Beyond dose: Antipsychotic risk categories and sex-specific vulnerability to hyperprolactinemia in real-world...

Antipsychotic-induced hyperprolactinemia is a common and clinically relevant adverse effect that may impair treatment adherence and long-term health outcomes. Although chlorpromazine-equivalent doses (CPZE) are frequently used to standardize antipsychotic exposure, the relative contribution of drug-specific prolactin liability and patient sex in real-world longitudinal settings remains insufficiently characterized.

We conducted a retrospective longitudinal cohort study including adult patients treated with antipsychotics in inpatient and outpatient psychiatric settings over a ten-year period. Repeated serum prolactin measurements were analyzed using generalized estimating equations to account for within-subject correlations. Antipsychotics were classified into low-, moderate-, and high-risk categories based on established prescribing guidelines. Associations between prolactin levels and sex, antipsychotic risk category, CPZE, therapy type, antidepressant co-treatment, and aripiprazole use were examined.

A total of 251 patients (539 prolactin measurements) were included. Female sex and treatment with high-risk antipsychotics were the strongest independent predictors of prolactin elevation. High-risk agents were associated with an average increase of approximately 40 ng/mL in prolactin levels, whereas low-risk agents were associated with significantly lower concentrations. Abnormal prolactin levels (>20 ng/mL in men; >25 ng/mL in women) were observed in 68.4% of men and 78.7% of women. Analyses using binary outcomes (normal vs abnormal prolactin) yielded conclusions consistent with the continuous models, with high-risk antipsychotic exposure significantly increasing the odds of hyperprolactinemia, particularly among women. After adjustment for drug-specific risk, CPZE was not independently associated with prolactin levels. Sex-stratified analyses showed greater susceptibility to hyperprolactinemia among women. Aripiprazole use was not independently associated with lower prolactin levels.

In this real-world longitudinal cohort, prolactin dysregulation during antipsychotic treatment was driven primarily by drug-specific prolactin risk and biological sex rather than cumulative dose. These findings support a risk-based and sex-informed approach to antipsychotic prescribing and prolactin monitoring, particularly in women treated with high-risk agents.