Gender differences in the dosing of antipsychotic medications

To the Editor

Physiological and psychosocial differences between men and women play an important role in disease prevalence, treatment and outcomes. At the present time, the practice guidelines usually recommend similar doses of typical or atypical antipsychotic medications in men and women treated for psychotic or mood disorders. However, there is evidence that men require higher doses of typical and atypical antipsychotics than women (Seeman, 2004). The issue of gender differences in the dosing of antipsychotic medications is not getting sufficient attention from clinicians and researchers despite the fact that appropriate dosing is essential for safety and efficacy of drugs.

A need for higher antipsychotic doses in men may be related to differences in illness characteristics. Compared to women, men have poorer premorbid adjustment, earlier age at onset of psychotic symptoms, worse negative symptoms and poorer response to antipsychotics resulting in a need for higher doses (Seeman, 2004). Men have higher rates of co-occurring substance use disorders compared to women which is commonly associated with poorer response and adherence to treatment (Lev-Ran et al., 2013). Other factors are related to physiological differences in pharmacokinetics between men and women. Although men have higher gastric acidity, gastrointestinal transit times and, therefore, higher antipsychotic bioavailability, they have a higher body mass index, larger organs and higher plasma protein-binding capacity resulting in lower proportion of protein-free drug molecules available to cross the blood–brain barrier. Men also have larger distribution volume than women, which results in lower initial plasma and cerebrospinal fluid concentration of active molecules. Their fat storage is less than in women leading to a shorter duration of action for antipsychotics, which are mostly lipophilic (Seeman, 2004). After a steady state is achieved, dosing intervals for women need to be longer than for men. Most of the antipsychotics are metabolized through the cytochrome P450 system (CYP450), and a sex difference in CYP450 enzyme activity may contribute to a necessity for higher doses of antipsychotics in men (Parkinson et al., 2004). Finally, men may be prescribed higher doses of antipsychotics than women because of a lower susceptibility to side effects due to differences in pharmacodynamics.

In summary, higher dosing of antipsychotics in men compared to women is multi-factorial including illness presentation, co-occurring substance use disorders, pharmacokinetics, pharmacodynamics and risk of side effects. Gender needs to be taken into account when prescribing. Future research is needed to develop sex-specific predictive models of antipsychotic dosing.