The relationship between migraine and mental disorders in a population-based sample

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1 Available online at General Hospital Psychiatry 31 (2009) The relationship between migraine and mental disorders in a population-based sample Gregory E. Ratcliffe, B.Sc. a, Murray W. Enns, M.D., F.R.C.P.C. a,b, Frank Jacobi, Ph.D. c, Shay-Lee Belik, M.Sc. a,b, Jitender Sareen, M.D., F.R.C.P.C. a,b,d, a Department of Psychiatry, University of Manitoba, Winnipeg, Manitoba, Canada R3E 3N4 b Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada R3E 3N4 c Epidemiology and Service Research Unit, Institute of Clinical Psychology and Psychotherapy, Technical University of Dresden, Dresden, Germany d Department of Psychology, University of Manitoba, Winnipeg, Manitoba, Canada R3E 3N4 Received 24 July 2008; accepted 3 September 2008 Abstract Objective: There is emerging evidence from clinical and community samples to suggest that migraines are associated with mental disorders. The present study utilized a large population-based sample to investigate the association between physician-diagnosed migraine and mental disorders. Method: Data were from the German Health Survey conducted between 1997 and 1999 (N=4181, response rate 61.4%, age years). Lifetime and 12-month history of migraines were assessed by self-report and by a physician. Past 12-month DSM-IV mental disorders were assessed using the Composite International Diagnostic Interview. Results: After adjusting for sociodemographic factors, past-year migraine was significantly and positively associated with depression, dysthymia, bipolar disorder, panic attacks, panic disorder, agoraphobia and simple phobia [adjusted odds ratios (AOR) ranging from 1.74 to 3.21]. After additionally adjusting for other mental disorders, any anxiety disorder (AOR=1.82) and any mood disorder (AOR=1.61) remained significantly associated with past-year migraine. Conclusion: Although causal inferences cannot be made due to the cross-sectional nature of the data, the present study adds to a growing body of literature that suggests a strong association between migraines and mood and anxiety disorders Elsevier Inc. All rights reserved. Keywords: Migraine; Mental disorders; Comorbidity, Community sample 1. Introduction An expanding body of literature has shown that migraine headaches are associated with higher rates of mental disorders. A recent review by Radat and Swendsen [1] examined the relationships between migraine and various The authors have no conflicts of interest. Preparation of this article was supported by (1) a CIHR New Investigator grant (#152348) awarded to Dr. Sareen, (2) a Manitoba Health Research Council Studentship awarded to Ms. Belik and (3) a Western Regional Training Centre studentship funded by Canadian Health Services Research Foundation, Alberta Heritage Foundation for Medical Research and Canadian Institutes of Health Research awarded to Ms. Belik. Corresponding author. Department of Psychiatry, University of Manitoba, Winnipeg, Manitoba, Canada R3E 3N4. address: sareen@cc.umanitoba.ca (J. Sareen). mental disorders in community-drawn samples [2 12]. Breslau et al. [2] found significant associations between migraine and lifetime major depressive disorder, anxiety disorders, nicotine dependence, and alcohol or drug abuse and dependence. Merikangas et al. [4,11] found that recurrent brief depression, panic disorder, phobia and generalized anxiety were more frequent among individuals with migraines than among individuals with tension headache or no headache. However, Merikangas et al. [4,11] did not find an association between migraines and major depression, hypomania, or alcohol and drug abuse. Studies by Wang et al. [5] and Lipton et al. [6] found associations between migraine and depression. Most recently, using a longitudinal prospective design, Swartz et al. [3] demonstrated significant association between migraines and life-time major depression, panic disorder and phobia, after adjusting for age and /$ see front matter 2009 Elsevier Inc. All rights reserved. doi: /j.genhosppsych

2 G.E. Ratcliffe et al. / General Hospital Psychiatry 31 (2009) sex. Their study did not find an association between migraine and alcohol or other substance abuse. A recent study, using the Canadian Community Health Survey, found migraine to be associated with major depressive disorder, bipolar disorder, panic disorder and social phobia [13]. In summary, there is inconsistency in the literature with respect to the type of mental disorders that are associated with migraines. There are three main limitations to previous studies. First, many of the studies may be limited in their generalizability to the entire population by using cohorts that were healthier than the general population [2,9,10] or by using young adult [2,4,9 11] or elderly populations [5]. Second, many studies have only looked at a limited number of mental disorders [5 8,10,12]. In particular, there is still conflicting opinion as to whether bipolar disorder, major depression and substance use disorders are associated with migraine [1]. Breslau et al. [2] found an association with bipolar disorder and alcohol abuse/dependence only for migraine with aura (no association between migraine without aura). Later, Breslau and Davis [9] again found an association between migraine and illicit drug use disorders. However, Swartz et al. [3] found no association between alcohol and other substance abuse and migraine after adjusting for age and sex. Jette et al. [13] did not find an association between migraine and alcohol or drug dependence either. Third, the conflicting findings of the relationship between migraines might be due to differences in methodology between studies on the assessment of migraines and mental disorders. The diagnoses of migraines in most community surveys have varied between selfreported diagnoses by health professional of migraines [13,14], to lay interviewers utilizing the International Headache Society criteria for diagnosis of migraine conducted by lay interviewers [2,3,6 10]. The diagnoses of mental disorders have also varied between DSM-III, DSM-III-R and DSM-IV criteria. To address these limitations, we utilized a unique survey The German National Health Interview and Examination Survey that specifically aimed to examine the relationship between physical conditions and mental disorders [15]. The strengths of this study were that migraines were diagnosed by a physician and that multiple DSM-IVbased mental disorders were evaluated by trained interviewers. The objective of this study was to determine whether migraine was associated with various mental disorders in a nationally representative sample. 2. Methods 2.1. Sample The sample of this core survey was drawn from the population registries of subjects 18 to 79 years of age, living in Germany in It represents a stratified random sample from 113 communities throughout Germany with 130 sampling units. The first sampling step was the selection of communities; the second step was the selection of sampling units; and the third step was the selection of the inhabitants. As a result, a representative gross sample of 13,222 persons was eligible according to the age, sex and community type criteria. The response rate was 61.4% (n=7124). The response rate including subjects completing only parts of the assessment was 77.8% [16]. The study was commissioned by the German Ministry of Research, Education and Science and approved by the relevant institutional review board and ethics committee. Written informed consent was obtained for both surveys. Subjects did not get any financial compensation for their study participation. Field work was done between November 1997 and April Comprehensive information about design and sample of the GHS is provided elsewhere [15,16] Mental disorders Mental disorders were assessed using the German National Health Interview and Examination Survey Mental Health Supplement (GHS-MHS). For financial and logistic reasons, data on mental disorders were gathered using a twostage design. The first stage entailed the administration of a standardized screening questionnaire for mental disorders at the end of the medical examination for the core survey described earlier [15]. The second stage involved the administration of a complete, structured, clinical interview used to obtain DSM-IV mental disorder diagnoses from all participants of the core survey who screened positive and 50% of those who screened negative for a mental disorder. Owing to the resulting oversampling of those who screened positive on the GHS-MHS, data were weighted in the later analyses. Most interviews occurred within 2 to 4 weeks of the core survey medical examination to ensure that data gathered in both examinations were contemporaneous. The GHS-MHS included only persons from the age of 18 to 65 years. Core survey participants aged 66 to 79 years were excluded because the psychometric properties of the Composite International Diagnostic Interview (CIDI) have not yet been satisfactorily established for use in older populations [17,18]. The conditional response rate of the GHS-MHS was 87.6%, resulting in a total of 4181 respondents (aged years) who completed both the core survey (physical assessment) and GHS-MHS. A detailed description of the design and methods of both the core survey and GHS-MHS is available elsewhere [16] Medical assessment In brief, the core survey consisted of (1) a self-report questionnaire, (2) a standardized computer-assisted medical interview, (3) anthropometric and blood pressure measurements and the collection of blood and urine samples, and (4) a screening for mental disorders, which served as the first stage of the GHS-MHS. The examination occurred in special centers at the study sites and started with a self-report questionnaire to evaluate subjects' current and past somatic

3 16 G.E. Ratcliffe et al. / General Hospital Psychiatry 31 (2009) symptoms and complaints, health care utilization, and impairments and disabilities. Completion of the questionnaires was followed by a structured interview by a study physician to reexamine and reevaluate the data from the self-report packet. This interview was computer assisted for standardization and integrity purposes. Diagnoses of physical disorders were then made. These diagnoses were revised on the basis of laboratory test results that became available 2 weeks later. The mean period of the overall assessment was 2 h Migraine diagnosis All respondents were systematically questioned about the diagnosis of migraines. First, study doctors (trained for general epidemiological studies but not specialized in the field of neurology) asked whether migraine was ever diagnosed Table 1 Independent and dependent variables utilized in the current study n (%) a Gender Male 1913 (50.3) Female 2268 (49.7) Education Grade 10 or high school equivalent 2314 (61.0) More than high school 1790 (39.0) Marital status Married 2617 (64.1) Single 493 (11.0) Separated/divorced/widowed 991 (24.9) Age years 517 (12.0) years 949 (24.9) years 992 (23.5) years 863 (18.8) years 856 (20.8) Past-year mental disorders Any mood disorder b 558 (11.9) Major depressive disorder 384 (8.3) Dysthymia 225 (4.5) Bipolar 40 (0.8) Any anxiety disorder c 662 (13.2) Panic attack 241 (4.7) Panic disorder 125 (2.4) Social phobia 94 (2.0) Generalized anxiety disorder 73 (1.5) Agoraphobia without panic disorder 105 (2.0) Simple phobia 388 (7.6) Any substance abuse/dependence d 194 (4.5) Alcohol abuse/dependence 174 (4.1) Drug abuse/dependence 36 (0.8) Any mental disorder 1074 (22.9) Past-year migraine 491 (11.7) a All n's were unweighted, and all percentages were weighted. b Any mood disorder includes major depressive disorder, dysthymia and bipolar. c Any anxiety disorder includes panic attacks, panic disorder, obsessivecompulsive disorder, social phobia, generalized anxiety disorder, agoraphobia without panic disorder, and simple phobia. d Any substance abuse/dependence includes alcohol abuse/dependence and illicit drug abuse/dependence. Table 2 Relationship between self-report questionnaire and physician diagnosis of migraine Response in self-report questionnaire by a physician. The physicians reviewed the key symptoms of migraines (if necessary they had to explain that migraines are headache attacks, occurring repeatedly and often in only one side of the head, that are often beginning in the morning and typically last for hours or days ). By their evaluation of the respondent's responses they corrected the originally selfreport questionnaire data as shown in Table 1; although the sensitivity and specificity of self-report migraine were high (N90%), the positive predictive value was much lower (74.2%). If doctors assigned the diagnosis, they assessed additionally age of first onset and recency (e.g., when occurred last time: past month past year longer than past year don't know). The International Headache Association criteria were not utilized in the assessment [15,16] Statistical analyses In all analyses, the appropriate statistical weight was used to ensure the data were representative of the national population. Standard errors were calculated using the Taylor Series Linearization method in the SUDAAN program [19]. We examined the relationship between past-year migraine and past-year mental disorders in the whole sample. First, multiple logistic regression analyses were utilized to examine the association between migraine and each of the mental disorders. In the second set of regressions, covariates of sociodemographic factors (age, gender, marital status and education) were included. In the third set of regressions, we included the following covariates: sociodemographics, any mood disorder, any anxiety disorder and any substance use disorder. Finally, we examined whether the migraines had an earlier age of onset than the comorbid mental disorder among cases where there was comorbidity. 3. Results Physician's decisions on lifetime migraine diagnosis Yes No Total Yes No Don't know or missing Total Sensitivity of self-report=true positives/(true positives+false negatives)=607/ (607+40)=93.81%. Specificity of self-report=true negatives/(true negatives+false positives)=3179/( )=93.77%. Positive predictive value (PPV) of self-report=true positives/(true positives+false positives)=607/( )=74.20%. Negative predictive value (NPV) of self-report=true negatives/(true negatives+false negatives)=3179/( )=98.75%. Table 1 describes the prevalence of all the independent and dependent measures utilized in the current study. Mental

4 G.E. Ratcliffe et al. / General Hospital Psychiatry 31 (2009) disorders and migraine were both prevalent in the population. The prevalence of migraines in this study was found to be 11.7%; this is in keeping with previous representative population studies showing past-year prevalence rates of migraine from 9% to 15% [3,13,14,20]. Table 2 shows the relationship between self-report and physician-diagnosed lifetime migraines. Although the sensitivity and specificity of self-report migraine were high (N90%), the positive predictive value was much lower (74.2%). Table 3 describes the associations between mental disorders and migraine. After adjusting for sociodemographics, past-year migraine was positively associated with any past-year mood disorder [adjusted odds ratio (AOR1) 2.18; 95% CI, ], major depressive disorder (AOR1 1.77; 95% CI, ), dysthymia (AOR1 3.17; 95% CI, ), bipolar disorder (AOR1 2.78; 95% CI, ), any anxiety disorder (AOR1 1.91; 95% CI, ), panic attacks (AOR1 1.94; 95% CI, ), panic disorder (AOR1 1.78; 95% CI, ), agoraphobia without panic disorder (AOR1 3.21; 95% CI, ), simple phobia (AOR1 1.97; 95% CI, ) and any mental disorder (AOR1 1.74; 95% CI, ). There were no associations between past-year migraine and social phobia, generalized anxiety disorder (GAD), alcohol abuse/dependence and drug abuse/dependence. Finally, any past-year mood disorder and any pastyear anxiety disorder are associated with migraine, after adjusting for sociodemographics and other mental disorders (AOR2 1.82; 95% CI, and AOR2 1.61; 95% CI, , respectively). Table 4 Order of onset of migraine and mental disorders Depression 173 (73.7) Dysthymia 54 (82.2) Bipolar NA Panic attacks 62 (66.8) Panic disorder 26 (61.3) Social phobia 7 (27.0) GAD 24 (76.4) Agoraphobia 15 (36.8) Simple phobia 35 (29.1) Alcohol abuse/dependence 18 (61.2) Illicit drug abuse/dependence 10 (64.5) Table 4 shows the temporal sequence of onset of migraines and mental disorders among those with comorbidity. In the majority of comorbid cases, migraines preceded the onset of the following mental disorders: major depression, dysthymia, GAD, panic attacks, panic disorder and substance use disorders. 4. Discussion Percent of individuals who had migraine prior to mental disorder, n (%) All n's are unweighted values; all percentages are weighted values. To the best of our knowledge, this is the first study to examine the relationship between physician-diagnosed migraine and multiple mental disorders in a nationally representative sample. The strengths of this study include a Table 3 Relationship between past-year migraine and past-year mental disorders Mental disorder No migraine, n (%) Migraine, n (%) OR (95% CI) AOR1 (95% CI) AOR2 (95% CI) Any mood disorder 439 (10.7) 119 (23.0) 2.50 ( ) 2.18 ( ) 1.82 ( ) Depression 305 (7.5) 79 (14.8) 2.13 ( ) 1.77 ( ) Dysthymia 164 (3.6) 61 (12.1) 3.64 ( ) 3.17 ( ) Bipolar 29 (0.7) 11 (2.1) 3.05 ( ) 2.78 ( ) Any anxiety disorder 534 (12.0) 128 (24.6) 2.38 ( ) 1.91 ( ) 1.61 ( ) Panic attacks 190 (4.2) 51 (9.5) 2.40 ( ) 1.94 ( ) Panic disorder 99 (2.1) 22 (4.6) 2.23 ( ) 1.78 ( ) Social phobia 76 (1.9) 18 (3.0) 1.60 ( ) 1.38 ( ) GAD 57 (1.4) 16 (3.0) 2.21 ( ) 1.80 ( ) Agoraphobia 72 (1.5) 33 (6.3) 4.24 ( ) 3.21 ( ) Simple phobia 310 (6.8) 78 (15.1) 2.43 ( ) 1.97 ( ) Any substance abuse/dependence 181 (4.7) 13 (2.6) 0.54 ( ) 0.83 ( ) 0.60 ( ) Alcohol abuse/dependence 162 (4.3) 12 (2.3) 0.52 ( ) 0.82 ( ) Illicit drug abuse/dependence 33 (0.8) 3 (0.7) 0.76 ( ) 1.06 ( ) Any mental disorder 891 (21.6) 183 (35.0) 1.95 ( ) 1.74 ( ) AOR1 adjusting for sociodemographics including age, marital status, gender and education. AOR2 adjusting for sociodemographics and each of the other any disorder categories simultaneously. Any mood disorder includes major depressive disorder, dysthymia and bipolar disorder. Any anxiety disorder includes panic attacks, panic disorder, obsessive-compulsive disorder, social phobia, GAD, agoraphobia and simple phobia. Any substance abuse/dependence includes alcohol abuse/dependence and illicit drug abuse/dependence. Pb.05. Pb.01. Pb.001. Pb.0001.

5 18 G.E. Ratcliffe et al. / General Hospital Psychiatry 31 (2009) large sample size, a standardized interview (CIDI) and physician-diagnosed physical health problems. The present study overcomes an important limitation of previous studies that relied upon self-report diagnosis of migraines. The present study's findings show a consistent positive association between a number of anxiety and mood disorders and migraines. The present findings that major depressive disorder, dysthymia, panic attacks, panic disorder, agoraphobia and simple phobia are associated with migraine are consistent with previous studies [2 12]. The present study also gives support to a paper by Swartz et al. [3] and Jette et al. [13] that showed substance abuse/ dependence disorders are not associated with migraine. Similar to Breslau et al. [2], the present study also found an association between bipolar disorder and migraine, although the Breslau et al. [2] study only found this association among individuals suffering from migraine with aura. The fact that this study did not find associations between social phobia and migraine is contrary to previous work [13]. Previous studies have demonstrated that, although migraine without aura was not associated with social phobia, migraine with aura was associated [11]. A study involving a diagnosis of aura is required to make further determinations. Although the cross-sectional nature of this study cannot determine causality, there are several possible explanations of the relationship between migraine and mental disorders. The two main theories that have been proposed are that (1) a common etiologic factor (environmental or genetic) is influencing both conditions, and (2) a causal relationship exists between mental disorders and migraines. There are many possible explanations for the common etiologic factor. Breslau et al. [10] demonstrated that migraine predicted first occurrence of depression and that depression predicted first occurrence of migraine [7]. Although our analysis of temporal onset of mental disorders and migraines suggests that migraines may be a risk factor for major depression, the longitudinal study by Swartz et al. [3] using the Epidemiologic Catchment Area study did not find this relationship. Previous studies have contemplated the role of serotonin as the cause of both migraine and mental health disorders [2,3]. Serotonin abnormalities have been implicated in the pathogenesis of migraine [21] as well as several mental disorders [22 27]. Breslau et al. [10] mentioned that low platelet monoamine oxidase activity had been observed in persons with migraine [28] and had also been implicated as an indicator of generalized vulnerability to psychiatric disorders [29]. Data from a study by Merikangas et al. [4] also suggested the idea of a shared etiologic risk factor. The theory that migraine and anxiety or depression share a syndromic relationship, rather than result from the same underlying etiologic factors, was first suggested by Merikangas et al. [30]. This paper observed that anxiety often preceded migraine and that migraine then preceded depression, a finding that was replicated in subsequent studies [2,3]. From the fact that family data do not support a genetic cause of migraine and depression, Merikangas et al. [31] suggested an environmental association. Current findings should be interpreted with four specific limitations in mind. First, as mentioned previously, the cross-sectional nature of the data precludes determination of causality. Our analyses allow associations to be made but prospective studies would be needed in order to better address whether migraine is a risk factor for the development of mental disorders or whether mental disorders are risk factors for the development of migraine, or both. Second, although the present study is the first to utilize physicians in assessment of migraines in a community sample, the physicians did not utilize the International Classification of Headache Disorders [32] to make the diagnosis of migraines. Future studies should consider using these criteria in epidemiologic surveys. However, the yielded migraine prevalence rates are credible (see above) and we are not aware of any hypotheses or findings to the fact that migraine diagnosis did not fully meet state-of-theart neurological assessment and would bias our results with regard to the relationships between migraine and mental disorders. Third, the presence of aura with respect to migraine was not assessed in the survey. Previous studies have shown differences between migraine with aura and migraine without aura in relation to mental disorders [2,4,7,8,11]. A fourth limitation includes the inability of this study to take into consideration the entire spectrum of contributors to migraine headache, such as family history of migraine and menstrually related migraine [33,34]. The above factors limit the extent to which conclusions can be reached from the data presented and call for more investigation into these relationships. In conclusion, the significant associations between migraine and mood disorders as well as panic attacks, panic disorder, simple phobia, and agoraphobia are important findings for psychiatry/psychology and general health care. It is important for the general physician to recognize the association between migraine and mental health and to include a proper history, physical examination and investigations for other conditions when mental or physical disorders are present. This knowledge is vital to the holistic treatment of these comorbid patients. 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