Seasonal variation in ammonia among euthymic women with Bipolar I Disorder treated with valproic acid in Turkey: a prospective study

Valproic acid (VPA)–induced hyperammonemia (VPA-IH) is a common metabolic complication in Bipolar I Disorder (BD-I). Although VPA creates a state of metabolic vulnerability, the influence of seasonal environmental stressors on ammonia homeostasis remains unexplored. This prospective longitudinal study followed 112 euthymic female patients with BD-I receiving stable VPA therapy over one year. Plasma ammonia levels and mood symptoms (YMRS, HAM-D) were assessed across four seasons: winter (January), spring (April), summer (July), and autumn (October). Repeated-measures ANOVA demonstrated a significant main effect of season on plasma ammonia levels ( p < 0.001, partial η² = 0.131). Ammonia concentrations peaked during summer (47.41 ± 8.48 µg/dL) and were significantly higher than winter (43.20 ± 8.20 µg/dL, p < 0.001), spring (44.18 ± 7.95 µg/dL, p < 0.001), and autumn (45.10 ± 6.99 µg/dL, p = 0.002). Autumn ammonia levels also remained modestly but significantly higher than winter ( p = 0.006). Mood scores remained within the euthymic range across all seasons, with no significant seasonal variation. A modest but significant positive correlation between YMRS scores and ammonia levels was observed exclusively during summer ( r = 0.245, p = 0.009). Plasma ammonia levels in VPA-treated patients exhibit a distinct seasonal pattern, peaking during summer despite sustained euthymia. These findings support a seasonally modulated “multi-hit” model of VPA-associated hyperammonemia and highlight the importance of season-informed metabolic monitoring and hydration strategies during warmer months.