Clinical and biochemical factors associated with hyperammonemia in inpatients with mental disorders treated with valproic acid: a cross-sectional analysis

Background: Valproic acid (VPA)-induced hyperammonemia is a common condition whose clinical presentations can range from asymptomatic cases to severe hyperammonemic encephalopathy. This can happen at any stage of treatment and is difficult to predict, as it often occurs without any alteration in liver function tests. Objectives: We aimed at exploring the association between hyperammonemia and clinical/biochemical characteristics among inpatients with mental disorders. Design: This cross-sectional study was conducted on adults consecutively admitted to two acute psychiatric inpatient units in the Milan metropolitan area from October 2022 to October 2024. All participants were treated with oral VPA during hospitalization. Methods: Sociodemographic, clinical, and biochemical data were retrieved from clinical interviews and electronic chart reviews. Univariate analyses and multiple logistic regressions were used to assess the association between hyperammonemia and candidate variables. Results: We included 130 participants (mean age: 38.2 ± 15.3 years; males: 77.7%). Bipolar I (36.9%), personality (31.5%), and schizophrenia spectrum (20.8%) disorders were the most common diagnoses. Mean serum ammonium levels were 46.4 ± 17.5 μmol/L, with hyperammonemia observed in 52 (40.0%) participants. Univariate analyses estimated an association of hyperammonemia with male sex, the concomitant use of 2+ medications (besides VPA), treatment with antipsychotics, and a diagnosis of alcohol use disorder (AUD). No further clinical/biochemical features were associated with hyperammonemia, including serum VPA levels and daily dose of VPA. Regression models showed that the concomitant use of 2+ other medications (coeff. = 1.03, p = 0.018) and AUD (coeff. = 1.32, p = 0.018), but not male sex (p = 0.12) and the use of antipsychotics (p = 0.09), were associated with hyperammonemia. Conclusion: Our findings highlight the potential influence of AUD and polypharmacy on the risk of hyperammonemia in subjects treated with oral VPA. Additional studies are needed to confirm these associations and to test their potential causal role in hyperammonemia. Clinical implications for limiting polypharmacy in people treated with oral VPA should be considered.