University of Groningen. Children of bipolar parents Wals, Marjolein

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1 University of Groningen Children of bipolar parents Wals, Marjolein IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2004 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Wals, M. (2004). Children of bipolar parents: prevalence of psychopathology and antecedents of mood disorders Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Familial Loading and Mood Disorders Chapter 3: Multiple dimensions of familial psychopathology affect risk of mood disorder in children of bipolar parents Marjolein Wals Jim van Os Catrien G. Reichart Manon H.J. Hillegers Johan Ormel Frank C. Verhulst Willem A. Nolen American Journal of Medical Genetics, part B, Neuropsychiatric Genetics, 2004, 127B (1),

3 Chapter 3 Abstract The aim of our study was to determine whether familial loading of unipolar disorder, bipolar disorder and substance use disorder are associated with DSM-IV mood disorders in adolescents at risk of bipolar disorder. One hundred and forty adolescents aged years of 86 bipolar parents participated in the study. Lifetime DSM-IV diagnoses of the bipolar offspring were assessed with the Schedule for Affective Disorders and Schizophrenia for School Age Children Kiddie-SADS-Present and Lifetime Version (SADS-PL). Parents were interviewed using the Family History Research Diagnostic Criteria (FH-RDC) which were used to calculate a continuous familial loading score (FL) for unipolar disorder, bipolar disorder and for substance use disorder in first- and second-degree relatives of the adolescents. Familial loading for unipolar disorder and substance use disorder were strong and independent predictors for lifetime mood disorders in the adolescents. The gender adjusted hazard ratios for mood disorders in the children were 1.5 (95% confidence interval (CI) = ) for familial loading of unipolar disorder and 1.8 (95% CI = ) for familial loading of substance use disorder. Expression of mood disorders in children of bipolar parents varies with the degree of additional familial loading of unipolar disorder and substance use disorder in the extended family. Key words: Bipolar disorder; Offspring; Family history, K- SADS, FH-RDC Introduction Children of parents with bipolar disorder (for reasons of brevity hereafter referred to as bipolar offspring) are at increased risk of developing psychopathology, especially mood disorders (DelBello and Geller, 2001; Lapalme et al., 1997; Chang et al., 2001). The reported risk of lifetime mood disorders is approximately 4 times higher for children of bipolar parents than for children of parents with no mental or no major mental disorder (Lapalme et al., 1997). Rates of mood disorders in child and adolescent offspring of bipolar parents range from 5 to 67% compared with rates in offspring of healthy volunteers of 0-38% (Delbello and Geller, 2001). In a previous study, we found a lifetime prevalence of mood disorder of 27% among a sample of 140 children, aged years, of bipolar parents (Wals et al., 2001). To advance our understanding of the etiology, prevention, and treatment of mood disorders it is important to know which factors contribute to their development. Given the frequently reported finding that familial clustering of mood disorders is largely the result of shared genes rather than shared family environment (Alda, 1997; Gershon et al., 1987; McGuffin & Katz, 1989), we hypothesized that the presence of mood-related disorders in family members other than the bipolar parents additionally affects the risk of disorder in the offspring. A number of studies reported an elevated prevalence of mood disorders in the families of patients with mood disorders (e.g. Gershon et al., 1982; Rice et 28

4 Familial Loading and Mood Disorders al., 1987). To our knowledge, there are no studies that determined to what extent the risk of mood disorders in bipolar offspring varies with the degree of familial loading (FL) of mood and related disorders in the extended family. The main aim of the present study was to examine the association between FL of bipolar and other mood disorders in first- and second-degree relatives and the lifetime prevalence of mood disorders in the adolescent offspring of parents with bipolar disorder. Since twin and adoption studies suggest that unipolar and bipolar disorder are not clearly distinct genetically (Goodwin & Jamison, 1990; Mendlewicz & Rainer, 1977), and a substantial proportion of depressive onsets in these children are likely to later revert to bipolar disorder (Geller et al., 2001) the risk of FL for the combined category of mood disorders was determined. To examine the specificity of the effects of FL on the risk of mood disorder, we also tested the association between FL and non-mood disorders in the offspring. Since a number of studies reported an association between bipolar disorder and substance use disorder (Regier et al., 1990; Strakowski et al., 2000; Strakowski and Debello, 2000; Winokur et al., 1995.), and substance use disorder may be related genetically to mood disorder (Kendler et al., 1993; Winokur et al., 1998), substance use disorders among first- and second-degree relatives may also be a risk factor for bipolar offspring to develop mood disorders. We therefore also examined the effects of FL of substance use disorder on mood disorders as well as non-mood disorders in the bipolar offspring. Thus, this study tested whether FL of mood and substance use disorders predicts mood or non-mood disorders in bipolar offspring. More specifically, we hypothesized that: 1) FL of unipolar and bipolar mood disorder is associated with mood and not with non-mood disorders in bipolar offspring; 2) FL of substance use disorder is associated with mood and not with non-mood disorders in bipolar offspring. Methods Subjects All subjects were enrolled into the study between November 1997-March Sixty-two parent responders of the Dutch Patient Association with 102 children aged years and 24 families, with 38 children aged years, of outpatient clinics from 9 psychiatric hospitals in The Netherlands agreed to participate. In order to prevent selection bias within participating families, a family was included into the study only if all children of one family aged 12 to 21 years agreed to participate. All bipolar parents were outpatients at the moment of recruitment. Only adolescents without a severe physical disease or handicap and with an IQ of at least 70 were included. After initial contact, all consenting adolescents fulfilled these criteria. The Medical Ethical Review Committee of the University Medical Center Utrecht approved the study. After a complete description of the study was given to all participating parents, their spouses and their offspring, written informed consent of all participants was obtained. For a more detailed description of the recruitment and demographic characteristics of the sample, we refer to Wals et al. (2001). 29

5 Chapter 3 Assessment of bipolar disorder in the parents DSM-IV bipolar I or II diagnoses were confirmed by administering the mood disorders section of the International Diagnostic Check List (IDCL) (Hiller et al., 1993) in the interview with the bipolar parent. We compared the IDCL-based diagnoses with the DSM-IV diagnoses made by the treating psychiatrist and did not find any discrepancies. Assessment of DSM-IV disorders in bipolar offspring The K-SADS-present and lifetime version (K-SADS-PL) (Kaufman et al., 1997) was used to derive DSM-IV diagnoses in the adolescent bipolar offspring. The K-SADS-PL (Kaufman et al., 1997) is an interviewer oriented diagnostic interview designed to assess current and past DSM-IV symptomatology resulting in diagnoses in children and adolescents, by interviewing the parent(s) and child separately. In 47 of the cases the parent informing on the offspring was the bipolar mother, in 65 cases both parents informed on the offspring and in 28 of the cases the informing parent was the non-bipolar mother. If parents and child disagreed on the presence of a symptom, greater weight was typically given to parents' reports of observable behavior and children's reports of subjective experiences (Herjanic and Reich, 1982). The K-SADS-PL was conducted by three of the authors (MW, MH, and CR), and by five intensively trained interviewers with graduate degrees in psychology. In addition to the K-SADS derived diagnoses (for mood, anxiety, attention deficit, conduct, substance abuse, eating, post traumatic stress, adjustment and tic disorders; enuresis/encopresis), we also screened for DSM-IV pervasive developmental disorders. Diagnoses in the offspring (the probands) were grouped into two categories: 1) any lifetime mood disorder (unipolar disorder, bipolar disorder, and other mood disorder; and 2) any lifetime non-mood disorder. Assessment of familial loading Lifetime prevalence of psychopathology in the parents (n = 177) and their nonoffspring first-degree relatives (n = 932) was assessed with the Family History- Research Diagnostic Criteria (FH-RDC; Andreasen et al., 1977) interview and administered to both parents. The following diagnoses: unipolar disorder, bipolar disorder, and substance use disorder among first and second degree relatives were described predominantly in the literature to be associated with bipolar disorder (Goodwin & Jamison, 1990). Therefore, we decided to apply only sections of the FH-RDC yielding these disorders. The FH-RDC was administered by two of the authors (MW, MH), and by five intensively trained interviewers with graduate degrees in psychology. As described by Todd et al. (1993), the completeness of FH-RDC information was rated by the interviewers on a five-point scale (1 = very good, 2 = good, 3 = fair, 4 = poor, 5 = essentially no information). A score of 1 was defined as a diagnosis of bipolar disorder, unipolar disorder or substance use disorder made by a clinician 30

6 Familial Loading and Mood Disorders or if the family member fulfilled the criteria of the disorder of e.g. bipolar disorder and was known to be treated with a mood stabilizer. A score of 2 was used when the exact diagnosis was not known but when symptoms were present which indicated the presence of a unipolar depression, a bipolar depression or a substance use disorder based on content, duration, and treatment in a treatment setting. Only individuals with scores of 1 or 2 were included. A panel consisting of the five interviewers and three of the authors (MW, CR MH) reached consensus on the disorders that raised rating problems. Although all children had at least one bipolar parent, the parents with bipolar disorder as well as the parents without bipolar disorder will differ in their level of background FL for mood and non-mood disorders, and therefore will have different probabilities to transfer vulnerability for these disorders to their offspring. Family history (FH) can be used as a dichotomous indicator of FL, but the use of a dichotomous FH+ and FH- variable does not take into account, for example, that two bipolar patients in a family of 10 with mean age 23 years is not the same as 2 bipolar cases in a family of 3 with mean age 60 years. Using a method developed previously for this purpose (Verdoux et al., 1996), we defined several variables reflecting the continuously distributed level of FL for mood and nonmood disorders transmitted from the parents to the child, taking into account i) the number of adult first-degree relatives of the parents and ii) their ages. For a more detailed description of the FL score we refer to the appendix. Statistical analysis Tests for associations between FL and psychiatric disorder in the probands were performed using Cox proportional hazard regression analysis. This analysis provides a convenient way of controlling for time in the analysis of cohort studies, in this case the cohort of children of bipolar parents who were assessed over varying periods of time (i.e. the period from birth to age at interview). Associations were expressed as the hazard ratio (HR). The HR is the exponentiated regression coefficient of the Cox proportional hazard regression procedure (STATA version 7.0) (StataCorp, 2001), and is equivalent to the relative risk of the specified psychiatric disorder in the children of bipolar parents with varying degrees of FL, but the independent/predictor variable is continuous rather than categorical. Because observations were clustered within families (47 families contributed more than one child), compromising statistical independence of the observations, standard errors were adjusted for clustering on family using the cluster and robust standard error options in the STATA regression procedure. First, models of mood and non-mood disorder in the children were examined with a FL variable as the independent variable. Second, the same models were assessed with adjustment for gender. We chose gender as covariate since gender may be associated with both the predictor variable (FL) and the outcomes (mood and non-mood disorders in the offspring). Gender as possible confounder was chosen a priori, not based on a statistical significant association between gender and mood or non-mood disorders among the offspring. 31

7 Chapter 3 Because of substantial co-morbidity between mood and non-mood disorders in adolescence (Verhulst et al., 1997) offspring with mood disorders (including those with comorbid non-mood disorders) were compared with offspring without any DSM-IV disorder and likewise offspring with non-mood disorders without comorbid mood disorders (see below) were compared with offspring without any DSM-IV disorder. To determine whether any association with one FL variable was independent of the other FL variables analyses were performed with all FL variables entered together. Results DSM-IV diagnoses in probands Table 1 shows the prevalence of lifetime K-SADS/DSM-IV diagnoses in the adolescents of our sample. At least one lifetime DSM-IV diagnosis was assigned to 61 (44%) out of 140 adolescents. Table 1: Number of adolescents with lifetime DSM-IV Diagnoses (n = 140) Lifetime Diagnoses n % Non-mood disorder a Anxiety disorder Attention deficit hyperactivity disorder 7 5 Disruptive behavior disorder 8 6 Substance use disorder 9 6 Other b Mood disorder c Bipolar disorder 4 3 Major Depressive disorder 8 6 Dysthymic disorder 8 6 Cyclothymic disorder 2 1 Depressive disorder NOS Adjustment disorder with depressed mood 1 1 Mood disorder NOS 2 1 Any disorder Note: a This is the number of adolescents with at least one non-mood disorder without com-morbid mood disorder; b This category consisted of enuresis, encopresis, pervasive developmental, tic, obsessive compulsive, and eating disorders; c This is the number of adolescents with at least one mood disorder. 32

8 Familial Loading and Mood Disorders Thirty-eight adolescents (27%) were assigned at least one mood disorder diagnosis of which 22 adolescents were also assigned a non-mood disorder. We decided to include these 22 in the mood disorder group and not in the non-mood disorders group. Twenty-three adolescents (16%) were assigned at least one non-mood disorder without comorbid mood disorder. These were included in the non-mood disorder group. Thus, the mood disorder group includes 38 unique individuals and the non-mood disorder group includes 23 unique individuals. There were no significant differences between the two samples in the distribution of gender and age. Familial Loading Table 2 shows the lifetime DSM-IV Diagnoses in 1st degree (n = 177) and 2nd degree (n = 932) relatives of 140 Children of Bipolar Parents. Thirteen percent of the FH-RDC assessed relatives (n = 1109) had a lifetime history of bipolar disorder, 11% of unipolar disorder and 2% of substance use disorder. The range of the FL scores (not shown in the table) were: -1.6 to 3.5 for unipolar disorder, 0.5 to 7.5 for bipolar disorder and 1.6 to 2.4 for substance use disorder. FL scores were not correlated with each other (Pearson correlation coefficient; for FL unipolar and FL bipolar disorders: r = -0.09, p = 0.30, for FL substance use and FL bipolar disorders: r = 0.08, p = 0.37, for FL substance use and FL unipolar disorders: r = -0.02, p = 0.79). Table 2: Lifetime DSM-IV Diagnoses in 1st degree (n = 177) and 2nd degree (n = 932) relatives of 140 Children of Bipolar Parents number of 1st degree relatives with at least one DSM-IV disorder (%) a number of 2nd degree relatives with at least one DSM-IV disorder (%) a number of 1st and 2nd degree relatives with at least one DSM-IV disorder (%) a Any mood disorder 101 (57%) 156 (17%) 257 (23%) Unipolar disorder 14 (8%) 103 (11%) 117 (11%) Bipolar disorder 87 (49%) 53 (6%) 140 (13%) Substance abuse 5 (3%) 20 (2%) 25 (2%) Note: a Percentage is the percentage of the total sample. 33

9 Chapter 3 Table 3 shows the associations between FL of mood and substance use disorders and mood and non-mood disorders in bipolar offspring. As described above, all analyses were adjusted for gender of the bipolar offspring. Table 3: Impact of familial loading (FL) with unipolar disorder, bipolar disorder, and substance use disorder on mood disorders (n = 38) versus no disorders (n = 79) in bipolar offspring Mood disorder Hazard Ratio 95% CI p Univariate FL unipolar disorder FL bipolar disorder n.s. FL substance abuse Multivariate FL with unipolar disorder, adjusted for: FL with bipolar disorder FL with substance use disorder FL with bipolar and substance use disorder FL with bipolar disorder, adjusted for: FL with unipolar disorder n.s. FL with substance use disorder n.s. FL with unipolar and substance use disorder n.s. FL with substance use disorder, adjusted for: FL with unipolar disorder FL with bipolar disorder FL with unipolar and bipolar disorder Note: CI = Confidence interval; n.s. = non-significant. Familial loading of bipolar disorder was not significantly associated with mood disorders in the offspring (HR = 0.8, CI = ), but FL of unipolar disorders was (HR = 1.5, CI = , see table 3). Thus, only higher FL of unipolar disorder is significantly associated with mood disorders in bipolar offspring. The association between FL of unipolar disorder and mood disorders in the offspring remained significant after controlling for the effect of FL of bipolar disorder (HR = 1.5, CI = ) and for the effect of FL of substance use disorder (HR = 1.5, CI = ) or both (HR = 1.5, CI = ). The association between FL of bipolar disorder and mood disorders in the offspring remained nonsignificant after controlling for the effect of FL of unipolar disorder (HR = 0.8, 34

10 Familial Loading and Mood Disorders CI = ) and for the effect of FL of substance use disorder (HR = 0.7, CI = ) or both (HR = 0.8, CI = ). FL of substance use disorder was significantly associated with mood disorders in bipolar offspring (HR = 1.8, CI = ) higher FL of substance use disorder is associated with an increased risk of mood disorders. The association between FL of substance use disorder and mood disorders in the offspring remained significant after controlling for the effect of FL of bipolar disorder (HR = 1.8, CI = ) and of FL of unipolar disorder (HR = 1.6, CI = ), or both (HR = 1.6, CI = ), indicating that substance use disorder in first- and second -degree relatives poses an independent risk of mood disorders. None of the associations between the three FL indices and the presence of non-mood disorders in the offspring were significant. Familial loading based on relatively distant relatives Results were calculated on the basis of FL scores based on grandparents, aunts, and uncles only. The association between FL of unipolar disorder and mood disorders in bipolar offspring remained significant (HR = 1.5, CI = , p = 0.004), even when adjusted for FL of bipolar disorder (HR = 1.6, CI = , p = 0.002), of substance use disorder (HR = 1.5, CI = , p = 0.002) or both (HR = 1.5, CI = , p = 0.001). The association between FL of substance use disorder and mood disorders remained significant (HR = 1.7, CI = , p = 0.004), even when adjusted for FL of unipolar disorder (HR = 1.7, CI = , p = 0.000), of bipolar disorder (HR = 1.8, CI = , p = 0.000), or both (HR = 1.7, CI = , p = 0.001). The association between FL of bipolar disorder and mood disorders all remained non-significant. The results for associations between FL scores without parents and nonmood disorders differed only slightly from the results based on the FL scores when parents were included. The association between FL of unipolar disorder and non-mood disorders remained non-significant, even after adjustment for FL of substance use disorder or bipolar disorder. The association between FL of bipolar disorder and non-mood disorders remained non-significant, even after adjustment for FL of unipolar or substance use disorder. The association between FL of substance use disorder and non-mood disorders, however, became significant (HR = 2.2., CI = , p = 0.04), even after adjustment for FL of unipolar and FL of bipolar disorder (HR = 2.2, CI = , p = 0.04) or both (HR = 2.5, CI = , p = 0.03). 35

11 Chapter 3 Associations between familial loading and unipolar disorders in bipolar offspring We reanalyzed the findings excluding the 4 offspring with a diagnosis of bipolar disorder from the group of offspring with a mood disorder. The association between FL of unipolar disorder and mood disorders in bipolar offspring remained significant (HR = 1.6, CI = , p = 0.003), even when adjusted for FL of substance use disorder (HR = 1.5, CI = , p = 0.003), for FL of bipolar disorder (HR = 1.6, CI = , p = 0.001) or both (HR = 1.5, CI = , p = 0.02). The association between FL of substance use disorder and mood disorders in bipolar offspring remained significant (HR = 1.9, CI = , p = 0.000), even after adjustment for FL of unipolar disorder (HR = 1.7, CI = , p = 0.007), bipolar disorder (HR = 1.8, CI = , p = 0.000) or both (HR = 1.6, CI = , p = 0.01). The association between FL of bipolar disorder and mood disorders in bipolar offspring remained non-significant. The associations between FL and non-mood disorders remained nonsignificant. However, if we corrected the association of FL of substance use disorder for FL of unipolar disorder the association between FL of substance used disorder and non-mood disorders became significant (HR = 2.1, CI = , p = 0.04). Discussion We aimed to test the risk of lifetime mood disorders in the adolescent offspring of parents with bipolar disorder, as a function of the occurrence of bipolar and unipolar mood disorder as well as substance use disorder in the family. We found that FL of unipolar disorder was significantly associated with the lifetime prevalence of mood disorders in our sample of adolescent and young adult offspring of bipolar parents. Another finding of this study was that FL of substance use disorder increased the risk of mood disorders in the offspring. Moreover, the increased risk remained significant after controlling for the effect of FL of bipolar disorder and unipolar disorder, indicating that substance use disorder in the family of bipolar offspring poses an additional risk of mood disorders. It may be that the first- and second-degree relatives with substance use disorder without comorbid mood disorder are false negative mood disorders, i.e. will develop a mood disorder later in their lives. It is also possible that substance use disorder and mood disorder share a common risk factor, resulting in clustering of the two traits across generations. However, the fact that there was no correlation between the liabilities for substance abuse and unipolar disorder in this sample argues against such an interpretation. In order to examine whether familial risk of mood disorders that are present in adolescence is predominantly genetic of origin or predominantly confers an environmental risk of age of onset of mood disorders in bipolar offspring, we 36

12 Familial Loading and Mood Disorders examined associations between FL scores based on relatively distant relatives. The results for the associations between FL scores for relatively distant second degree relatives and mood disorders did not differ from the results based on the FL scores when parents were included. FL based on relatively distant seconddegree relatives was significantly associated with the development of mood disorders in children of bipolar parents. Based on these findings we believe that we may conclude that the familial risk of disorders that are present in adolescence seems to be predominantly genetic of origin. FL of unipolar disorder and substance use disorder increased the risk of mood disorders in offspring in a specific way, because we did not find increased risks for non-mood disorders in relation to FL of mood disorders. The findings, therefore, were suggestive of homotypy rather than heterotypy. Our results are in line with those of Weissman et al. (1984) who reported that adults who developed major depressive disorder prior to the age of 20 years had higher levels of FL of major depressive disorder in first- and second-degree relatives than adults who developed major depressive disorder after the age of 20 years, indicating that early onset of mood disorder is associated with higher levels of FL for major depressive disorders. In the present study, age of onset was the dependent variable in the Cox regression analysis for censored individuals. Therefore, results are interpretable not only in terms of censoring (onset per se) but also in terms of age of censoring. Adolescents who did not meet the criteria for lifetime mood disorder at the assessment might develop one later. It is possible that the FL is significantly associated with mood disorders at the moment of study, but that as the adolescents become older, those with low FL may also develop a mood disorder with a possible consequence that in the future in our sample the association will change or even disappear. The conservative interpretation of our finding therefore is that FL at least influences the age at which a mood disorder will first manifest itself in children of bipolar parents, higher loading being associated with earlier expression. The study by Weissman et al. (1984) is different from ours in that these authors studied adult patients with unipolar depression, whereas our sample comprised offspring of parents with bipolar disorder of whom 4 (2.8%) had bipolar disorder and 34 (24.2%) other, nonbipolar, mood disorders. FL of bipolar disorder was not significantly associated with lifetime prevalence of mood disorders in our sample. One explanation of this finding may be that the fact that every participating adolescent in our sample had a bipolar parent resulted in a ceiling effect; the variance of FL of bipolar disorder ranged from individuals with high FL to individuals with extremely high FL (the variance was always positive), whereas the variance of FL of unipolar and drug use disorder ranged from no loading to extremely high FL. The main finding was that even given the presence of a strong vulnerability for bipolar disorder, which highly exceeded the FL of unipolar and substance use disorder, unipolar disorder and substance use disorder in the extended family still independently influenced the expression of mood disorder over and above the influence of FL of bipolar disorder. In addition, the associations between FL of unipolar and substance use disorder and mood disorders in children of bipolar 37

13 Chapter 3 parents are not solely due to associations between FL of unipolar and substance use disorder and bipolar disorders in the offspring; even when the offspring with bipolar disorder are excluded from the analysis the associations remain significant. Thus, FL of unipolar disorder and substance use disorder are not unique risk factors for the development of bipolar disorder in children of bipolar parents, but for the development of unipolar disorders as well. There are several explanations for the findings. First, genetic liability for bipolar disorder could be phenotypically expressed as a bipolar disorder, but also as a unipolar disorder and a substance use disorder (pleiotropy). If this were the case, than it would be expected that those adolescents with more than one loading would develop higher rates of any of these three disorders. However, FL with bipolar, unipolar and substance use disorders were not significantly correlated with each other, i.e. adolescents with high FL with unipolar disorder did not show high FL with substance use disorder and vice versa. This suggests that substance use disorders and mood disorders are not phenotypic variants of a single underlying liability. This is in line with the study of Duffy et al. (1998) who did not find an association between the degree of FL for mood disorders and the risk of alcoholism in the relatives of 121 bipolar patients, and with a study of Maier et al. (1994), who also found unipolar disorder and alcoholism to be transmitted independently. A second explanation for the findings is that unipolar, bipolar and substance use disorder do not overlap genetically but do have an impact on the expression of each other, through epistasis or gene-gene interaction. If this were true, than the findings in this study can be taken to indicate that given a certain amount of risk of bipolar disorder, an additional FL with unipolar disorder and/or substance use disorder results in a greater probability of expression of mood disorders or at least in an earlier expression. For example, the fact that the FL of substance use disorder resulted in a higher risk of mood disorder in the offspring rather than substance use disorder itself suggests that FL of substance use disorder potentiated FL of (bipolar) mood disorder rather than influencing transmission of substance use disorder itself. However, a controlled study is needed in order to verify whether the effects of FL of unipolar disorder and substance use disorder on the rate of these disorders in the offspring of bipolar patients are similar or possibly even lower than in a comparison group of offspring of normal individuals. A third, non-exclusive, explanation is that unipolar, bipolar and substance use disorder do not overlap genetically but influence the expression of each other through gene-environment interaction. For example, it may be that the environmental influence of growing up with a bipolar parent is more likely to result in mood disorders if there is additional FL of mood and/or substance use disorder. If this were true, however, one would have expected more heterotypy in the transmission of disorders. For example, if the presence of a bipolar parent acted as a non-specific environmental risk factor, one would have expected more children with higher FL of substance use disorder to develop conduct disorders and substance use disorders. 38

14 Familial Loading and Mood Disorders Limitations The sample in the present study was rather young (12-21 years). Only 4 of the offspring had a bipolar disorder. Therefore, follow-up assessments of our sample are needed in order to unravel whether FL of unipolar disorder poses a risk to the development of both unipolar and bipolar disorder. In addition, the sample is not population-based. Only patients and theit children who were willing to participate were included. In addition, no control groups were included in the analysis. Hence, no conclusions about the specificity of the findings can be made. Consequently, the study s findings cannot be readily generalized beyond children of bipolar parents. There was relatively low comorbidity between substance use disorders and mood disorders in the families of the bipolar offspring, whereas another study suggests high levels of comorbidity of these two disorders (Strakowski et al., 2000). This could be due to misidentification of individuals with substance use disorders who should have been identified as having both substance use disorders and mood disorders. Substance use disorders in the extended family may have masked the underlying mood disorders. As the FH-RDC is relatively insensitive for the diagnosis of mood disorders when compared to the family study method (Andreasen et al., 1977), we may have missed diagnoses. Direct interview of a relative is well known to be more accurate than a family history report. However, in a study by Zimmerman et al. (1988), the test-retest interrater reliability of the FH-RDC was good to excellent for specific FH-RDC diagnoses. In addition, in this study a higher diagnostic threshold was associated with greater reliability, especially for the diagnosis of depression. As described above, FH-RDC information was rated by the interviewers as to completeness on a five-point scale (1 = very good to 5 = essentially no information). We only used the top two categories and therefore applied a relatively high threshold for family members to be diagnosed as mood disordered, but it increases type II error. Implications All subjects in our sample were similar in that they shared the risk that one of their parents had a bipolar disorder. In addition to this risk, the familial occurrence of unipolar disorder increased the risk of mood disorders in our sample. This finding can help clinicians and researchers be aware of the fact that FL of unipolar disorder increases the risk of mood disorders in children of bipolar parents. Follow-up assessments of our sample may add to the discussion of specific and shared vulnerabilities in the development of bipolar versus unipolar disorder. Another implication results from our findings that the occurrence of substance use disorder in the extended family of bipolar offspring poses a risk of the development of mood disorders over and above the risk of mood disorders associated with unipolar or bipolar disorder. This finding implies that, in addition to the literature on the comorbidity between bipolar disorder and substance use disorder, substance use disorder in the family also represents an independent risk factor for the development of mood disorders in bipolar offspring. 39

15 Chapter 3 Appendix To calculate the FL index, each child is regarded as either a potential "familial" or a "sporadic" case. This designation is a conceptual starting point, not some real characteristic. In the case of bipolar disorder, it is assumed that the lifetime risk of this disorder in a first-degree relative is 10% for "familial" probands, whereas for unipolar disorder and substance use disorder this risk was estimated at 20% (Jenkins et al., 1997). As the lifetime risk of "sporadic" bipolar probands is not precisely known, we arbitrarily assumed that this lifetime risk is 0.5%, i.e. half of the lifetime risk of "familial" plus "sporadic" bipolar illness, which is approximately 1%. In addition, we assumed that the age at risk extended from 10 to 50 years, and that in this age range risk increases linearly with age from zero at 10 years to the lifetime risk at 50 years. The probability that a relative of age X is affected with bipolar disorder if the proband is "familial" is therefore (0.1)(x-10)/(50-10) and the probability that such a relative is unaffected is 1 minus this. Similarly, the probability that a relative of age X is affected if the proband is "sporadic" is (0.005)(X-10)/(50-10). The likelihood ratio for whether the proband is familial or sporadic, given that a relative of age X is affected is therefore [(0.1)(X-10)/(50-10)]/[(0.005)(X-10)/(50-10)]=20, and a similar ratio can be defined for an unaffected relative, although this ratio will be dependent on age. Such a likelihood ratio was calculated for every relative of a proband, and an overall likelihood ratio for whether the proband is "familial" or "sporadic" was obtained by multiplying these individual likelihood ratios. Because this overall likelihood ratio is likely to be highly skewed, we took its common logarithm and defined it as the FL score. A FL score of 0 indicates that there is equal support for the proband to be "familial" or "sporadic", a positive score indicates that there is greater support for the proband to be "familial", while a negative score indicates that there is greater support for the proband to be "sporadic". A similar procedure was followed for unipolar disorder and substance use disorder. The lifetime risks for unipolar disorder and substance use disorder for sporadic probands are also unknown and were assumed at 5%, i.e. half of the lifetime risk of familial plus sporadic illness of approximately 10%. Only 2 relatives showed a substance use disorder, therefore the FL score for substance use disorder comprised mostly relatives with alcohol use disorder. If we change the assumptions about the rate of disorder in "sporadic" cases (the unknown variable in the calculation), from half the rate of familial AND sporadics (i.e. population prevalence) to one fourth the rate of familial AND sporadics, the correlations between the FL scores calculated under the two different assumptions are all > 0.99 and analyses with these scores produce similar results. Similarly, relaxing the assumptions to 3/4 the rate of familial AND sporadics also gives correlations between scores of at least Therefore, these sensitivity analyses show that results are robust to assumptions. 40