Trajectories of Clozapine Concentrations in Women Across Menopausal Age

During menopause, estrogen levels change dramatically, which may decrease clozapine blood concentrations in women via estrogen's inhibitory effect on CYP1A2 activity. This reduction could contribute to increased relapse rates seen in older women with psychotic disorders.

Clozapine blood concentration data were retrieved from the University Medical Center Groningen, the Netherlands. A total of 982 patients (720 men, 262 women), aged 40-60, with 17 104 measurements, were included for analyses. Latent class growth analysis (LCGA) assessed clozapine trajectories by sex, while linear mixed-effects models (LMEM) assessed sex differences between trajectory classes.

The optimal LCGA model (7-quantile splines) identified 3 clusters. Most women (n = 157, 60%) showed a decline in clozapine levels from 520 to 400 μg/L between the ages of 40-60. In contrast, most men (n = 392, 54%) had stable levels (mean 460 μg/L). Two other trajectories appeared in both sexes: a mild increase starting at age 45 (men: n = 272, 38%; women: n = 97, 37%) and a marked increase from 40 to 60 (men: n = 56, ~8%; women: n = 8, ~3%). LMEM showed significantly higher levels in women than men with stable trajectories (estimate = 177.03, t = 2.62, P < .01). A significant age-by-sex interaction (estimate = -0.067, t = -2.63, P < .01) suggested these differences varied over time.

Sex-specific longitudinal trajectories of clozapine concentrations showed declines in 60% of women aged 40-60, while most men remained stable. As decreasing blood levels could increase relapse vulnerability, monitoring clinical efficacy and side effects is warranted during menopause.