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Background Family history of affective disorders has long been recognized as one of the strongest risk factors for the onset and maintenance of the disorders. Familial risk for affective disorders represents an integration of an underlying genetic vulnerability and the familial clustering of unfavorable family circumstances in (early) life. In order to alleviate some of the burden that affective disorders are causing, it is necessary to better understand how the disorders and their associated features operate within families to increase psychopathology. This thesis extensively examined familial risk for affective disorders, with a broad focus on the role of genetic, clinical, and psychosocial vulnerability, and poor immunometabolic health. Methods Data came from the Netherlands Study of Depression and Anxiety (NESDA), an ongoing longitudinal cohort study (2004-present) on the long-term course and consequences of affective disorders. The baseline sample consisted of 2,981 participants (18-65 years), including 2,319 persons with a lifetime affective disorder and 652 healthy controls. Participants were assessed in face-to-face interviews at baseline and 2-, 4-, 6-, and 9-year follow-up. Among a broad range of demographic, psychiatric, genetic, and biopsychosocial measures, the 9-year follow-up included a detailed family history assessment; 1,425 lifetime affected NESDA participants had valid family history data. During the 9-year follow-up, full-biological siblings of NESDA participants with a lifetime affective disorder (i.e. ‘probands’) were additionally recruited to participate in the NESDA sibling study. This included a total of 380 siblings, related to 256 probands (N = 636 from 256 families). Discussion of main findings Lifetime affected patients with higher familial risk showed higher genetic vulnerability and a more unfavorable disease and psychosocial risk profile. Although a dichotomous family history measure is an informative indicator, familial risk for affective disorders seems to be better captured by a continuous score that incorporates family- and disorder-specific characteristics. Furthermore, prevalence of current (26.8%) and lifetime (50.3%) affective disorders in siblings of lifetime affected probands was substantial, and two- to three- times higher as compared to Dutch population frequencies. As compared to healthy controls without affected relatives, probands’ unaffected siblings showed enhanced social vulnerability and rumination. Despite this, the majority of affective symptoms and psychosocial vulnerabilities were, in fact, not elevated in unaffected siblings as compared to healthy controls, which may indicate their underlying resilience. Moreover, proband-sibling resemblance in affective symptoms, psychosocial vulnerability, and poor immunometabolic health was mild to moderate, indicating that these features, to a certain extent, cluster within families, but that lifetime affected patients and their siblings still show considerable individual differences despite their shared familial disposition. Finally, between siblings of the same at-risk family, cross-trait associations of affective symptoms appear to be relevant in the link with psychosocial vulnerability, but less in the link with poor immunometabolic health. Concluding remarks Findings illustrate that familial risk for affective disorders is a complex and dimensional construct that deserves attention in research and clinical practice. Having identified a wide variety of clinically-relevant factors that may explain heightened familial risk, the next generation of research should focus on preventing the onset of affective disorders and fostering resilience in at-risk relatives. Both within research and clinical practice, it is of particular importance to direct attention to family members when evaluating the risk for affective disorders, as this may contribute to a better understanding of the role of within-family processes in the etiology and maintenance of the disorders, and help identify pathways through which resilience is promoted. This knowledge may ultimately contribute to more effective treatment, the early identification of affective problems, and possibly preventing new onset of disorder, severe disability and intensive treatment in those at the highest risk.

Background Family history of affective disorders has long been recognized as one of the strongest risk factors for the onset and maintenance of the disorders. Familial risk for affective disorders represents an integration of an underlying genetic vulnerability and the familial clustering of unfavorable family circumstances in (early) life. In order to alleviate some of the burden that affective disorders are causing, it is necessary to better understand how the disorders and their associated features operate within families to increase psychopathology. This thesis extensively examined familial risk for affective disorders, with a broad focus on the role of genetic, clinical, and psychosocial vulnerability, and poor immunometabolic health. Methods Data came from the Netherlands Study of Depression and Anxiety (NESDA), an ongoing longitudinal cohort study (2004-present) on the long-term course and consequences of affective disorders. The baseline sample consisted of 2,981 participants (18-65 years), including 2,319 persons with a lifetime affective disorder and 652 healthy controls. Participants were assessed in face-to-face interviews at baseline and 2-, 4-, 6-, and 9-year follow-up. Among a broad range of demographic, psychiatric, genetic, and biopsychosocial measures, the 9-year follow-up included a detailed family history assessment; 1,425 lifetime affected NESDA participants had valid family history data. During the 9-year follow-up, full-biological siblings of NESDA participants with a lifetime affective disorder (i.e. ‘probands’) were additionally recruited to participate in the NESDA sibling study. This included a total of 380 siblings, related to 256 probands (N = 636 from 256 families). Discussion of main findings Lifetime affected patients with higher familial risk showed higher genetic vulnerability and a more unfavorable disease and psychosocial risk profile. Although a dichotomous family history measure is an informative indicator, familial risk for affective disorders seems to be better captured by a continuous score that incorporates family- and disorder-specific characteristics. Furthermore, prevalence of current (26.8%) and lifetime (50.3%) affective disorders in siblings of lifetime affected probands was substantial, and two- to three- times higher as compared to Dutch population frequencies. As compared to healthy controls without affected relatives, probands’ unaffected siblings showed enhanced social vulnerability and rumination. Despite this, the majority of affective symptoms and psychosocial vulnerabilities were, in fact, not elevated in unaffected siblings as compared to healthy controls, which may indicate their underlying resilience. Moreover, proband-sibling resemblance in affective symptoms, psychosocial vulnerability, and poor immunometabolic health was mild to moderate, indicating that these features, to a certain extent, cluster within families, but that lifetime affected patients and their siblings still show considerable individual differences despite their shared familial disposition. Finally, between siblings of the same at-risk family, cross-trait associations of affective symptoms appear to be relevant in the link with psychosocial vulnerability, but less in the link with poor immunometabolic health. Concluding remarks Findings illustrate that familial risk for affective disorders is a complex and dimensional construct that deserves attention in research and clinical practice. Having identified a wide variety of clinically-relevant factors that may explain heightened familial risk, the next generation of research should focus on preventing the onset of affective disorders and fostering resilience in at-risk relatives. Both within research and clinical practice, it is of particular importance to direct attention to family members when evaluating the risk for affective disorders, as this may contribute to a better understanding of the role of within-family processes in the etiology and maintenance of the disorders, and help identify pathways through which resilience is promoted. This knowledge may ultimately contribute to more effective treatment, the early identification of affective problems, and possibly preventing new onset of disorder, severe disability and intensive treatment in those at the highest risk.