Clinical predictors of bipolar disorder onset in high-risk offspring: a systematic review

Background

Early identification of youth at high risk for bipolar disorder (BD) remains a major clinical challenge. Offspring of parents with BD represent a well-established high-risk population in whom illness onset is often preceded by a prodromal stage marked by affective, behavioural, and functional changes. Despite growing evidence, the integration of clinical predictors across developmental stages remains limited, hindering early recognition and preventive strategies. Improving the identification of early markers may contribute to more timely diagnosis and targeted interventions.

Aims

This study systematically reviewed clinical, behavioural, and functional predictors associated with transition to BD in children and adolescents at familial high risk.

Methods

A systematic search was conducted following PRISMA guidelines. PubMed/MEDLINE and LILACS were searched, yielding 98 records. After duplicate removal, 84 studies were screened and 28 full texts assessed for eligibility, with 16 longitudinal observational studies included. Eligible studies included children and adolescents who were offspring of parents with BD and employed longitudinal designs assessing diagnostic outcomes over time. Studies focusing exclusively on adults, lacking longitudinal follow-up, or without clearly defined diagnostic outcomes were excluded. Outcomes included prodromal symptoms, early clinical markers, and predictors of conversion based on standardized diagnostic criteria. Data extraction included study design, sample characteristics, follow-up duration, and main clinical outcomes. A qualitative synthesis was performed due to heterogeneity in study designs, assessment tools, and follow-up periods.

Results

Across studies, BD onset was consistently preceded by a prodromal stage characterised by affective instability and predominantly depressive symptoms, supporting a depressive-onset trajectory rather than initial mania. Early manifestations included anxiety, hypersensitivity, emotional dysregulation, and somatic complaints. These features evolved into persistent depressive symptoms, sleep disturbances, and functional impairment, particularly affecting academic performance and social functioning. During school-age years, internalising symptoms and behavioural difficulties became more prominent, often accompanied by increasing functional decline. In adolescence, irritability, mood lability, increased energy, and racing thoughts were frequently observed, suggesting a developmental progression of symptom expression toward more recognizable mood instability. Subclinical manic symptoms—particularly euphoria, decreased need for sleep, and racing thoughts—emerged as the strongest predictors of conversion, while depressive symptoms were also associated with later mood episodes. Combinations of clinical features demonstrated greater predictive value than isolated symptoms, indicating that multifactorial models may improve risk stratification. Findings were largely consistent across longitudinal high-risk cohorts despite variability in methodology and follow-up duration.

Conclusions

BD onset in high-risk offspring is preceded by a clinically meaningful prodromal stage characterised by subclinical manic symptoms, affective instability, and functional decline. Predictive accuracy improves when multiple domains are considered, supporting staging models and early identification strategies. These findings have important clinical implications, highlighting the potential for structured monitoring and targeted early interventions in high-risk youth. Future large-scale prospective studies are needed to refine risk prediction models, improve early detection, and guide interventions.

The authors declare no conflicts of interest regarding this work.

References

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