Genetics, age, height, weight, lean-fat ratio, diet, exercise, concurrent disease, smoking and alcohol, and the administration of concomitant drugs all contribute to antipsychotic drug response, as does end-organ sensitivity.  Together,  these factors can account for a 10-fold variability in the dose needed for effective response. Men and women show differences in all of these variables, either as a result of the action of sex-specific hormones or of divergent gender roles. So the stage is set for a somewhat different response to medication in the two sexes.

In a prospective drug-naive population, antipsychotic response was shown to be superior in women (49),  and in a chronically ill population, men were found to require twice as high a dose as women for effective maintenance (50). But studies comparing response in men and women are few. As a group, women have higher antipsychotic plasma levels than men after receiving the same dose of drug (51).  Male sex was associated with nonresponse at 1 year in a first-episode sample (52) but not with likelihood of relapse after response (53).

In the most methodologically rigorous study, with age of onset,  course of illness,  prior hospitalizations,  and premorbid functioning controlled,  no gender-specific difference was found in neuroleptic dose or dose by weight (54).

It has been postulated that hormonal fluctuations within phases of the menstrual cycle may influence pharmacokinetics and pharmacodynamics of drugs. Menstrual cycle variations do occur in renal,  cardiovascular,  hematological,  and immune systems (4) and could theoretically also affect protein binding and the volume of distribution of a particular compound.  When age and menstrual status (but not menstrual phase)  were controlled, one study found no dose-by-sex difference (55).

One group found no effect of menstrual cycle on cytochrome enzymes 2D6, 3A, or 1A2, suggesting that antipsychotic levels should be impervious to menstrual phase (56–58).  Smoking status,  as we will see,  has strong effects on the metabolism of certain drugs, and one research team has speculated that such antipsychotic dose differences as have been found between men and women are due to more men smoking and smoking more heavily than women (59).

Goff et al.  (60)  compared prescribed antipsychotic dose in smokers and nonsmokers.  Current smokers received a mean dose of 1160 mg/day in chlorpromazine equivalents,  while nonsmokers were given 542 mg/day in chlorpromazine equivalents.  Overall,  multivariate analysis of covariance demonstrated a significant main effect for smoking status but not gender or the interaction between gender and smoking.

After an oral dose,  plasma concentrations of haloperidol (metabolized by means of CYP2D6) are significantly lower in smokers than in nonsmokers (61,  62).  Smoking may induce CYP2D6,  but the story is probably more complicated. A recent study found no significant difference in the haloperidol concentration-to-dose ratio between nonsmokers and smokers.  In patients with a non-2D6*10 homozygous genotype, smokers had a significantly lower haloperidol concentration-to-dose ratio than nonsmokers, but this was not the case for smokers with a 2D6*10 homozygous genotype (63).  This suggests that the effect of smoking on the concentration-to-dose ratios of drugs depends on a person’s genotype (64).  Kelly et al.  (65),  in a fixed-dose study,  found that women had higher plasma concentrations of olanzapine than men. But the greater prevalence of smoking in men could have been responsible for these findings,  since tobacco is an inducer of CYP1A2, the main metabolizing enzyme for olanzapine (66, 67).

Taking smoking and other factors into account,  however,  the consensus for olanzapine is that there continues to be a tendency for higher concentrations in women.  Being a woman,  shown through recent therapeutic drug models, accounted for 27% of observed interindividual variability (68,  69).  The enzyme CYP1A2 appears to be less active in women than in men, leading to relatively higher blood concentrations in women, not only of olanzapine (65, 69) but also of clozapine (70).  A recent study of patient-related variables on clozapine concentrations found non-significantly higher median steady-state plasma concentrations in women than in men and higher concentrations in nonsmokers than in smokers (71). Neither gender nor age apparently has a significant effect on plasma levels of ziprasidone, which is metabolized by CYP3A4 (72).

Mary V. Seeman, M.D.

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