Olanzapine

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 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 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].

Pharmacokinetics and dosing

The pharmacokinetics of single-dose olanzapine differ from steady state conditions. A pooled analysis of two single-dose randomized trials in healthy Caucasian volunteers (33 men, 30 women) reported no sex differences in pharmacokinetics after adjusting for weight [4]. In addition to this, a single-dose randomized cross-over study of 5 mg olanzapine in healthy volunteers (10 men, 10 women) found no sex differences in pharmacokinetics of olanzapine [5].In a pooled analysis of two double-blind randomized clinical trials in patients with schizophrenia or Alzheimer’s disease (332 men, 191 women), men had a 27% higher clearance of olanzapine than women [6]. In hospitalized psychiatric patients with schizophrenia or bipolar disorder treated with oral olanzapine (239 men, 115 women), the oral clearance of olanzapine was 23% higher in men than women [7].In a single dose study (44 men, 5 women) showed 31% lower clearance and 12% longer half-life in women [8].  According to the manufacturer, the half-life in women is longer than in men (36,7 hours vs. 32,3 hours) and clearance is reduced in women (18,9 L/hour vs. 27,3 L/hour). The recommended starting dose is 5-10 mg and, in some populations, e.g., nonsmoking women ≥65 years of age, recommended starting dose is 5 mg and dose escalation should be performed with caution [9, 10].Furthermore, several therapeutic drug monitoring (TDM) studies of oral olanzapine in psychiatric patients (10 966 men, 7937 women) show that women have higher concentration/dose ratio (range 30-220%) than men [11-19]. Lower clearance in women can be a cause of these findings.

Effects

The efficacy studies on olanzapine-treatment have used different evaluation-scales and treatment durations when assessing efficacy outcomes, which makes the interpretation difficult. A double blind randomized parallel clinical trial in 1336 patients with schizophrenia and treatment with olanzapine 5-20 mg/day over a period of 6 weeks reported no differences in drug efficacy measured by Brief Psychiatric Rating Scale total scores (BPRS) between men and women [20]. Contrary to this, in a randomized double-blind parallel clinical trial during 6 weeks in patients with schizophrenia treated with olanzapine (868 men on daily dose 14.1 mg, 467 women on daily dose 12.5 mg), women had a better treatment response after four to five weeks than men measured by BPRS. Premenopausal women had better treatment response than postmenopausal women regardless of chronicity [21]. Furthermore, a subgroup analysis of the EUFEST-trial (first episode schizophrenia treated with haloperidol vs. atypical antipsychotics) [22], among the patients treated with olanzapine (49 men, 34 women), women had a significantly greater decrease in the positive and negative syndrome scale (PANSS) total PANSS compared to men after 12 months (-47 vs -32.9, p<0.05). This suggests a better treatment response in women [23].In a prospective observational study of patients with schizophrenia (2528 men, 1861 women) treatment response measured by physicians as Clinical Global Impression showed no difference between men and women. However, the women reported greater improvements in quality of life (EQ-VAS) [24, 25].

Adverse effects

Metabolic changesA meta-analysis of 26 clinical trials compared weight change in men and women treated with olanzapine, risperidone, or no medication. Duration of treatment was divided into four strata: <6 weeks, 6– 16 weeks, 16–38 weeks and >38 weeks. In the olanzapine group (451 men, 300 women), weight gain was statistically significant in both men and women. No significant sex difference in weight gain could be observed, except in the treatment-duration group between 16 and 38 weeks where men gained approximately 5 kg more than women (p= 0.032). However, according to the authors these could be random findings [26].A randomized double-blind clinical trial during 14 months in 1336 patients with schizophrenia treated with olanzapine 5-20 mg/day showed no sex differences in weight change [20]. In a post-hoc analysis of a randomized study TEOSS-study (97 males, 22 females aged 8-19 years), mean weight gain was +7.29 kg in the olanzapine-group after 8 weeks but no significant difference between the sexes was observed [27]. A randomized controlled study in patients with psychotic depression (93 men, 166 women) during 12 weeks treatment with a mean dose of olanzapine 14.3 mg daily showed that there was no sex difference in BMI increase, however men had lower total cholesterol than women [28].In contrast to this, clinical trials of patients with schizophrenia (870 men, 467 women) [29] and early psychosis (101 men, 32 women) [15] men on olanzapine had a greater increase in weight and BMI than women on olanzapine [15, 29]. However, findings from a prospective analysis of a randomized, double-blind, placebo-controlled trial in elderly patients with Alzheimer’s disease (186 men, 235 women) showed that women treated with olanzapine, quetiapine, risperidone, or placebo during 36 weeks showed an increase in BMI while men did not [30].

Prolactin increaseA randomized double-blind parallel clinical trial during 14 months in 1336 patients with schizophrenia treated with olanzapine 5-20 mg/day showed no clinically sex differences in prolactin elevation [20]. Two single-dose pharmacokinetic studies in healthy volunteers (total 62 men, 58 women) showed that women had 33-37% higher prolactin Cmax increase from baseline and 46-47% higher prolactin AUC increase from baseline than men respectively [4, 31]. Women carrying the DRD2 A1+receptor gene had a higher increase in prolactin compared to baseline in Cmax and AUC [31].Small clinical trials of patients with schizophrenia receiving olanzapine 5-10 mg/day show greater increase of plasma prolactin levels in women than in men  [32, 33]. Premenopausal and postmenopausal women had similar plasma concentrations of the drug as well as of prolactin [32].In an observational study on psychiatric patients with different antipsychotics, the mean increase in prolactin levels was higher in women compared to men (2.46 vs. 1.59 times the normal value) [34].

Extrapyramidal symptomsNo studies analyzing sex-differences in extrapyramidal symptoms from olanzapine treatment alone have been found. A retrospective observational cohort study of 51,878 elderly patients with dementia treated with risperidone, quetiapine, or olanzapine found men 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 [35]. In a cross-sectional study of psychiatric patients (129 men, 84 women aged 18-65 years) treated with second-generation oral antipsychotics, patient’s sex was not associated with an increased risk of developing extrapyramidal symptoms [36].

Other adverse effectsA pooled analysis of two single-dose randomized trials of 5 mg olanzapine in healthy Caucasian volunteers (33 men, 30 women) showed that women had a higher frequency of dizziness than men (40% vs. 12%). There was no sex difference in QT prolongation 2 h and 5 h after dosing [4].

Reproductive health issues

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