Sex differences in clinical response to olanzapine compared with haloperidol
Introduction
Few studies of antipsychotic response in schizophrenia have focused on differential response in men and women, even though early studies of response to haloperidol reported differences by sex, e.g. Hogarty et al., 1974, Goldstein et al., 1978, Young and Meltzer, 1980. Seeman and colleagues first reported that premenopausal women had a more rapid and better treatment response to typical antipsychotics than men with schizophrenia (Seeman, 1983, Seeman, 1995, Seeman and Lang, 1990, Häfner et al., 1991, Szymanski et al., 1995, Kulkarni et al., 1996). Sex differences in treatment, however, dissipated with age, suggesting a potentially protective effect of estrogens, which was lost after menopause.
The findings were consistent with animal studies suggesting a modest antidopaminergic effect of estrogens (Raymond et al., 1978, DiPaolo et al., 1981, Häfner et al., 1991). They were also consistent with studies showing sex differences in receptor distribution and volumetric changes during normal brain aging, which may influence treatment response over time (Gur et al., 1991, Kaye et al., 1992, Murphy et al., 1996). Recent clinical studies have suggested a significant treatment interaction of level of estrogen activity and symptom exacerbation in women (Hallonquist et al., 1993, Gattaz et al., 1994, Reicher-Rössler et al., 1994, Kulkarni et al., 1996). It has been proposed that the conventional use of higher antipsychotic medication doses among men than women was no longer evident in later life (Seeman and Lang, 1990, Seeman, 1995), and that age, age of illness onset and duration of illness influenced sex differences in treatment response after 50 years of age (Salokangas, 1995). In addition, recent work has suggested that sex differences in treatment response may be, in part, accounted for by sex differences in the pharmacokinetics of antipsychotic medications, given sex differences in plasma concentration levels (Kelly et al., 1999) and other dimensions of drug metabolism (Yonkers et al., 1992).
However, not all studies of sex differences among typical antipsychotic medication recipients have demonstrated a significant difference. A recent study by Pinals and colleagues argued that earlier studies were methodologically flawed, citing the lack of double-blindness, inadequate drug-free washout periods, little control for dose and subject's weight, and lack of adequate matching of men and women (Pinals et al., 1996). In their own study, which took these factors into account, no significant sex differences in response to typical antipsychotics were noted.
‘Atypical’ antipsychotic medications are being increasingly used in clinical practice (Meltzer, 1991). Characteristics of atypical antipsychotics make them particularly attractive for women, such as the relative lack of treatment-emergent elevation of prolactin, resulting in less disruption of the menstrual cycle, increased capacity to block other dopamine receptors aside from D2 alone, and affinity for serotonin receptors. These factors may play a role in understanding sex differences in treatment response because dopamine (Beyer et al., 1991) and serotonin (Baum and Tobet, 1993, Fink et al., 1998) receptors have been found to be differentially distributed by sex and modulated by estradiol (Sumner and Fink, 1995, Österlund et al., 1999), since estrogen and androgen receptors have been found to co-localize with these as well as other neurotransmitters.
Studies of clozapine showed that men with schizophrenia had a better treatment response than women. However, it was unclear whether this was due to selection bias, as noted by the authors themselves (Lieberman et al., 1994, Szymanski et al., 1996). That is, the sample included treatment-resistant cases. Treatment-resistant women represent a more severely ill sample than women with schizophrenia in general, potentially attenuating a sex effect (Goldstein, 1993, Walker and Lewine, 1993). Thus, it remains unclear whether, and if so how, men and women differ in treatment response to clozapine or any other atypical antipsychotic medication.
The purpose of the present study was to test whether men and women with schizophrenia exhibited a differential response to the atypical antipsychotic medication, olanzapine, compared to haloperidol. The analyses were designed to unconfound the relationships of sex, chronicity of illness, i.e. first vs. multiply hospitalized cases, and pre- vs. postmenopausal status, on treatment response. We hypothesized that women would respond more quickly and show greater clinical improvement than men on haloperidol or olanzapine. We further hypothesized that a sex difference in treatment response would be greatest among first admission cases and women who were premenopausal.
Section snippets
Methods
Patients for the present analysis were obtained from a large international clinical trial of olanzapine compared with haloperidol. The study was approved by the institutional review boards responsible for the 174 investigational sites, and patients gave written informed consent. Details of the study are presented elsewhere (Crawford et al., 1997, Tollefson et al., 1997). Briefly, the patients met DSM-III-R criteria for schizophrenia, schizophreniform, or schizoaffective disorders; were in an
Results
Table 2 presents a summary of the average BPRS scores for men and women on Olz and Hal at each follow-up visit. At baseline, regardless of drug, the men and women were similar and not significantly different in overall severity of symptomatology. Table 2 shows that women on Olz had the largest reduction in total BPRS score beginning in week 4 and that this difference persisted for the rest of the trial (week 6). At week 4, when men and women began to differ in BPRS decrease, there were no
Discussion
Findings in the present study demonstrated that in response to the atypical antipsychotic, olanzapine, women showed significantly greater improvement in overall severity of symptomatology compared with men, regardless of chronicity and, in women, menopausal status. Although the sex difference in overall symptomatology on Olz would be considered clinically small, women on Olz showed a larger drop in symptomatology over a 6-week period than any other group. In contrast, sex differences were not
Acknowledgments
This work was supported by a grant from Eli Lilly and Company to LSC and JMG. Preparation of the manuscript was also supported by an N.I.M.H. grant to JMG (RO1 MH56956). The authors would like to thank Christine Fetterer for her help with manuscript preparation.
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