Longitudinal Impact of Birthweight and its Polygenic Risk Score on Glucose and Antipsychotic-Induced Weight Gain in First Episode Psychosis

Background and Hypothesis: Patients with first-episode psychosis (FEP) frequently experience early metabolic alterations, including antipsychotic-induced weight gain (AIWG) and fasting glucose dysregulation. Birth weight (BW), a marker of the intrauterine environment and development, and its genetic proxy—the polygenic risk score for BW (PRSBW)—may influence these trajectories. This study investigated whether PRSBW and BW are associated with the progression of AIWG and fasting glucose levels over 24 months in individuals with FEP. Study Design: A total of 277 FEP patients with genetic, BW and longitudinal metabolic data were included. Linear mixed-effects models assessed associations of BW and the PRSBW with mean AIWG and glucose, as well as interactions with time. BW was analyzed both as a continuous variable and categorically (Lower/Higher vs. Intermediate BW). Study Results: BW was significantly associated with mean AIWG across 24 months (p=.009), with higher BW linked to greater AIWG. In contrast, neither BW nor the PRSBW were associated with mean fasting glucose levels. Significant time×BW and time×PRSBW interaction effects emerged for AIWG (p=2.2e-06 and p=4.6e-04, respectively), indicating steeper AIWG trajectories in individuals with higher BW or PRSBW. Conclusions: Our findings suggest that both BW and PRSBW influence the progression of AIWG in early stages of psychosis, reinforcing the role of early-life, both environmental and genetic, factors in shaping metabolic vulnerability. The consistent association between BW-related markers and AIWG highlights their potential value for early risk stratification and targeted prevention of adverse metabolic outcomes.