Migraine life-time prevalence in mental disorders: concurrent comparisons with first-degree relatives and the general population.

Trino Baptista¹, Euderruh Uzcátegui², Yinet Arapé², Ana Serrano², Xiorella Mazzarella³, Segundo Quiroz⁴, Clara Isabel Ramirez⁵ and Alix Padrón de Freytez⁵

¹Department of Physiology, ²Department of Psychiatry, Los Andes University Medical School. Mérida, Venezuela. ³Caracas Psychiatric Hospital, Caracas, Venezuela. ⁴Department of Statistics, School of Economics and Social Sciences, ⁵Department of Neurology, Los Andes University Medical School. Mérida, Venezuela

Corresponding author: Trino Baptista. Department of Physiology, Los Andes University Medical School, Mérida, 5101-A, Venezuela. E-mail: trinbap@yahoo.com

Abstract. The authors quantified the prevalence of migraine in subjects with mental disorders, first-degree relatives and the adult general population (GP) in Mérida, Venezuela. After validation, a modified, short version of the Lipton’s diagnostic scale was administered to consecutively admitted in- and out-patients (n = 1059), their first-degree relatives (n = 445) and a probabilistic sample of the GP (n = 516). In the GP, the frequency of migraine (percentage and 95% confidence interval) was 14.9 (11.8-17.9). The migraine frequencies were (percentage and odd ratio probability against the GP: bipolar disorder (15.7%, p = 0.5), schizophrenia (8.3%, p = 0.08), depression and dysthimia (24.4%, p = 0.2), anxiety disorders (10.0%, p = 0.02), personality disorders (11.4%, p = 0.15), all other disorders (15.5%, p = 0.4), relatives of bipolar patients (4.4%, p < 0.001), relatives of schizophrenia patients (3.5%, p = 0.003), and relatives of patients with all other mental disorders (12.8%, p = 0.4). Migraine was more common in women (p < 0.001), and the bipolar patients presented the highest female to male ratio (8:1). A high variability was observed in migraine prevalence among the diagnostic categories, but it was particularly high in subjects with affective disorders, mainly in women, who thus deserve special attention from clinicians.

Prevalencia de migraña en trastornos mentales: comparación concurrente con familiares de primer grado y con la población general.

Resumen. Los autores cuantificaron la prevalencia de migraña en sujetos con trastornos mentales, sus familiares de primer grado y la población general (PG) en Mérida, Venezuela. Se utilizó una versión abreviada de la escala diagnostica de Lipton. Luego de un estudio de validez, tal escala se administró a pacientes ambulatorios u hospitalizados atendidos en forma consecutiva (n = 1.059), a sus familiares de primer grado (n = 445) y a una muestra probabilística de la PG (n = 516). La frecuencia de migraña en la PG (porcentaje e intervalo de confianza de 95%) fue de 14,9 (11,8-17,9). La frecuencia para los diversos trastornos (porcentaje y probabilidad asociada a la razón de momios (odds ratio) con respecto a la PG) fue: trastorno bipolar (15,7%, p = 0,5), esquizofrenia (8,3%, p = 0,08), depresión y distimia (24,4%, p = 0,2), trastornos de ansiedad (10,0%, p = 0,02), trastornos de personalidad (11,4%, p = 0,15), todos los otros trastornos (15,5%, p = 0,4). En los familiares, la frecuencia fue: trastorno bipolar (4,4%, p < 0,001), esquizofrenia (3,5%, p = 0,003), otros trastornos (12,8%, p = 0,4). El diagnóstico de migraña fue más frecuente en mujeres (p < 0,001), y los sujetos con trastorno bipolar presentaron el mayor índice mujer:hombre (8:1). Se observó una alta variabilidad en la prevalencia de migraña en las diversas categorías diagnósticas. Tal frecuencia fue particularmente elevada en sujetos con trastornos afectivos, principalmente en mujeres, las cuales ameritan una atención especial por parte de los médicos tratantes.

Received: 10-07-2011 Accepted: 27-10-2011

INTRODUCTION

Migraine, a class of primary headache (1), is a severe neurological disorder which affects between 12 and 28% of people at some point in their lives (2-8). The one-year prevalence of migraine in the general population (GP) ranges from 6% to 15% in adult men and from 14% to 35% in adult women (2-8). At all ages, migraine without aura is more common than migraine with aura, with a ratio between 1.5:1 and 2:1 (6, 7). 

An association between general psychopathology and migraine was observed as early as in 1873 by E. Liveing (cited by Low et al., ref. 9). Subsequent studies confirmed a complex relationship between migraine and mental disorders in community (9-17) and clinical samples (18-40). Specifically, an elevated frequency of migraine has been reported in psychiatric conditions as dissimilar as eating (18), personality (19-21) and anxiety disorders (21-25), substance abuse (26) and most notably, mood disorders (27-37). 

Recent studies have emphasized the association between migraine and bipolar disorders (BPD) (9, 16, 17, 30-37). This issue is of considerable clinical interest because converging evidence suggests that patients with this comorbidity have a more severe impairment in mental health and social performance than those without it (9, 13,16, 36, 37). In addition, the diagnosis of migraine is often overlooked by patients and doctors (32-34). 

In this study, we first validated a short scale for the diagnosis of migraine. We then applied this instrument to a heterogeneous sample of consecutive psychiatric patients attending in- and out-patient facilities, their available first-degree adult relatives and a probabilistic sample from the Venezuelan GP from Mérida city as a key comparison group. Our aim was to describe the migraine prevalence in psychiatric patients according to their specific clinical diagnosis and to have a concurrent comparison with the GP. Besides, by assessing first-degree relatives, we aimed to gain some insight into the family aggregation, particularly in schizophrenia and BPD. There are not published studies on this topic in Venezuela. 

METHODS 

This study was conducted between January 2007 and December 2010 at the following Venezuelan institutions: Los Andes University Hospital and private clinics (Mérida state), CATESFAM (Center for Attention of Schizophrenic patients and their relatives, Zulia and Táchira states), and Caracas Psychiatric Hospital (Distrito Capital). In sites outside Mérida city, only subjects with schizophrenia, schizoaffective and bipolar disorders were evaluated. The ethics committee of each institution approved the study, and a written informed consent for voluntary participation was signed by each subject. 

Subjects 

Consecutively admitted adult patients, with age equal or higher than 18 years, attending out-patient (all clinics) or in-patient (only Mérida and Caracas) facilities and their available first-degree adult relatives (parents, siblings and off-springs), were asked to voluntarily fill a short inventory of headache symptoms (see Scale Validation below). In the case of illiterate subjects, the scale was filled by the interviewer. Psychiatric diagnosis was verified by using the Structured Clinical Interview for the DSM-IV (41). 

The GP was assessed in Mérida through a probabilistic sample (n = 516) stratified by gender and age according to the last Venezuelan population census. For this purpose, thirteen public places (stores and parks) representing the main city neighborhoods were selected. Thirteen trained and properly identified interviewers selected every third adult passer-by, and requested voluntary participation for answering the scale. Each interviewer completed a previously determined quota of interviewees and no single subject rejected to enter the study. 

Scale validation 

The instrument was a self-administered screener for life-time migraine symptoms and family history (42) which is compatible with the International Classification of Headache Disorders (1) (Table 1). The scale had 11 items, and each one counted as (1) when positive and (0) when negative. A specific subject could thus have a maximum score of 10 and a minimum of 0 since items 6.1 and 6.2 excluded each other. The interviewers were trained to guarantee a uniform methodology, particularly in the illiterate subjects.

Lipton et al. (42) showed that a three-item subset of their scale for migraine detection in primary care, composed by disability, nausea, and sensitivity to light, provided optimum performance with a sensitivity of 0.81, a specificity of 0.75 and a positive predictive value of 0.93. These three items were incorporated in our instrument (Table I, items 2-4) and were also used in the main analysis. 

In the validation study, the 11-item scale was administered to 88 patients from the Department of Neurology of Los Andes University Hospital who were diagnosed by an expert neurologist as positives (n = 34) or negative (n = 54) for migraine, according to the International Classification of Headache Disorders (1). 

The following figures were obtained for the 11-item scale and for the 3-item subset as defined by Lipton et al. (42): Content Validity as assessed by 5 expert neurologists and the Cronbach’s Alfa Coefficient of Internal Consistence (43, 44). In addition, by using the clinical judgment as the gold standard criteria for migraine diagnosis, we calculated the Kappa Coefficient, Sensitivity, Specificity, Positive and negative Predictive Value, Reliability and the ROC curve (Receiver Operation Characteristics) for cut-off point calculation (44). 

Statistical analysis 

The SPSS. version 17.0 Inc. (Chicago, Illinois, USA) was used for the analysis. Data normality was estimated with the one-sample Kolmogorov- Smirnov test and Levene’s test for the equality of variances. Since age was not normally distributed, it was analyzed with the Kruskal-Wallis chi-square test. Gender distribution was analyzed with the two- tailed chi-square test with continuity correction followed by the Ryan test as post hoc. Binary logistic regression was conducted to assess the migraine frequency distribution with age and gender as independent variables. Odd ratios between each diagnostic group and the GP were obtained. Results were considered significant when p < 0.05. 

RESULTS 

Scale validation 

Results are summarized in Table II. For calculation of the positive and negative predictive values, we used a migraine prevalence value of 20% (2). The content validity figure was “acceptable” for the 11-item (0.73) and for the 3-item (0.89) scales. The Kappa coefficient showed “good agreement” with the clinical diagnosis for both scales (0.69 and 0.73, respectively). The positive and negative predictive values were above 90% for both scales, and in the case of the 3-item scale, the positive predictive value was 100%.

For the classification of patients as positive or negative according to the ROC curve results, cut-off points of 5 and 3 were selected when using the 11-item and 3-item scale, respectively. We used the 3-item scale for the migraine frequency analysis. 

Prevalence of migraine 

No subject refused the interview. The whole sample comprised 2020 subjects distributed as follows: GP (n = 516), schizophrenia (n = 132), BPD (type I n = 84, type II n= 32, non-specified n = 41, schizo-affective n = 34), depressive disorders (major depression [n = 69] and dysthymia [n = 14]), anxiety disorders (n = 130), personality disorders (n = 105), all other disorders (n = 418), schizophrenia relatives (n = 85), BPD relatives (n = 181), and all other disorder relatives (n = 179). Table III presents the age and gender distribution of the sample.

Fifty eight percent of the subjects were women. This trend was observed in all the groups except in the GP and in subjects with schizophrenia (Table III). 

In the logistic regression analysis all the independent variables (diagnosis, gender and age) were significantly associated with migraine. Migraine was diagnosed in 13.0% of the whole sample, and it was more frequent in women than in men: 16.7% vs. 7.8%, odds ratio (OR) (95 %CI) = 2.6 (1.9-3.6), p < 0.001. 

The migraine frequency (percentage and 95% Cl) in the GP was 14.9% (11.8-17.9) (Table IV). Subjects with BPD, depression/dysthymia, or the other disorder group showed a higher but not statistically significant frequency of migraine than the GP. All the other groups displayed lower migraine frequencies than the GP, but the figures only reached statistical significance in the anxiety disorder, schizophrenia and BPD relative groups (Table IV).

Table V displays the frequency of migraine according to the subtype of BPD and in the schizoaffective group. No figure reached statistical significance when compared to the GP (p > 0.05).

The frequency of migraine increased with age. When compared to subjects under 20 y of age, the figures (OR and 95% CI) were: 20-40 y group, OR = 2.1 (1.2-3.8), p = 0.01; 41-60 y group, OR = 1.8, (0.9-3.3), p = 0.056 and > 60 y group: OR = 1.2 (0.6-2.3), p = 0.7. 

Female to male ratio 

As mentioned above, the prevalence of migraine in the whole sample was significantly higher in women than in men. Fig. 1 shows that this gender-related difference was recorded in all categories. Interestingly, the highest female to male ratio was observed in the BPD patients with a value of 7.9:1.0.

DISCUSSION 

Due to the high level of illiteracy in the Venezuelan psychiatric population, in this pilot study we used a simple scale for the life-time diagnosis of migraine instead of a more complex one, such as that derived from the International Classification of Headache Disorders. Besides, we intended to evaluate subjects with severe mental disorders such as schizophrenia, where perceptual and other aura-related symptoms may be difficult to differentiate from the primarily psychiatric symptoms. 

The whole scale (11-item scale) and the Lipton’s subscale (3-item scale) showed a fairly similar validity and reliability, as assessed in the validation study with neurological patients. However, the frequency of migraine was almost two-fold with the 11-item instrument (23.9%) when compared to the 3-item scale (13.0%). Even though this study does not allow additional comparisons between both scales, we speculate that the 3-item scale provides a more reliable approach to migraine diagnosis. 

Additional distinctive features of this study were the concurrent assessment of subjects from the GP who made up the main reference group and the direct assessment of first degree relatives. 

Migraine in the general population 

In agreement with previous studies in the GP, migraine was more frequent in women than in men (45) and declined in the elderly (2). The lifetime prevalence of migraine reported here (total= 14.9%; women: 19.6%; men = 11.4%) is within the range reported by authors in other countries (12-28%) (2-8), but it is higher than that reported in Venezuela using a face to face interview based on the International Headache Society Criteria (12.2% for women and 4.7% for men) (4). 

Bipolar disorder, major depression and dysthymia 

Subjects with depressive disorders had the highest prevalence of migraine in the whole sample and in women. 

The whole BPD group and BPD females displayed the second highest (though non-significant) frequency of migraine. By contrast, migraine frequency in bipolar men was among the lowest. Interestingly, as shown in Fig. 1, the highest women to men ratio in migraine frequency was observed in the BPD group. The higher frequency of migraine in BPD females than in BPD males has been reported by some authors (9, 11, 16, 38); but not by others (30, 32). Hence, while these results did not reach strict statistical significance, they confirm that migraine is a clinically relevant co-morbidity in subjects with affective disorders, particularly in women. 

Comparisons between the BPD and the depression/dysthymia groups are of special interest. As stated above, the prevalence of migraine was the highest in the depression/dysthymia group. Few studies have concurrently compared the frequency of migraine between BPD and depressive unipolar subjects. Fasmer (33), for example, found a rather similar frequency in BPD (44%) vs. unipolar (46%) patients, but his sample was not powered enough to conduct gender analysis. However, that study allowed subjects with cyclothymic or hyperthymic affective temperament to be labeled as BPDII, whereas we here used a narrower definition. Thus, it remains unclear whether the frequency of migraine would have been higher in our BPD group had we considered temperament analysis. Another factor that may underestimate the actual frequency in BPD subjects is the late onset of manic or hypomanic episodes (9), or the difficulty in recalling or identifying the latter as abnormal in subjects labeled as unipolar depressives. This issue remains to be properly addressed. It is important to underscore that the ratio female:male in the depression/ dysthymia group was close to 1, and contrasts to the high value in the BD group. 

Regarding the impact of migraine on general health, McIntyre et al. (16) showed that bipolar women with migraine had more comorbid medical disorders and were more likely to require help with personal or instrumental activities of daily living when compared to bipolar women without migraine. These authors also showed that, compared with BPD males without migraine, those with both disorders were more likely to use primary and mental health services, live in a low income household and receive welfare and social assistance. McIntyre et al. (16) also reported that these subjects present an earlier age of onset of BPD and have a higher lifetime prevalence of comorbid anxiety. Along the same lines, Ortiz et al., (37) showed that BPD patients with co morbid migraine had significantly higher rates of suicidal behavior, social phobia, panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder. It is worthwhile mentioning that an elevated frequency of migraine has also been observed in children and adolescents with BPD (39). 

Altogether, these results confirm that BPD patients with migraine are a clinical subpopulation with a considerable health burden that requires particular attention from the mental health system. 

An unexpected finding was the significantly low prevalence of migraine in BPD relatives. We did not find any published study on the family prevalence of migraine in BPD subjects. However, Low et al. (9), reported a higher frequency of positive family history for migraine and psychiatric disorder in BPD patients with migraine than in those without it. Disalver et al. (46) also reported that a family history of BPD increases the risk for migraine in patients with major depression or BPD. We cannot assess here the bias magnitude and the frequency of lifetime diagnosis in our sample of relatives. Besides, when assessing the frequency of migraine, we did not conduct separate analysis for BPD probands with or without migraine. At any rate, this finding indirectly points out that migraine could be related to the BPD phenotype expression rather than to the shared genetic endowment. 

As for the neurobiology of migraine and BPD, some studies suggest a role for a polymorphism in the serotonin transporter (47), a migraine linkage locus on chromosome 4 and a susceptibility locus on chromosome 20, which harbors a gene for the migraine/BPD phenotype (48). 

Migraine and schizophrenia 

A distinctive feature of this study is the assessment of patients with schizophrenia and their first-degree relatives. Their migraine prevalence was the lowest among all the patients (8.3%): it reached marginal statistical significance compared to that recorded in the GP (p = 0.08). We did not find any published study on migraine prevalence in patients with schizophrenia. It must be acknowledged though, that for this clinical population, migraine symptoms and the aura phenomenon can be difficult to distinguish from the perceptual abnormalities often found in the disorder itself. Hence, the reliability of migraine symptoms’ assessment in schizophrenia remains an open question. 

It is important to point out that the frequency of migraine among schizophrenia relatives was the lowest among all the groups (3.5%, p = 0.003 compared to the GP). Since this group sample was not powered enough and since we did not obtain a probabilistic sample, this result suggesting a protective effect of the schizophrenia genotype on migraine, should be investigated further. 

Migraine, anxiety and personality disorders 

To expand the clinical perspective, this pilot study also considered three heterogeneous groups: anxiety, personality and all other disorders. The former group included patients with generalized anxiety, panic and obsessive-compulsive disorder. The second group encompassed most types of personality disorders, and the all other disorder group was mainly formed by patients in psychotherapy because of problems in interpersonal relationships. In consequence, the sample size in these three groups was not large enough to allow the analysis of specific disorders. 

Previous studies assessing the prevalence of migraine in anxiety disorders have mainly focused on panic disorders and phobias (17, 21-25). Recent studies reported the following figures for specific anxiety disorders: generalized anxiety disorder (3.0-14.6%), social phobia (3.0-6.7%), specific phobia (5.6-15.1%), panic disorder (4.6-5.6%), post-traumatic stress disorder (4.5%), and obsessive-compulsive disorder (2.2%) (17-49). In this study, the migraine frequency in the anxiety group (10.0%) was significantly lower than that observed in the GP (p = 0.02). 

Migraine, particularly without aura, has been associated with high levels of neuroticism (19, 50). It has also been shown that personality traits influence the migraine course in the long term (51). For example, in women above 60 years, the risk for active migraine was strongly associated with a history of stress susceptibility and high levels of somatic trait anxiety (21). Regarding specific personality disorders, migraine has been particularly associated with borderline personality (52). 

We present here the prevalence of migraine in a heterogeneous group of subjects with personality disorders as defined in the DSM-IV criteria without attempting a detailed subtype analysis. In our patients, 13.3% of the whole sample was classified as positive for migraine, and the frequency was clearly higher in women (15.6% vs. 4.8%). The global figure was lower (though no statistically significant) than that observed in the GP. 

Finally, the all other disorder group comprised patients in psychotherapeutic counseling (mainly marital disputes) and organic mental disorders. Their migraine frequency and that of their relatives was remarkably similar to that recorded in the GP. 

General discussion and limitations 

We did not find any diagnostic group with a significantly higher prevalence of migraine compared to values concurrently obtained from the GP. As has been reported by other researchers, subjects with depressive disorders had the highest frequency of migraine, and the highest female to male ratio was observed in the BPD group. Interestingly, the schizophrenia (p = 0.08) and the anxiety disorder (p = 0.02) groups and the first-degree relatives of schizophrenia (p = 0.003) and of BPD patients (p < 0.001) displayed rather lower levels than those observed in the GP. 

The comparison of our results with previous studies is hampered by methodological differences and limitations of our study, the most important ones being that we concurrently evaluated the GP and used a very short diagnostic instrument that did not discriminate between the different types of migraine and the presence of aura (53). Besides, we did not evaluate the disability degree, the frequency of specific mental disorders in patients with or without migraine (54), and the impact of comorbidity and illiteracy. Hence, the rather similar or lower frequency of migraine in several groups compared to the GP must be considered as preliminary results. Our findings did not provide any additional clue on the well-known impact of the migraine comorbidity on the clinical course of specific mental disorders. Besides, we could not control for overweight, tobacco and alcohol consumption. The GP was assessed with a probabilistic sample only in Mérida, whereas patients and relatives were selected with a non-probabilistic method that did not allow control for place of habitation. However, with the use of a simple diagnostic instrument, we have been able to confirm the importance of assessing migraine in psychiatric practice, hereby providing a testable hypotheses for future studies.

ACKNOWLEDGMENTS

This study was supported by FONACIT, Caracas, Venezuela, grant G-2005-000-384. We would like to thank the participating institutions, Dr. Françoise Salager-Meyer for her editorial assistance and the following colleagues who participated in the evaluation of the general population: Karla Abreu, Ricardo Salcedo, Heidy Delgado, Gustavo Sarmiento, Albis Pabón, Edgar López, Alfredo Pugliesse, Rosa Márquez, Yarira Araque, Sandy Durán, Bianca Birbal, Manuel Rengel and Johana Mogollón.

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