Prospective Associations between Somatic Illness and Mental Illness from Childhood to Adulthood

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1 American Journal of Epidemiology Copyright 1998 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved Vol. 147, No. 3 Printed in U.S.A. ORIGIL CONTRIBUTIONS Prospective Associations between Somatic Illness and Mental Illness from Childhood to Adulthood Patricia Cohen, 1 " 3 Daniel S. Pine, 23 Aviva Must, 4 Stephanie Kasen, 23 and Judith Brook 5 The association between somatic illness and psychiatric illness is well established in adults but is less clear in childhood and adolescence. A cohort of over 700 randomly selected children in Upstate New York were studied from ages 1-10 years in 1975 to young adulthood in Psychiatric and physical health were assessed by means of follow-up youth and parent interviews at 8-, 2V2-, and 6-year intervals (in 1983, , and ). Cross-sectional and longitudinal analyses investigated: 1) the consistency of the relation between physical illness and mental illness in childhood; 2) the specificity of major depressive disorder (MDD) in accounting for the relation; 3) the specificity of immunologically mediated medical disorders in this relation; and 4) whether this relation was attributable to risks associated with low socioeconomic status. Cross-sectionally, ill health was associated with increased risk of psychiatric disorders at all ages, with significant odds ratios (ORs) ranging from 1.76 to In prospective analyses, ill health increased the risk of new-onset MDD at all ages (ORs = ). MDD also predicted subsequent ill health, independent of prior health problems (ORs = 3.81 and 4.04). Relations were not attributable to familial socioeconomic status. Associations were particularly strong between MDD and medical disorders associated with alterations in immunologic factors (ORs = ). Theories of common immune-mediated vulnerabilities to medical illness and depression are consistent with these associations. Am J Epidemiol 1998; 147: child; depression; health; mental disorders A large body of research has established an association between depression and physical illness (1-6). This association is found in a variety of sampling frames, including the clinic and the community (6-8), as well as in a wide age range from adolescence (9-11) to old age (12, 13). The underlying mechanisms for this association, however, are not yet entirely clear: Either 1) somatic illness may produce stress (a psychological and physiologic process (14)), which contributes to the development of depression; 2) depression may affect the course of physical illness because of associated health-relevant behaviors; or Received for publication February 6, 1997, and in final form September 9, Abbreviations: DISC, Diagnostic Interview Schedule for Children; MDD, major depressive disorder. 1 Division of Epidemiology, School of Public Health, Columbia University, New York, NY. 2 Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY. 3 New York State Psychiatric Institute, New York, NY. 4 Department of Family Medicine and Community Health, School of Medicine, Tufts University, Medford, MA. 5 Department of Community Health, Mt. Sinai School of Medicine, New York, NY. Reprint requests to Dr. Patricia Cohen, New York State Psychiatric Institute, Box 47, 722 West 168th Street, New York, NY ) common biologic vulnerabilities or environmental risks may account for the association. Because any of these causal processes may have become self-perpetuating by adulthood, investigation of these relations in childhood should provide us with key insights for understanding possible mechanisms. Several studies in young people have compared children with serious chronic illness with controls. In general, the conclusion drawn from such studies is that, with the exception of children suffering from conditions directly involving the nervous system, psychiatric disorders are not more frequent in chronically ill children than in their healthy counterparts (15 17). Most such studies of somatic and mental illness use symptom inventories to assess psychiatric problems. Such studies may be insensitive to some forms of psychopathology in comparison with full diagnostic interviews (7, 8). Other studies are based on clinically referred samples which may have limited generalizability (6). This investigation examined the association between physical illness and major depressive disorder (MDD) in an epidemiologic sample of more than 700 children studied from early childhood through 232

2 Relation between Somatic Illness and Mental Illness 233 adulthood. The children were assessed by means of structured psychiatric diagnostic interviews with both the young people and parental informants. Three central questions on the nature of the association between childhood physical illness and MDD were addressed. First, is physical illness in childhood associated with adult MDD, independent of earlier MDD? Although a few studies have examined the cross-sectional relation between physical illness and adolescent MDD using structured interviews based on the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, only one study examined such associations prospectively, following adolescents over a 1-year period (11). These studies suggest that physical illness is related to adolescent MDD, but it is unclear whether earlier MDD accounts for this relation. Longitudinal data are needed to provide insights on the causal pathways linking somatic illness and MDD. For example, if long term predictability is absent, it is likely that relatively temporary effects of stress or relevant behavioral changes may mediate this relation. If longer term prospective relations are established between somatic illness and MDD after having controlled for previous MDD, causal effects of somatic illness on MDD or a common environmental or biologic pathogenesis is more probable. In the current study, we examined cross-sectional associations between illness and MDD, short term prospective associations over a period of 2Vi years, and long term associations over periods of 6-8 years. Second, is there specificity of the relation between somatic illness and MDD as compared with mental illness more generally? If somatic and psychiatric illness in general are related, it is more probable that these relations result from environmental risks shared by several psychopathologies, such as poverty, family dissolution, and maternal psychopathology and related maladaptive child-rearing practices. However, if the relation is relatively specific to MDD, a biologic paradigm is more likely, although environmental factors are not ruled out. Finally, is the relation of somatic illness to MDD specific to one type of illness, or general to somatic health? Most epidemiologic studies of the association between major depression and physical illness have relied on global ratings of physical illness, derived by summing responses to a series of questions about illnesses and injuries (9-11). Studies of adults suggest that the association between MDD and overall health may result from relations between MDD and specific pathophysiologic processes also implicated in somatic illness. For example, MDD appears to be associated with deficits in immunologic function (18, 19), raising questions about the nature of associations between immunologically mediated medical diseases and adolescent depression. Such diseases include allergic or infectious illnesses. Preliminary evidence suggests that such somatic diseases are related to both depressive disorders and anxiety disorders in children and adults (19-21). The current study explored these issues by using both global indices of illness and more specific indices of immunologically related diseases. In summary, this study addresses three specific issues related to the association between somatic illness and psychiatric disorders in childhood and adolescence: 1) the extent to which cross-sectional relations between the constructs are observed prospectively; 2) the degree of specificity among mental illnesses; and 3) the degree of specificity among physical illnesses. MATERIALS AND METHODS Study population The study sample consisted of a cohort of 976 young people who were randomly selected in 1975 from age-eligible children living in an equal number of randomly selected households in two semirural Upstate New York counties (22). At that time, the children in the sample ranged in age from 1 year to 10 years; 85 percent of eligible families participated. s were interviewed with regard to health, development, behavior, parenting, and a range of other factors relevant to the children's well-being. The first follow-up survey was initiated in 1983 when the children were aged 9-18 years. At that time, 54 families from a low-income urban area were randomly sampled to replace selective losses due to failure to locate original participants. With this supplement, the sample of 776 youths closely matched US Census characteristics of the area (23). The sample as a whole covered a wide range of socioeconomic status; included substantial representation of rural, suburban, and urban areas; was more than 50 percent Catholic; and was 8 percent black and 49 percent female. Other ethnic minorities were present only in very small numbers. s and youths were interviewed separately but simultaneously in their homes, with a protocol that included questions on the child's health and a fully structured psychiatric diagnostic interview (24). Additional follow-up interviews of youths and parents were conducted in 1986 ( ) and 1992 ( ); each time, 96 percent of the follow-up families were seen, and 830 families were seen for two or more assessments.

3 234 Cohen et al. Measures Assessment of psychiatric disorders. In 1983 and 1986, parent and child interviews established the presence of various psychiatric disorders by assessing diagnostic criteria (25), using a modification of the highly structured Diagnostic Interview Schedule for Children (DISC) (26). In 1992, young adults (but not parents) provided diagnostic information using an expanded DISC devised for this purpose. Because crossinformant agreement is invariably poor (27), a number of options have been proposed for combining information obtained from parent and child informants. In accordance with current practice, diagnoses were made when diagnostic criteria were met according to the information provided by either self-report or parental report. Diagnoses were further refined by incorporating the degree of elevated symptomatology/ impairment by combined reports, to define disorder of severity more comparable to that of clinical cases. This method of combining information tends to balance concerns about sensitivity and problems with specificity (28). The reliability of the DISC has been extensively studied (29, 30). Test-retest reliability is comparable to that of other instruments; the 2- to 4-week test-retest kappa value for major depression is generally in the range. Full details on the prevalence of various psychiatric disorders in this sample, by age and sex, are provided elsewhere (31). The most prevalent diagnoses at these ages were conduct disorder, opposition/defiance disorder, and anxiety disorders. Comorbidity among these disorders is common, with approximately two thirds of all children with one diagnosis having at least one other diagnosis. For these analyses, we examined both the presence of any one or more disorders and MDD specifically. Assessment of somatic illness. Questions regarding health status in this study were similar to those employed in the National Health Interview Survey (32). They included days missed from school, hospitalizations, medications, an overall health rating, a checklist of chronic conditions (e.g., heart problems, chronic respiratory conditions, chronic pain, orthopedic problems), and the duration and extent of impairment associated with these chronic conditions. We omitted consideration of injury-related problems in this study, as there is reason to be concerned that their inclusion may result in poor specificity of outcome. When children were aged 1-10 years, information on health status was provided by the mothers only. Both parents and children provided information in 1983 and 1986; but overall illness measures from parents and youths were analyzed separately, both because of the possibility of depression's influencing youth responses to questions on somatic illness and because separate consideration allows for quasi-replication of findings. For the young adult (1992) analyses, we had data on somatic illness from the youth interviews only, but we also had information on specific chronic diseases from the parent interviews, which was combined with information on these diseases obtained from the young people. When information about the specific illnesses investigated in this study was available from both sources, the measure used considered illness to have been present when so indicated by either respondent. Analyses were also carried out for illnesses reported by only one informant: These analyses were consistent, but they had larger confidence intervals because of the lower prevalences (data not shown). Because the questions asked in different data waves combined atopic illnesses in different ways, we also included as a separate item the presence of any hay fever, allergies, or asthma. Infectious mononucleosis was included in the third wave of assessments only. In addition to individual illnesses, we created a summary measure to reflect overall illness status. Because of sample size limitations and because of minor variations in how health was assessed at different follow-up points, this summary measure combined all illness-related information additively into a single index. This procedure, employed previously in several studies of childhood health status (9-11, 32), increased the statistical power of the analysis for factors associated with these positively correlated health indicators, and improved the consistency of the findings across the four waves of data collection in comparison with the separate items. The illness score consisted of the sum of overall health rating, number of days missed from school or work due to illness, proportion of the previous year in which the youth was impaired because of chronic illness, and extent of impairment due to chronic illness, each measured on a four-point scale, plus the number of chronic conditions. This score was converted to percentage of the maximum possible score, assuming a maximum of three chronic illnesses. The resulting mean values are presented in table 1. Variation in means from one wave of data collection to the next may be attributable to changes in the number or wording of items, rather than a consequence of age effects; however, we had no data with which to directly discriminate between these alternatives. Children whose scores exceeded one standard deviation above the sample mean were considered "ill," in contrast to the remainder of the sample. In the maternal interviews conducted when the children were aged 1-10 years, questions regarding illnessassociated impairment and days missed from school

4 Relation between Somatic Illness and Mental Illness 235 TABLE 1. Prevalence of psychiatric disorders and somatic illnesses among children in two Upstate New York counties, * \fear(s) of data collection Mean age (years) (2.8)t (2.7) 1986 ( ) (2.8) 1992 ( ) (2.7) Prevalence of psychiatric disorder (no. with disorder/total no.) Any psychiatric disorder Major depressive disorder Atopic illnesses Asthma Allergies Hay fever Any atopic illness Mononucleosis High level of mother-reported illness Mean mother report score# High level of youth-reported illness Mean youth report score* $ 36/776 (5%) 127/776 (16%) 29/776 (4%) 67H/774 (9%) 233/774 (30%) 11.2(18.3) Ki A INM 140/776 (18%) 25/776 (3%) 100/770 (13%) 12.3 (6.9) 114/760(15%) 11.0(6.7) 124/776 (16%) 22/776 (3%) 235/748(31%) 47/748 (6%) 102/776(13%) 16.1 (11.2) 97/748(13%) 19.9(11.8) 237/776 (31%) 67/717 (9%) 252/751 (34%) MA 112/750(15%) 21.5(14.1) * A total of 776 families participated in each wave of data collection and at least one other wave, t Numbers in parentheses, standard deviation or percentage. $, question not asked at that time. Includes 1.1% with dysthmyia. Cases with dysthmyia in earlier assessments also met criteria for major depressive disorder. D Any atopic illness reported in that interview and less than excellent health. # Score is represented as the percentage of the maximum possible illness score based on all items asked at that time. were not asked; a simple dichotomization of the mother's overall health rating for the child defined the "ill" group for this wave. Data analysis We used logistic regression to explore the crosssectional and prospective relations between somatic illness and psychiatric illness. Cross-sectional associations between indices of somatic and psychiatric illness were estimated as odds ratios, both raw and adjusted (adjusted for age, sex, and socioeconomic status). Socioeconomic status was measured by a composite of parental education, occupational status, and family income described elsewhere (33). To explore the specificity of associations for MDD as opposed to psychopathology in general, we carried out logistic regression analyses for any psychiatric diagnosis versus no diagnosis, excluding cases with MDD, and for MDD versus no MDD. To explore the specificity of associations for immunologically mediated illnesses, we compared analyses employing illness status with analyses employing measures of immunologically mediated illness only. Prospective associations between somatic illness and psychopathology were examined using a similar strategy. Because of the low prevalence of most of the disorders investigated here (table 1), it was not feasible to stratify the sample by age or sex. All relations described here were tested for interactions with age and sex, and no evidence of significant variation by these demographic variables was seen. RESULTS The prevalences of psychiatric disorders at each of the four assessments are presented in table 1. As noted above, variations in illness status across ages may represent differences in the questions and in the rater (maternal report vs. self-report). Prevalences of MDD were low, except in young adulthood, and MDD represented only a relatively small fraction of childhood psychiatric disorders. Table 2 presents cross-sectional associations between psychiatric and somatic illness, using both youth and parental reports of somatic illness. Seven of 10 odds ratios had 95 percent confidence intervals that excluded 1.0, suggesting significant associations between somatic and psychiatric illness, both for MDD and for any other disorder, using cross-sectional data. Point estimates were generally similar across informants and for MDD and other disorders, suggesting moderately strong associations. Table 3 presents data on the prospective relation between somatic illness and psychiatric disorders, controlling for psychiatric disorders concurrent with earlier somatic illness. The relations were examined

5 236 Cohen et al. TABLE 2. Cross-sectional odds ratios for major depressive disorder (MDD) and other psychiatric disorders associated with youth- and mother-reported somatic illness, New York State, Psychiatric disorder and illness report MDD Youth 1983 (mean age, 13.7 years) (n = 776) OR«,t * (mean age, 16.0 years) (n = 776) (mean age, 22.1 years) (n=717) * Other disorders Youth * OR, odds ratio; Cl, confidence interval;, not asked, t Adjusted for age and sex. over four waves of data collection, from the mean age of 5.7 years to 13.7 years, 16.0 years, and 22.1 years. These analyses also controlled for familial socioeconomic status. Parallel analyses that did not control for socioeconomic status produced odds ratios that were slightly larger, but did not alter the overall pattern. Illness status was not related significantly to psychiatric disorders when cases of MDD were removed. However, illness status as reported by one or another informant prospectively predicted future MDD across all three intervals. The significant odds ratios were in the range for the prediction of depression from age 5.7 to age 13.7 and, using youth-reported illness, from age 13.7 to age 16, suggesting a moderately large association of a magnitude at least comparable to that of the cross-sectional relations. All relations predicting subsequent psychiatric illness were significant when prior psychiatric disorder was not controlled (data not shown). Thus, the prospective data suggesting a causal link are stronger for the connection of somatic illness to subsequent MDD than they are for the relation of somatic illness to other psychiatric disorders. TABLE Table 4 presents the odds ratios for subsequent ill health among youths with and without MDD and youths with and without other psychiatric disorders, controlling for prior illness, age, sex, and familial socioeconomic status. Because MDD was not diagnosed in 1975, these analyses only considered changes from mean ages 13.7 years to 16 years and 16 years to 22.1 years. For both periods, MDD was associated with subsequent ill health, with odds ratios of approximately 4.0 in both the adolescent interval and the adolescent-young adult interval. When the analyses were restricted to subjects with and without psychiatric illness other than MDD, no comparable associations were apparent. Table 5 presents data on the prospective relation between particular somatic illnesses (those defined as immunologically mediated) and subsequent new-onset MDD. These associations were examined separately for hay fever, allergies, asthma, and infectious mononucleosis, as well as for a combined item indicating the presence of any of the first three illnesses. The prospective relation between somatic illness and future Odds ratios for psychiatric disorder associated with prior somatic illness, New York State, Follow-up interval (from mean age 5.7 to mean age 13.7)$ (n = 720) Illness report Major depressive disorder (MDD) OR*,t 3.53 * Psychiatric disorders other than MDD (from mean age 13.7 to mean age 16.0) (n = 734) Youth (from mean age 16.0 to mean age 22.1) (n = 685) Youth * OR, odds ratio; Cl, confidence interval. t Adjusted for age, sex, socioeconomic status, and the same psychiatric disorder indicator measured at the earlier time. $ Information on prior psychiatric disorders was not available.

6 Relation between Somatic Illness and Mental Illness 237 TABLE 4. Odds ratio* for youth-reported somatic illness associated with prior psychiatric disorder, New York State, Follow-up Interval Predicted Irom major depressive disorder OR'.t» Predicted from other psychiatric disorders (from mean age 13.7 to mean age 16.0) (n = 734) (from mean age 16.0 to mean age 22.1) (n = 737) * OR, odds ratio; Cl, confidence interval. t Adjusted for age, sex, prior illness, and socioeconomic status. depression may be particularly strong for illnesses that are immunologically mediated. Relations were statistically significant for mononucleosis, hay fever, and the combined index of hay fever, asthma, and allergies, but not for either asthma or allergies alone. Point estimates of all odds ratios were greater than 1.5, and several were substantial, despite the long time intervals and the control for prior MDD. DISCUSSION Three main findings emerged from this prospective epidemiologic study of childhood psychopathology. First, we noted cross-sectional associations between mental and physical illness at three follow-up points. Furthermore, longitudinal associations were bidirectional. Poor physical health predicted an increased risk of future depression, independent of prior depressive episodes and demographic covariates. Additionally, major depression predicted an increased risk of future poor physical health, independent of prior physical health and demographic covariates. Second, among the mental disorders, major depression exhibited the strongest and most consistent prospective associations with physical illnesses, indicating some specificity of relation. Third, among the somatic disorders, specificity was also in evidence. Immunologically mediated disorders exhibited strong associations with subsequent onset of major depression. In considering the implications of these findings, it is important to note the prospective nature of the data. The long time intervals between assessments (8 years, Vh years, and 6 years) tended to minimize concerns about potential contamination of measures, such as physical symptoms that may be manifestations of depressive lethargy, and sleeping or eating problems. Similarly, depressive symptoms resulting from illnessrelated physical impairment are lessened in prospective analyses examining the prediction of later MDD from somatic illness while controlling for earlier depression, although they do not remove the possibility of effects on mood of medications used to treat these disorders. Study data were insufficiently detailed to rule out this potential source of influence. Findings suggest that the associations were unlikely to have arisen purely from an artifact related to self-report, as they were also found when based on maternal reports. Whether children with current depression may report fewer or more physical symptoms to their mothers or to interviewers is not known. Most importantly, the prospective nature of the data provides insight into the TABLE 5. Odds ratios for new-onset major depressive disorder associated with specific prior somatic illnesses, New York State, Asthma Allergies Hay fever Any atopic illness Mononucleosis (from age 5.7 to age 13.7) (n=734) OR'.t * * Follow-up interval (from age 5.7 to age 22.1) (n = 717) -t $ (from age 16.0 to age 22.1) (n=685) * OR, odds ratio; Cl, confidence interval;, not asked. t Adjusted for age and sex. $ Wave 4 combined inquiries about asthma with questions on severe hay fever. Wave 3 pooled asthma, allergies, and hay fever; wave 2 did not assess individual illnesses.

7 238 Cohen et al. underlying mechanisms accounting for these associations. The bidirectionality of the prospective associations suggests that the relation between somatic illness and depression may result from etiologic factors common to both conditions. A number of potentially common etiologic factors, such as familial stress or discord, could account for the relations observed between somatic illness and depression, socioeconomic status had negligible effects on most of the associations, although it did markedly reduce the prospective association between depression in 1986 and ill health in Socioeconomic status did not moderate the strength of other associations. A number of socioenvironmental variables beyond socioeconomic status could contribute to the associations. For example, both major depression and physical illness are influenced by the quality of social relationships. Future research might consider the role that alterations in social relationships play in the association between somatic and psychiatric health in adolescents. The specificity of associations between immunemediated illness and major depression raises questions about the role of biologic variables implicated in both depression and somatic illness. Accumulating evidence from biologically oriented studies of adults links major depression with abnormalities in the immune system. For example, major depression is associated with abnormalities in lymphocyte membrane receptor profiles (33) and abnormal regulation of inflammatory processes (20, 34-36). This includes abnormalities in lymphokine production and T-cell-mediated cytotoxicity. With regard to the specific associations found in the current study for hay fever, allergies, asthma, and mononucleosis, there is evidence that depression is associated both with abnormalities in the atopic process (20), the mediator of clinical allergies or hay fever, and with abnormalities in the immunologic response to the Epstein-Barr virus, the causal agent in infectious mononucleosis (34, 37). Despite the consistency of our findings with data on the immunologic correlates of depression, the mechanisms by which depression might be associated with such immunologic abnormalities remain poorly understood (34-40). There is evidence both that depression can alter immune function and that immune modulators can affect biologic systems implicated in depression (21, 34, 35, 41). Moreover, to our knowledge, no study has directly and simultaneously linked major depression with both alterations in immunologic measures and the types of physical illness assessed in this study (20, 35). Our findings should encourage continued efforts to understand the relations among these three factors. Limitations in our study design suggest two important directions for future research that might ultimately clarify the mechanisms by which depression and physical illness are linked in adolescents. First, our study was specifically designed to examine the prevalence, risk factors, and developmental outcomes of psychiatric disorders. Examination of the relation between somatic illness and psychiatric illness was a secondary goal. As a result, we relied on self-reports and parental reports of somatic illness. It is not clear whether similar findings would be found with physician-diagnosed medical illnesses. Subject reports of chronic disease have been shown to be valid in adults (42-44), but less is known about their validity in younger populations, or about maternal reports. The possibility of misclassification-induced bias in estimates of effects of and on somatic illness are thus of particular concern, although a degree of misclassification of psychiatric disorders doubtless also occurred. In general, it is most likely that such bias would operate to weaken observed relations. Second, we did not directly assess any of the immunologic variables that could play a role in the association between depression and medical illness. Future epidemiologic studies might acquire data on routinely assessed immunologic parameters which have been implicated in major depression. In conclusion, while extensive research has examined the relation between somatic illness and psychiatric illness, more epidemiologic data, particularly in children, are needed to replicate the current findings. The current data indicate the presence of prospective as well as cross-sectional associations between somatic (immune-mediated) and psychiatric (depressive) illness. There is some evidence of specificity in the associations, from both the somatic (immune-related) perspective and the psychiatric (MDD) perspective. Furthermore, the bidirectionality of the associations suggests the presence of common etiologic factors. Future epidemiologic studies of the link between somatic and psychiatric illness might integrate recent technologic advances in immunology to shed further light on the mechanisms that underlie the associations we observed. ACKNOWLEDGMENTS This work was supported by the following grants: grants MH36971 and MH54161 to Dr. Patricia Cohen from the National Institute of Mental Health (NIMH); an NIMH Scientist Development Award for Clinicians (MHO 1391) to Dr. Daniel Pine; grants DA00244 and DA03188 to Dr. Judith Brook from the National Institute of Drug Abuse; and NIMH Center Grant MH43878 to Dr. David Shaffer.

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