. 11 In this regard, it is interesting that the gene CACNA1A, iden- tified to cause an autosomal dominant variant of migraine called familial hemiplegic migraine (FHM I), 13 has overlapping functional similarities to CACNA1C, a gene that was recently associated with bipolar disorder in a collaborative genome-wide association anal- ysis of 4387 cases. 14 Both these genes encode an > 1 subunit of a voltage-dependant calcium channel. This resonates with evidence pointing toward alterations in sodium and calcium ion channel function as central factors for understanding the pathophysiology of migraine 15Y18 and bipolar disorders. 19Y23 Both migraine and bipolar disorders have been linked to disturbances in the serotoner- gic, 24Y27 dopaminergic, 28,29 and glutaminergic systems. 30,31 Further, several pharmacological treatments are successful in the prevention of both disorders. The most notable is valproate. 32Y34 Previously, population studies have revealed that there is a 2- to 3-fold increased prevalence of migraine in patients with bipolar disorders. 6,9 These investigators found that patients with the bipolar/migraine phenotype were more severely impaired than those who had bipolar disorder that was not comorbid with migraine. Furthermore, some studies have indicated that this rela- tionship might be particularly strong in patients with bipolar II disorder, 5,7 whereas others 10 have demonstrated that merely having a family history of bipolar disorder is associated with an increased risk of having migraine headache among patients with mood disorders. We used the nationwide Norwegian Prescription Database to describe coprescription to determine whether there is a posi- tive relationship between the prescription of medications used to treat migraine and the mood-stabilizing agents lithium, carba- mazepine, valproic acid, and lamotrigine. These pharmaceutical agents are officially categorized by the Norwegian government, with the exception of lithium, which also has an indication for recurrent unipolar depression, solely for the treatment of a bi- polar disorder if prescribed for a psychiatric disorder. Whereas lithium, carbamazepine, and valproate are indicated in the acute and prophylactic treatment of bipolar disorder in general, lamo- trigine monotherapy is not indicated in patients needing acute or prophylactic treatment of manic episodes but is primarily indi- cated in the treatment of patients who need treatment for the pre- vention of the recurrence of bipolar depression. In light of other evidence that migraine and bipolar disorder are comorbid phenomena, we decided to conduct a pharmaco- epidemiological study designed to test the hypothesis that this is indeed the case. To do this, we used the National Norwegian ORIGINAL CONTRIBUTION 734 www.psychopharmacology.com Journal of Clinical Psychopharmacology & Volume 31, Number 6, December 2011 From the *Moodnet Research Group, Haukeland University Hospital; †Depart- ment of Clinical Medicine, Section of Psychiatry, University of Bergen, Bergen, Norway; ‡Comprehensive Doctors Medical Group, Arcadia, CA; §Apotekene Vest HF Bergen; ||Department of Public Health and Primary Health Care, Uni- versity of Bergen, Bergen, Norway; ¶Department of Psychiatry, VA San Diego Healthcare System; and #Department of Psychiatry, University of California, San Diego, CA. Received November 16, 2010; accepted after revision June 28, 2011. Reprints: Ketil J. Oedegaard, MD, Moodnet Research Group, Haukeland University Hospital, and Department of Clinical Medicine, Section of Psychiatry, University of Bergen, Norway, PB 23 Sandviken, N-5812 Bergen, Norway (e-mail: keti@haukeland.no). This work was supported by an unrestricted grant from MoodNet, Norwegian Regional Health Department Y West. Copyright * 2011 by Lippincott Williams & Wilkins ISSN: 0271-0749 DOI: 10.1097/JCP.0b013e318235f4e9 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.