Bipolar disorder (BD) is a severe and functionally impairing mental disorder that poses significant burden to family members. Offspring of parents with bipolar disorder (OBD) are at elevated risk for affective disorders. This risk is attributable to both genetic and environmental risk factors, which influence underlying stress-response systems such as the hypothalamic-pituitary-adrenal (HPA) axis. Given that OBD display dysregulated HPA functioning, which in turn prospectively predicts later affective disorders, the HPA axis might play an important role in the development of affective disorders. Programs aimed at preventing affective disorders, particularly in the OBD, have grown considerably. However, relatively few programs have targeted OBD during childhood, prior to the development of affective disorders. Furthermore, little research has examined how prevention programs impact functioning of the stress sensitive HPA axis, or how HPA axis functioning impacts individual response to such interventions. Study 1 of this dissertation was a systematic review that consisted of 33 articles from 19 studies that examined intervention programs for youth at genetic risk for BD and/or exhibiting prodromal clinical presentations (PROSPERO #443438). Preventive interventions were associated with generally positive mental health outcomes, including decreased affective and non-affective symptoms. Numerous child, parent, and environmental factors were identified to mediate program efficacy. Study 2 examined the impact of the Reducing Unwanted Stress in the Home (RUSH) prevention program on HPA axis functioning in OBD. This quasi-experimental study examined a sample of OBD (N=26) and healthy control (N=29) children (6-11 years old) at baseline, post-, 3-, and 6-months post-intervention. Only OBD participated in the RUSH program. No group differences were observed at baseline, but OBD had lower cortisol levels than controls. Although no main effect of the intervention on cortisol levels was observed, OBD who experienced improvements in family organization and cohesion following RUSH exhibited elevated and rising cortisol levels across time. Study 3 examined whether indices of HPA functioning at baseline predict how children respond to the RUSH program. Low cortisol levels at baseline predicted improved internalizing symptoms over time in OBD, but not in controls. These studies highlight the importance of early intervention for improving mental health outcomes in the at-risk OBD. This dissertation also highlights how the HPA axis is sensitive to environmental change in families with a parent having BD, and how the neuroendocrine system may be used as an indicator of individual sensitivity to prevention
