Risperidone

Additional information

A higher risk of all psychotic disorders and schizophrenia in men compared to women has been reported in a meta-analysis with male-to-female incidence rate ratio of 1.4 and 1.7 [1].The onset of schizophrenia in men is typically 3-5 years earlier than in women with a peak onset 21-25 vs 25-30 years. Women also have a second peak of onset after the age of 45. The course of the schizophrenia is generally more severe in men. Furthermore, men present more often with more negative symptoms and women with more mood disturbance and depressive symptoms [2, 3].In a review of 40 trials of long-acting aripiprazole, risperidone and paliperidone, only 36.41 % of the total patients were women. Only 6 of the 40 trials performed a separate analysis of the main variable between men and women [4].

Pharmacokinetics and dosing

Several studies of psychiatric patients treated with risperidone (in total 247 men and 234 women) show no difference in plasma concentration of risperidone or the active metabolite 9-hydroxyrisperidone between men and women (some studies used dose-corrected concentrations, while some did not) [5-9]. An analysis of pooled data from two single-dose randomized cross-over bioequivalence trials in healthy volunteers (in total 35 men, 35 women) showed no difference in the pharmacokinetics of risperidone and 9-hydroxirisperidone between men and women. Variability in CYP2D6 was of greater importance than patient’s sex [10].

In contrary an observational study of risperidone in psychiatric patients (150 men, 127 women), women had 30% higher risperidone concentration/dose ratio and a higher weight-corrected concentration/dose ratio than men [11]. In another study (277 men, 275 women, 7-92 years) higher risperidone and 9-hydroxyrisperidone concentration/dose-ratio were observed in women compared to men in adults and elderly, however no difference was seen in children [12]. In a therapeutic drug monitoring (TDM) study (847 men, 1063 women), women had 18.7% higher dose-adjusted concentrations of risperidone + 9-hydroxirisperidone [13]. However, it is not clear if the differences in plasma concentrations are clinically relevant.

Effects

Specific for risperidone

In an efficacy study evaluating risperidone in men and women (932 men, 675 women), no sex differences were observed in overall CGI response and EQ-VAS after adjusting for baseline differences [14]. In another study of children aged 3-18 years (72 boys, 23 girls) with autism spectrum disorder and risperidone treatment, no significant difference in CGI between boys and girls was observed  [15].

Antipsychotics in general

Three studies show similar effect in men and women [16-18] and one study shows better results in men [19] and one in women [20]. 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 [16].

Adverse effects

Metabolic changes

Some studies found boys/men to be more likely to gain weight [15, 17, 21, 22] and some found girls/women to be more likely to gain weight [23, 24] while other found no difference [17, 25]. In a meta-analysis of 20 studies with risperidone-treated adult patients (529 men, 350 women), no difference in weight gain was observed between men and women [26]. Increased levels of insulin, C-peptide and insulin resistance index were found to be elevated similarly in men and women with schizophrenia (56 men, 56 women) [27].

Hyperprolactinemia

Hyperprolactinemia can cause hypogonadism with infertility and menstrual disturbances and sometimes galactorrhea in premenopausal women. Postmenopausal women don’t usually get symptoms from hyperprolactinemia. Hyperprolactinemia in men can cause hypogonadism with decreased libido, impotence, infertility, gynecomastia or galactorrhea. The degree of hyperprolactinemia does not always correlate with severity of symptoms [7, 28-31]. Studies of risperidone (718 men, 641 women, in all) showed prolactin elevation to be higher in girls/women than in boys/men [5, 7-9, 28, 32-34] most commonly around 2-3 times higher.Prolactin elevation has been found to be more pronounced in premenopausal women than in postmenopausal women (269 women, in all) [9, 28, 33] but unaffected by age in 68 men [33].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) [7-9] one study found a correlation between 9-hydroxirisperidone and prolactin in men and women (127 men, 91 women) [7], while another found a correlation in women but not in men (21 men, 19 women) [8]. In another study female risperidone plasma levels were associated with prolactin increase, while prolactin increase in men was correlated to 9-hydroxyrisperidone levels [35].

Extrapyramidal symptoms

In a study in children (72 boys, 23 girls) treated with risperidone there were no significant difference in frequency of extrapyramidal symptoms in boys and girls [15]. 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 [36].

Other adverse events

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) [5].In a cohort study of 95 children aged 3-18 years (72 boys, 23 girls) with autism spectrum disorder treated with risperidone somnolence occurred in 69.56% of female patients, as compared to 34.72% of male patients. In other side effects (extrapyramidal symptoms and hyperprolactinemia), no significant difference between boys and girls was observed [15].In a prospective study (289 males, 280 females) patients with schizophrenia were randomly assigned to risperidone, olanzapine and aripiprazole and followed for one year. After one year more women had reported dermatological side effects (rashes) than men in the risperidone group [37].

Reproductive health issues

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