Migraine and depression: Association and familial transmission

J. psychiat. Res., Vol. 22, No. 2, pp. 119-129, 1988. Printed in Great Britain.

MIGRAINE

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0022-3956/88 $3.00+ .00 Pergamon Press pie

DEPRESSION:

FAMILIAL

ASSOCIATION

AND

TRANSMISSION

KaTrttEE~r R. MERIKANOAS*]"11, Neil J. Risch t~, JhMES R. Mwgw_a_~OAS*, MYgNA M. WmssM~'q§, and I~NNErI-I K. KmD*:~ *Department of Psychiatry, l'Departmentof Epidemiologyand PublicHealth and ~Departmentof Human Genetics, Yale UniversitySchoolof Medicine, New Haven, CT, U.S.A., §Department of Psychiatry, Collegeof Physicians and Surgeons of Columbia University, New York, NY, U.S.A. (Received 25 March 1987; revised 13 October 1987; accepted 4 December 1987)

Summary--We have studied the association between migraine and major depression in a group of 133 probands with major depression, a group of 82 normal community controls and 400 interviewed first-degree relatives of the probands and controls. There was a significant association between depression and migraine among both the probands and the relatives. We also found that concomitant symptoms of anxiety were prominent among the depressed persons with migraine. Both depression and migrainewere stronglyfamilial but their associationdid not appear to be highly transmissible. Rather, our data suggested that depression may either be a sequela of migraine or the diathesis which results in both migraine and depression. INTRODUCTION MIGRAINE headache is a highly prevalent condition in the general population. Lifetime prevalence estimates range from 4-19% for adult males and 8-29% for adult females (LnCET and STEW~RT, 1984). Although specific diagnostic criteria for migraine are controversial, usual definitions of migraine include the presence o f cyclic headaches associated with a variety of gastrointestinal and neurologic symptoms (AD H o c C O - - T r E E Or~ CL~SSWICAXlO~ Or H~AOACrm, 1962). The severity o f migraine ranges from mild to nearly total degrees of disability. Migraine is more c o m m o n among women, persons between the ages of 20 and 45, and those in upper socioeconomic groups (Cusp et al., 1977). There is striking similarity between the epidemiology o f migraine and that of so called " n e u r o t i c " psychiatric disorders, including depression and anxiety. Major depression is also a c o m m o n disorder with estimates o f lifetime prevalence ranging from 5 to 25% for women and 2 to 12% for men. Rates of depression are higher in women, young adults, and tend to decrease with increasing age (WvissMa_~ et al., 1984). The psychic manifestations of migraine, including confusion, depression, ill humor, impaired memory, terror and drowsiness were reported as early as 1873 ( L i w m o , 1873). The association between migraine and a particular constellation of personality traits including obsessionality, rigidity, excessive drive, and over conscientiousness has also been noted in clinical literature for over 50 yr (WoLff, 1937; HV.NR~K-GUTT and R ~ s , 1973). Although studies that employed systematic measurement o f these traits have failed to ~Address reprint requests to: Dr Kathleen R. Merikangas, Yale University School of Medicine, Department of Psychiatry, 350 Congress Avenue, New Haven, CT 06519, U.S.A. 119

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confirm this association (LINET and STEWART, 1984; CRISP et al., 1977; FRIEDMAN, 1982), the validity of measurement o f such subjective traits is highly questionable. There are several studies that have examined the association between migraine and psychiatric symptom patterns or disorders among patients in treatment for migraine (MoERSCH, 1924, SV.LBYand L~cv., 1960; KASHINVAGIet aL, 1972; COUCH et aL, 1975; KUDROW, 1978), patients in treatment for depression (CASSIDYet al., 1957; DIAMOND, 1964; GARV~Yet al., 1984), and subjects from the general population (CgISr et al., 1977; PAULING et al., 1985). Most of these studies provide evidence for an association between migraine and either depression or anxiety. However, wide variability in the magnitude of the association, sex differences in the association, and different symptom patterns involved in the association were observed. The lack of consistency in the findings can be partially attributed to the following differences in methodology: definitions of migraine, measurement of psychopathology, and sample characteristics. Most of these studies have been based on data from symptom checklists administered to clinical samples. Few studies have been controlled or conducted with epidemiologic samples from the community to address the potential bias of increased treatment seeking among persons with both disorders. Systematic diagnostic interviews with established reliability and validity were rarely employed. Nevertheless, despite the methodologic variability, there was only one uncontrolled study in which no association between migraine and depression was observed (G,~RVEY et al., 1984). Migraine is a familial disorder with approximately 36-710/0 positive family history reported among probands with migraine. The results of most, but not all, twin studies of migraine have suggested that genetic factors account for a significant degree of the variance of the trait. Two-to-seven fold increases in monozygotic versus dizygotic concordance rates have been reported (HARvALDand HAUGE, 1956; ZIEGLERet al., 1975; LUCAS, 1977). Depression has also been shown to be familial with a 1.5-fold to 3-fold greater risk of depression among relatives of depressed probands (WEIsSMANet aL, 1982). The results of twin and cross-fostering studies have suggested the involvement of genetic factors in the etiology of some types of depression. The observation that monozygotic twin concordance rates for non-bipolar depression, which range from 35 to 50°70 are significantly less than 10007o also underscores the importance of non-genetic factors in the etiology of depression (GERsHON et al., 1976). The present study was designed to compare the association and patterns of familial transmission among patients in treatment for depression, normal controls drawn from a community sample, and their interviewed first-degree relatives.

SUBJECTS A N D METHODS

Subjects Data for this analysis were collected in the Yale University Family-Genetic Studies of Depressive Disorders (WPIsSMANet al., 1982). There were 133 probands (i.e. index cases) with non-bipolar major depression defined according to modified Research Diagnostic Criteria (RDC) (SPITZERet aL, 1978) and 82 controls with no history of psychiatric illness or treatment either by history or at three interviews obtained between 1967 and 1976. Subjects

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for the present analysis were the 400 interviewed first-degree relatives, which included parents, siblings, and offspring over the age of 18.

Methods Complete pedigrees for each proband were systematically obtained and lifetime diagnostic assessments according to RDC or every living or deceased first degree relative. A best estimate diagnostic procedure was employed in which information from both the direct structured interview and from multiple informants and medical records was pooled in order to make diagnoses of the relatives. All diagnoses were made blindly with respect to the status of the proband. Lifetime history of migraine was also assessed via direct interview. Because the study was not originally designed to assess migraine, systematic data on symptoms, frequency, duration, and treatment were not collected. Therefore, the amount of information on migraine was highly variable. A review of the information from interviewers' notes by a neurologist (J.M.) revealed that sufficient data were available to make a probable or definite diagnosis of migraine in 56% of those persons who reported a positive history. The other subjects reported a positive history of migraine without describing specific details of clinical symptoms or treatment. Only two persons who responded positively to the migraine probe and gave a clinical description of headaches did not meet criteria for migraine. Data from other sources show that the sensitivity of self-report of the presence of migraine is quite high, with approximately 88% of the true cases being detected, and a very low false negative rate has been reported (CRISPet al., 1977; WATERS and O'CONNOR, 1975). Because of the longitudinal design of our study, we were able to examine the consistency of reporting of migraine over time. At the six year follow-up, we found that 86o7o of the subjects who reported the presence of migraine did so at the second interview as well. Logistic regression analysis In the present study, logistic regression, a specific type of log-linear analysis, was used. Logistic regression is analogous to standard multiple linear regression and is appropriate when the outcome variable is binary, (Cox, 1970). In logistic regression analysis, a logistic transformation of the dependent variable is made, which yields the logit or log odds (EWRITT, 1977). The multiplicative factor by which the odds increase or decrease with changes in the predictor variables is then determined. The contribution of each predictor can be assessed independently of the possible effects of other predictors (BISHOPet ai, 1975). In this report, the aim of the statistical analysis was to compare the relative frequency of migraine and depression in first degree relatives according to the presence of these conditions in the probands. Since other variables are also related to the frequency of migraine in relatives, the effects of the following variables were examined: Sex of relative (male vs female); Age (18-29 yr; 30-44 yr; over 45 yr). The measure of association between levels of the independent variables with the response variable in the analysis was the odds ratio, which is the multiplicative factor relating the predictor to the outcome. A statistical test of significance of effects in the models was the Likelihood Ratio x2. The computer analysis was conducted using the Logist Procedure of the Statistical Analysis System ( R ~ T , 1980).

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Proportional hazards analysis The proportional hazards (PH) model, a general quasiparametric multivariate model introduced by Cox, was used to analyze the data (Cox, 1972; LEE, 1980). The PH model applies the multiple-regression method to a survival distribution, or another one-time event such as onset of a disorder, The PH procedure yields a ratio of the hazards, or the agespecific incidence, of the outcome variables (i.e. diagnosis of relatives) for the groups of interest, while simultaneously controlling for other independent variables that may be related to the outcome. A stepwise model with all main effects and two-way interactions was used to fit the data. Statistical significance of the effects was determined by the X2 statistic using Maximum Likelihood Estimates. The computer program used in the analysis was the Proportional Hazards General Linear Models procedure of the Statistical Analysis System (RP.I~t-ta~DT, 1980).

Co-segregation analysis The model that we used to study the co-transmission of the two disorders was a bivariate polygenic threshold model. This is a generalization of the general multifactorial model of disease transmission originally proposed by FALCONER(1965) (Fig. 1). The liability, or propensity for transmitting the disorder, is plotted on the y-axis. The shaded sections represent the proportion of affected individuals. The multifactorial model specifies that numerous genetic and environmental factors are involved in an individual's liability for a particular disorder. The liability is assumed to be normally distributed with a mean of 0 and a variance of 1. The threshold T is defined as the point after which the disorder becomes manifest. The location of T is determined by the population prevalence of the disorder (i.e. the area under the normal curve beyond 7). This model was extended to a bivariate multifactorial model to determine whether the association between two traits could be attributed to familial (transmitted) or non-familial (non-transmitted) factors. The analysis is based on frequencies of both traits among the relatives of probands with different diagnoses (e.g. none or both traits). REICHet aL (1972) further extended the bivariate method to nuclear families as the unit of analysis, which provides additional power, but considerably greater computational complexity.

Affected

I LIABILITY

:t,.

T

M=0 E=I FIo. 1. Polygenic thresholds model of disease transmission.

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TABLE 1. PARAMETERS OF POLYGENIC

(MULTIFACTORIAL) THRESHOLD MODEL FOR CO-TRANSMISSION OF DEPRESSION AND MIGRAINE

Td Threshold for depression Tm Threshold for migraine

Components o f variance H d Unique transmitted component for depression H m Unique transmitted component for migraine r2H Correlations between heritable components r2E Correlations between environmental components E d Unique random environmental component for depression ( 1 - H d ) E m Unique random environmental component for migraine (1-Hm)

The model employed here is described by Surrn (1976). We assume two distinct continuous liabilities underlying depression and migraine. The liabilities are assumed to have a bivariate normal distribution, whose correlation is determined by both transmitted and non-transmitted components. The following parameters of the model are given in Table 1: two threshold values Td and Tm for depression and migraine, respectively; the heritabilities Hd and Hm for depression and migraine, respectively; the random environmental components Ed = 1 -- Hd and Era, respectively; and the correlations between the heritable components, (r2~) and the environmental components (r2E) for the two traits, respectively. Hence, there are six independent parameters. The unit of analysis is the frequency of the four possible disease outcomes (depression and migraine, depression only, migraine only, normal) among the relatives of the four different types of probands, yielding a total of 12 independent cells. The formulas for determining these rates in terms of the model parameters have been given by SmTH (1976). Because there are 12 independent cells and six model parameters, it is possible to perform an overall goodness-of-fit test of the model. Here we perform a likelihood ratio X2 goodness-of-fit test with six degrees of freedom. To test hypotheses about significance of various parameters, we perform likelihood ratio tests, which have an asymptomtic X2 distribution with one degree of freedom (for each variance component set equal to zero). Likelihoods for this model were obtained with the Fortran computer program COSEG (Risch N., an unpublished FORTRAN program for multivariate polygenic threshold analysis). Likelihoods were maximized under the program MAXLIK (KAPL~ and ELSTON, 1972). RESULTS

There was a total of 86 persons with a history of migraine, of whom 71% were females and 29°/o were males. The mean age of onset of migraine in this sample was 22.4 yr. In accordance with previous studies, we showed that depression was familial (WEISS~t~N et al., 1982). There was a two-fold increase in rates of depression among the interviewed relatives of depressed compared to normal probands (22 vs 1007o respectively). Similarly, migraine was also found to be familial. Relatives of probands with migraine were significantly more likely to have migraine than were relatives of probands without migraine (i.e. 21 vs 10070 respectively). There was a strong association between the diagnoses of depression and migraine among

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KATI:ILEEN R. MEIHKANGASet al. TABLE 2. RATES OF MAJOR DEPRESSION IN RELATIVES OF DEPRESSED AND NORMAL PROBANDS BY PRESENCE OR ABSENCE OF MIGRAINE

Rates/100 major depression in relatives Migraine Migraine Relative present absent risk Depressed proband

41.3

20.1

2.1

Normal proband

26.3

7.6

3.5

All

35.4

15.9

2.2

Relatives

the probands, with 18.7% of the 133 depressed vs 7% of the 82 normal probands reporting a history of migraine (odds ratio = 2.9). Likewise, migraine and major depression were associated among the interviewed firstdegree relatives. Twenty-three percent of the relatives with major depression had migraine as compared to 9.5°7o of the relatives without major depression (relative risk=2.5). Conversely, thirty-five percent of the relatives with migraine had major depression as compared to 16% of the relatives without migraine (Table 2). The increased risk of major depression among relatives with migraine was found both among the relatives of depressed probands and those of normal controls. The potentially confounding effects of sex and birth cohort of the relative were controlled in a proportional hazards analysis, which examined the effects of depression and migraine in the probands and migraine in the relatives, on the age-specific incidence of major depression in the relatives (Table 3). After controlling for the effects of sex and age of the relative and history of depression and migraine in the proband, there was a significantly elevated ratio of the hazard of depression among relatives with migraine compared to that for relatives without migraine. A similar analysis was conducted to examine the effects of major depression in the relative on the risk of migraine among relatives, after controlling for age and sex of the relative, and migraine and depression in the proband. The analysis described in Table 3 was also conducted via logistic regression in order to examine the comparability of the two methods. Logistic regression rather than a proportional hazard analysis was conducted because reliable data on age-of-onset of migraine among the relatives were not available. The results of these analyses are presented in Table 4. Only models providing the best fit to the data are shown. TABLE 3. RATIO OF HAZARDSOY MAJORDEPRESSIONAMONGRELATIVES

Depression in proband Migraine in proband Migraine in relative

95°70 Ratio of hazards*

Confidence limits

P

2.40 1.32 2.45

1.36-4.24 0.78-2.25 1.41-4.23

0.002 N.S. 0.003

*Controls for effects of year of birth of rdative and sex of relative.

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TABLE 4. EFFECTS OF BEST FITTING LOGISTIC REGRESSION MODELS OF MIGRAINE AND DEPRESSION IN RELATIVES

Effects in model (Odds ratio/95% confidence intervals) Relatives (N= 400) Migraine Depression

Factor Migraine in proband Depression in proband Depression in relative Migraine in relative Sex of relative

2.1 (1.03-4.3) 0.6 (0.3-1.13) 2.9 (1.5-5.7):~

1.5 (0.8-2.8) 2.7 (1.4-5.1)~:

1.9 (1.01-3.9)*

3.0 (1.5-6.0)* 1.2 (0.7-2.5)

* =P < 0.05 "~=P< 0.01 ;~=P < 0.001 These results confirm the above-cited significant degree of familial transmission o f migraine after controlling for age and sex of the relative, as well as the above-cited association betwen depression and migraine a m o n g the relatives. The lack of a significant effect of depression in probands on migraine in relatives and the converse, suggest that the association between depression and migraine does not result f r o m transmissible factors which predispose to either disorder or both. The expectation f r o m the latter explanation for the association is that the effects of both migraine and depression in probands should significantly predict migraine among the relatives. However, this expectation was not met for either of the two disorders. Table 5 presents the mutually exclusive categorization of the probands and relatives according to the presence or absence o f migraine and depression. These data show that both depression and migraine are transmitted. However, we were interested in determining whether they shared a transmissible factor or factors that could account for their association. The data in this table were used as a basis for the subsequent polygenic threshold analysis. Table 6 shows the results of the bivariate polygenic threshold analysis for the full model and the other models which fixed the correlations at 0. Significant components in the full model included the heritability for depression (i.e. 0.631), and the heritability for migraine (i.e. 0.605). Both the correlation in the heritability and the correlation in environmental components for the two disorders were positive, but not significant. The model which set TABLE5. CATEGORIZATION OF PROBANDS AND RELATIVES BY PRESENCE OR ABSENCE OF MIGRAINE AND DEPRESSION

Relatives Depressed Not-depressed Migraine No migraine Migraine No migraine N (°70) N (°70) N (°70) N (°70)

Probands Depressed

Migraine No migraine

Not depressed Migraine No migraine

5 7

(9.4) 11 (20.8) 4 (7.6) 33 (62.3) (3.3) 36 (17.1) 13 (6.7)154 (73.3)

2 (10.0) 1 3 (2.6) 8

(5.0) 4 (20.0) 13 (65.0) (6.8) 10 (8.6) 96 (82.1)

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al.

TABLE6. PARA~TERESTIMATESANDSTANDAI~DEI~OgSOFPOLYGENIC(MOLTIFACTORIAL) TI-IRESItOLD M O D E L S F O R C O - T R A N S M I S S I O N OF D E P R E S S I O N A N D M I G R A I N E

Full model Td Tm Hd Hm rH rE -21nL

1.274 1.340 0.631 0.605 0.200 0.497

(0.147) (0.138) (0.182) (0.258) (0.267) (0.465)

650.16

Model I 1.248 1.265 0.616 0.582

(0.144) (0.094) (0.184) (0.264) 0 0.730 (0.360)

Model II 1.302 1.434 0.631 0.612 0.441

650.71

(0.145) (0.111) (0.181) (0.245) (0.178) 0

651.44

Model III 1.269 1.276 0.622 0.549

(0.145) (0.094) (0.177) (0.227) 0 0

658.50

both correlations to zero (Model III) was rejected (X2= 8.34, 2 d.f., P < 0.05) (giving significant evidence for association between the two traits); however, the models excluding either correlation alone were not rejected (X2=0.55, 1 d.f., and x2=1.28, 1 d.f., respectively for Models I and II). Hence, we could not definitively resolve whether the source o f correlation between the two disorders was attributable to a transmissible or a non-transmissible c o m m o n component or both. The goodness-of-fit of the full model was 6.52 with six degrees of freedom, indicating an acceptable fit of the model to the data. For the full model, the heritability of migraine was 0.61 and that of depression was 0.63. This indicates that a large proportion of the variance in each of these disorders can be attributed to transmissible factors. DISCUSSION The results of the present study confirm those of previous studies that have demonstrated a relationship between major depression and migraine. This association was observed among probands in treatment for depression, their first-degree relatives, and relatives of normal controls who were selected at random from the population. The strong relationship between depression and migraine in the latter sample enabled us to exclude the hypothesis that the association was an artifact of treatment-seeking bias among individuals with both disorders. However, persons with both migraine and depression were rarely characterized as " p u r e " depressives. More than 75°70 of the depressed persons with migraine also reported a history o f anxiety including phobias, panic attacks, a n d / o r generalized anxiety. The s y m p t o m profile and course of these subjects will be described in a separate report. Rates of the other m a j o r psychiatric disorders such as alcoholism, drug abuse, antisocial personality, obsessive-compulsive disorder, and schizophrenia were not significantly different among the migraine vs non-migraine subjects. These data also confirm the well-known familial aggregation of both depression and migraine. However, the familial transmission of the association has not been previously studied. Application of the polygenic threshold model enabled us to explore several alternative explanations for the association between depression and migraine headache. The bivariate threshold model could not conclusively distinguish whether the association between migraine and depression is transmissible or not, although a shared liability was indicated. However, the results of the logistic regression analysis provided more suggestive evidence for an environmental association between migraine and depression. This

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interpretation is based on the finding that depression in the relative was a stronger predictor of migraine in the relative than was depression in the proband. Similarly, migraine in the relative was more strongly associated with depression in the relative than was migraine in the proband. Evidence for a transmissible common component would be derived from a stronger association between depression in the proband and migraine in the relative after controlling for migraine in the proband and the converse. Neither of these findings was observed in our data. Further examination of Table 4 reveals a moderate increase in depression among the relatives of probands with migraine. With stratification for migraine among the relatives, a highly significant association emerged between migraine in the proband and depression in the relatives who also have migraine. Taken together with the above findings, this suggests that neither a transmissible nor a non-transmissible association alone provides an adequate explanation of the data. An interpretation that would be more consistent with our findings would be the existence of a non-transmitted intervening factor that either simultaneously lowers the threshold or leads to a predisposition to both disorders. This factor could be an endogenous factor or event such as a viral infection, a head injury, or a dietary agent. There are several possible biological and psychological mechanisms that could explain this type of association between migraine and depression. Because disturbances in the same neurochemicai systems have been implicated in both disorders (MoI-II,lS, 1980) perturbation of a particular system or systems related to migraine may decrease the threshold for depression and precipitate affective symptoms. The efficacy of antidepressant drugs in the treatment of migraine regardless of the presence of depression, would further support this hypothesis (ColJcI-I, 1976). However, because these agents effect diverse neurochemical systems, etiologic inferences from selective drug response are not valid. Iatrogenic factors could also explain a non-transmissible association between migraine and depression. That is, depression could be secondary to drug treatment of the migraine. A significantly higher proportion of the migraine subjects (i.e. 65°70 as compared with the non-migrainous in our sample) had a history of use of medication for non-psychiatric disorders. Furthermore, the majority of individuals with migraine report a history of use of medications to alleviate the pain associated with headaches. Therefore, it would be possible to evaluate systematically this explanation. Another explanation for a non-transmissible association is that the chronic incapacitation in social functioning which results from migraine could lead to symptoms of depression. This has been suggested by several clinicians who have treated migraine patients for long periods of time (FRmDMAN, 1982). This explanation could also be evaluated by measuring depression as a function of chronicity or treatment response in migraine subjects. Our findings must be viewed as preliminary due to the lack of systematic symptom data and clinical evaluation of migraine and the relatively small sample size which precludes our distinguishing with certainty between the models in our threshold analyses. Nevertheless, these findings warrant further study and have possible implications for treatment intervention with persons with migraine. Early and vigorous treatment of migraine headaches may prevent the occurrence of incapacitating major depression.

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Acknowledgements--This work was supported in part by Alcohol, Drug Abuse and Mental Health Administration Grants MH28274 from the Centre for Epidemiologic Studies; by the Center for Studies of Affective Disorders; and Research Scientist Development Award MH00499 from the National Institute of Mental Health (Dr K. Merikangas) and Research Career Development Award HD00648 from the National Institute of Health (Dr Risch). We are grateful to Theodore Reich, M.D. for his helpful comments on this manuscript.

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