Risperidone

Additional information

Pharmacokinetics and dosing

Several rather large pharmacokinetic studies including a comparative number of women and men have not shown any difference between men and women in plasma concentration of risperidone or the active metabolite 9-hydroxrisperidone [4-8].

An analysis of pooled data from two single-dose randomized cross-over bioequivalence trials in healthy volunteers (35 men, 35 women) showed no difference in the pharmacokinetics of risperidone and 9-hydroxirisperidone between men and women. The variability of CYP2D6 metabolism was higher in men than in women and polymorphisms in CYP2D6 was of greater importance than patients’ sex [9]. This is in contrast to an observational study of risperidone in psychiatric patients (150 men, 127 women). In this study, women had 30% higher risperidone concentration/dose ratio and a higher weight-corrected concentration/dose ratio than men [10].

Effects

Results on sex differences in the response to risperidone are conflicting. We have identified three studies showing similar effect in men and women [11-13] one study showing better results in men [14] and one in women [15].

A meta-analysis of 32 randomized studies of treatment with risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole in acute schizophrenia (5200 men, 2064 women, 30% participating in risperidone studies) showed that men and women improved in a similar way. A larger proportion of men participated in placebo-controlled studies (78% overall) than in active-controlled studies (64%). However, the authors conclude that sex had no significant influence on improvement after treatment [11].

In contrast to this, two studies, not included in the meta-analyses mentioned above, showed contrary results. In a double-blind controlled study, chronic schizophrenia patients (60 men, 18 women) were randomized to risperidone or haloperidol during 12 weeks. The levels of superoxide dismutase (SOD) and IL-2 at baseline were correlated to severity of symptoms. Antipsychotic treatment yielded a greater reduction of the levels and a better response in women than in men [15]. In a study at acute psychiatric care, severely agitated patients (31 men, 12 women) were randomized to treatment with risperidone, haloperidol or olanzapine. Aggression (measured with PANSS score) was lowered more in men than in women during the 5 days study period [14].

Adverse effects

Differences in reported adverse events between men and women in risperidone studies vary. Women were found to have more headache (31% vs 11%), other neurological side effects (80% vs. 49%), and hypotension (17% vs. 0%) in an analysis of pooled data from two single-dose randomized cross-over bioequivalence trials in healthy volunteers (35 men, 35 women) [4].

In a large retrospective observational cohort study of 51,878 elderly patients with dementia treated with risperidone, quetiapine, or olanzapine men were found to have an overall 2.3 times higher risk than women for developing Parkinsonism in all treatment groups. The most pronounced sex difference in hazard ratio for developing Parkinsonism was found in the high dose quetiapine group [1].

Weight gain/increased BMI has been reported as an adverse event in several studies. Some found men to be more likely to gain weight [2,12,16] some women [3] while other found no difference [12,17].

Increased levels of insulin, C-peptide and insulin resistance index were found to be elevated similarly in patients with schizophrenia (56 men, 56 women) [18].

Prolactin elevation is another adverse effect of risperidone. Studies of risperidone (546 men, 439 women, in all) showed prolactin elevation to be 2-3 times higher in women than in men [4,6-8,19-21], more pronounced in premenopausal women than in postmenopausal women (269 women, in all) [8,19,21], and unaffected by age in 68 men [21]. A pooled analysis of five clinical trials of treatment with risperidone at steady state in children and adolescents 5-14 years old (489 boys, 103 girls) showed that prolactin levels reached a peak in treatment weeks 4-7 and then declining toward normal values earlier in girls than in boys (8-12 vs 16-24 weeks) [22].Even though some studies didn’t find any correlation between plasma risperidone and prolactin in neither men nor women (170 men, 132 women, in all) [6-8] one study found a correlation between 9-hydroxirisperidone and prolactin in men and women (127 men, 91 women) [6], while another found a correlation in women but not in men (21 men, 19 women) [7].Treatment with risperidone or conventional antipsychotics in 90 premenopausal women showed that elevated prolactin and testosterone in combination with reduced estradiol was a predictor for the risk of menstrual abnormality [19]. However, prolactin alone did not correlate to menstrual disturbances [19]. sexual side effects in men or women (127 men, 91 women) [6], adverse events in men or in women (582 men, 259 women) [23] nor to other possible prolactin related adverse events in children and adolescents (489 boys, 103 girls) [22].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

In a study comparing risperidone and haloperidol treatment (102 men, 38 women), no difference between sexes were found in symptoms of schizophrenia analyzed with the Positive and Negative Syndrome Scale (PANSS) [24].

A meta-analysis of schizophrenia antipsychotic trials published between 1993 and 2005 (14365 men, 6825 women, in all) showed 36% women in risperidone trials. Studies with center location in North America had 24% women and Europe had 40%. Pharmacological companies financed 90% of the trials [25].