2026 ECNP Congress

PS03-3226

Integrating birth weight and its polygenic architecture to shape longitudinal metabolic outcomes in first-episode psychosis

Nora Guasch-Capella — N. Rodríguez, P. Gassó, A. Martínez Pinteño, L. Rubio Unguetti, D. Olivares-Berjaga, M. Bioque, M.F. Forte, S. Amoretti, A. Martinez-Aran, E. Vieta, A. Mane, I. Baeza, C.M. Diaz-Caneja, L. Pina Camacho, M. J. Cuesta, D. Berge, C. García-Rizo, G. Mezquida, A. G Segura, P. Group · Universitat de Barcelona, Basic Clinical Practice, Barcelona, Spain

2026 ECNP Congress

Patients with first-episode psychosis (FEP) exhibit a high vulnerability to early metabolic disturbances, including antipsychotic-induced weight gain (AIWG) and alterations in glucose regulation. These changes emerge early in the illness course and are only partially explained by medication exposure, suggesting pre-existing biological vulnerability [1–3]. Birth weight (BW), as an integrative marker of intrauterine development, and its genetic counterpart, the polygenic risk score for birth weight (PRSBW), have been implicated in long-term metabolic outcomes and developmental programming of disease risk [4–5]. However, their role in shaping longitudinal metabolic trajectories in psychosis remains unclear. This study examined whether BW and PRSBW are associated with AIWG and fasting glucose progression over 24 months in FEP.

A total of 277 individuals with FEP were included from a multicentre longitudinal cohort with genetic, perinatal, and metabolic follow-up data. Linear mixed-effects models assessed associations between BW and PRSBW with (i) mean AIWG and glucose, and (ii) longitudinal trajectories via time interactions. BW was analysed continuously and categorically (Lower/Higher vs. Intermediate BW groups). Models were adjusted for sex, age, antipsychotic exposure, waist circumference (AIWG), BMI (glucose), and population stratification (PRS analyses).

BW was significantly associated with mean AIWG over 24 months (p = 0.009), with higher BW linked to greater weight gain, an effect mainly observed in males. No association was found between BW and glucose (p = 0.410). PRSBW was not associated with AIWG (p = 0.198) or glucose (p = 0.849).

AIWG increased significantly over time (p = 6.1 × 10⁻⁶), whereas glucose remained stable (p = 0.505). Both BW and PRSBW significantly moderated AIWG trajectories, with time × BW (p = 2.2 × 10⁻⁶, p.adj = 8.8 × 10⁻⁶) and time × PRSBW (p = 4.6 × 10⁻⁴, p.adj = 6.1 × 10⁻⁴) interactions, indicating steeper weight gain in individuals with higher BW or genetic liability. Effects were stronger in males; in females, BW remained significant while PRSBW did not.

Exploratory analyses showed that a quadratic BW model improved fit for AIWG and glucose only in females, with no non-linearity in other models. Stratified analyses revealed a significant time × BW interaction for AIWG in the Intermediate BW group but not in Lower/Higher groups. A nominal difference in AIWG between BW groups was observed at 2 months (p = 0.049), which did not survive FDR correction. No glucose differences were significant after correction.

BW and its polygenic liability contribute to the longitudinal course of AIWG in early psychosis, without consistent effects on glucose. These findings support the role of early developmental and genetic factors in shaping metabolic vulnerability in FEP and highlight their potential utility for early risk stratification during antipsychotic treatment, particularly in identifying individuals at increased risk of sustained weight gain trajectories and informing preventive metabolic monitoring strategies.

References

  1. Garcia-Rizo C, Kirkpatrick B, Fernandez-Egea E, Oliveira C, Bernardo M. Abnormal glycemic homeostasis at the onset of serious mental illnesses: A common pathway. Psychoneuroendocrinology. 2016;67. doi:10.1016/j.psyneuen.2016.02.001
  2. Garcia-Rizo C, Fernandez-Egea E, Oliveira C, et al. Metabolic syndrome or glucose challenge in first episode of psychosis? European Psychiatry. 2017;41. doi:10.1016/j.eurpsy.2016.10.001
  3. Garcia-Rizo C, Fernandez-Egea E, Oliveira C, Justicia A, Bernardo M, Kirkpatrick B. Inflammatory markers in antipsychotic-naïve patients with nonaffective psychosis and deficit vs. nondeficit features. Psychiatry Res. 2012;198(2). doi:10.1016/j.psychres.2011.08.014
  4. Gluckman P, Hanson M. Developmental Origins of Health and Disease. Cambridge University Press; 2006. doi:DOI: 10.1017/CBO9780511544699
  5. Hales CN, Barker DJP. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35(7). doi:10.1007/BF00400248