© 2014 COPYRIGHT PHYSICIANS POSTGRADUATE PRESS, INC. NOT FOR DISTRIBUTION, DISPLAY, OR COMMERCIAL PURPOSES. e1 J Clin Psychiatry Original Research Gender Differences, Clinical Correlates, and Longitudinal Outcome of Bipolar Disorder With Comorbid Migraine Erika F. H. Saunders, MD; Racha Nazir, MD; Masoud Kamali, MD; Kelly A. Ryan, PhD; Simon Evans, PhD; Scott Langenecker, PhD; Alan J. Gelenberg, MD; and Melvin G. McInnis, MD ABSTRACT Objective: Migraine is a common comorbidity of bipolar disorder and is more prevalent in women than men. We hypothesized comorbid migraine would be associated with features of illness and psychosocial risk factors that would differ by gender and impact outcome. Method: A retrospective analysis was conducted to assess association between self-reported, physician- diagnosed migraine, clinical variables of interest, and mood outcome in subjects with DSM-IV bipolar disorder (N = 412) and healthy controls (N = 157) from the Prechter Longitudinal Study of Bipolar Disorder, 2005–2010. Informed consent was obtained from all participants. Results: Migraine was more common in subjects with bipolar disorder (31%) than in healthy controls (6%) and had elevated risk in bipolar disorder women compared to men (OR = 3.5; 95% CI, 2.1–5.8). In men, migraine was associated with bipolar II disorder (OR = 9.9; 95% CI, 2.3–41.9) and mixed symptoms (OR = 3.5; 95% CI, 1.0– 11.9). In comparison to absence of migraine, presence of migraine was associated with an earlier age at onset of bipolar disorder by 2 years, more severe depression (β = .13, P = .03), and more frequent depression longitudinally (β = .13, P = .03). Migraine was correlated with childhood emotional abuse (P = .01), sexual abuse (P = 4 × 10 -3 ), emotional neglect (P = .01), and high neuroticism (P = 2 × 10 -3 ). Protective factors included high extraversion (P = .02) and high family adaptability at the trend level (P = .08). Conclusions: Migraine is a common comorbidity with bipolar disorder and may impact long-term outcome of bipolar disorder, particularly depression. Clinicians should be alert for migraine comorbidity in women and in men with bipolar II disorder. Effective treatment of migraine may impact mood outcome in bipolar disorder as well as headache outcome. Joint pathophysiologic mechanisms between migraine and bipolar disorder may be important pathways for future study of treatments for both disorders. J Clin Psychiatry © Copyright 2014 Physicians Postgraduate Press, Inc. Submitted: June 5, 2013; accepted November 7, 2013. Online ahead of print: April 15, 2014 (doi:10.4088/JCP.13m08623). Corresponding author: Erika F. H. Saunders, MD, Department of Psychiatry, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, 500 University Drive, PO Box 850, Mail Code: HO73, Hershey, PA 17033-0850 (esaunders@hmc.psu.edu). B ipolar disorder is an illness that affects 2.1% of the population 1 and is one of the top 10 contributors of years of life lived with disability for persons aged 15–44 years. 2 In addition, health care for bipolar disorder costs more on a per capita basis than for depression, asthma, coronary artery disease, or diabetes, 3 and comorbid medical conditions negatively affect quality of life and contribute to the burden of illness. 4–6 Migraine is a common comorbidity of bipolar disorder. In population-based studies, the rate of migraine in the general population is 9%–15%, 7–12 whereas the rate of migraine comorbidity with bipolar disorder is 16%–54%. 9,10,13–17 Migraine is more prevalent in women (15%–20%) than in men (6%), 7,12 and, although bipolar disorder has no gender differential, comorbidities that affect women at a higher rate may be associated with a different course of illness or presentation of bipolar disorder. 18 Women with bipolar disorder are at higher risk for bipolar II disorder, comorbid anxiety disorders, and suicide attempts. 19,20 We hypothesized that individuals with comorbid migraine and bipolar disorder have features of more severe illness, such as earlier age at onset; mixed symptoms; suicidal ideation and psychosis; more frequent, severe, and variable mood during longitudinal follow-up; and more severe psychosocial risk factors, such as trauma and stressful life events. Neuroticism, a tendency to experience negative affect such as depressed mood and anxiety, has been associated with both migraine 21 and bipolar disorder, 22 and we hypothesized that neuroticism would be elevated in those with migraine and bipolar disorder. We hypothesized that the presentation of migraine in bipolar disorder would differ by gender, specifically that women with migraine would be more likely to have bipolar II disorder, rapid cycling, anxiety disorders, and suicide attempts. By identifying risk factors and outcomes associated with comorbid migraine, we highlight the need for attention to the frequent comorbidity of migraine in bipolar disorder and the possibility of treatments that target both illnesses. METHOD We retrospectively investigated differences in baseline characteristics and longitudinal outcome in 412 subjects with DSM-IV bipolar I and II disorder; schizoaffective disorder, bipolar type; and bipolar disorder not otherwise specified (270 females; 142 males) and 157 healthy control subjects (86 females; 71 males) with and without comorbid migraine. Patients with bipolar disorder and healthy controls with no personal or family history of mood or psychotic disorder were recruited to the Prechter Longitudinal Study of Bipolar Disorder at the University of Michigan between 2005 and 2010. This study was approved by the University of Michigan Institutional Review Board; informed consent was obtained from all participants. Diagnostic interviews were completed with the Diagnostic Interview for Genetic Studies (DIGS), 23 and clinicians rated mood with the Hamilton Depression Rating Scale (HDRS) 24 and the Young Mania Rating Scale. 25 Interviewers included physicians, psychologists, and masters’-level mental health professionals,