Olanzapine in male and female adolescent patients with schizophrenia and related disorders: minor sex differences in outcomes.
To the Editors: S chizophrenia is often first diagnosed in early adulthood, but in about one third of the cases, the disorder already developed during adolescence. Adolescent-onset schizophrenia is considered to be associated with a particularly poor prognosis, which underscores the need for a safe and effective treatment. In addition, sex differences in schizophrenia have been of particular interest. Although lifetime risk and prevalence seem comparable for male and female patients, differences in various aspects of the disease have been reported, for example, age of onset, premorbid state, pathophysiology, symptoms, course, coping and social skills, cognitive performance, structural brain abnormalities, treatment response and outcome, many of the variables indicate that females are more likely to manifest less severe forms of the illness. Children and adolescents are at particularly high risk for treatmentemergent extrapyramidal symptoms during treatment with typical antipsychotics, therefore, atypical antipsychotics are often considered the treatment of choice. But there are few regulatory approvals for this population, for example, the US Food and Drug Administration recently approved risperidone and aripiprazole for schizophrenia (ages 13Y17 years) and manic/mixed episodes in bipolar I disorder (ages 10Y17 years), and there is still a lack of large prospective long-term studies. Olanzapine has been approved for the treatment of adults with schizophrenia and bipolar disorder. Together with risperidone, olanzapine is currently the most commonly used atypical antipsychotic in pediatric patients (aged 18 years or younger), and therefore merits further evaluation of its effectiveness and tolerability . It is currently not regulatoryapproved for the treatment of children and adolescents. Various open-label studies have suggested that olanzapine may be effective in this population, but these studies showed a number of limitations. A first large prospective open-label multicenter trial with an atypical antipsychotic compound (olanzapine) in this age group (12Y21 years; N = 96) was performed in Germany. Then, 2 placebo-controlled trials with olanzapine in adolescents (schizophrenia, bipolar mania) have been published. There is only very limited information on sex differences in adolescent patients with schizophrenia. Thus, the objective of secondary analyses was to compare male and female adolescent patients from the German study with respect to selected BL (BL) characteristics plus effectiveness and tolerability parameters in an exploratory approach. This was a 24-week, open-label, prospective trial of olanzapine in male and female adolescent patients with Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia (methods in Dittmann et al). Qualified patients started treatment as inpatients. After week 6, responders only (Brief Psychiatric Rating Scale [BPRS]0Y6 improvement, Q30%) continued as outpatients in an open-label extension (18 weeks). Outcome measures comprised: BPRS0Y6, Clinical Global Impression of Severity (CGI-S), CGI Improvement scales; a self-rated subjective well-being scale (SWN, 20-item short form; higher scores = better well-being), spontaneously reported treatment-emergent adverse events (TEAEs), the Udvalg for Kliniske UndersLgelser (UKU) side effects scale, weight, body mass index (BMI), vital signs. Olanzapine plasma levels and serum leptin levels were assessed. Treatment with olanzapine was adjusted within a dose range of 5 to 20 mg/d. Statistical methods have been described; subgroup analyses (2-s.), for example, comparingmale versus female (m/f ) patient groups, were performed. Data are based on 96 patients; 80 (83.3%) completed the 6-week acute study period, 60 (62.5%) were responders, 34 (35.4%) completed the 24-week study, 68 (70.8%) patients were male, mean age was 15.9 (T 1.4) years. Baseline mean BPRS total score was 39.2 (T13.4); 38.3 (T 14.1) for males and 41.4 (T 11.3) for females (P 9 0.20). For males, the mean BL BMI was 20.9 (T 2.8); for females, 21.3 (T 4.0; m/f; P 9 0.50). The mean of the last olanzapine dose was 14.2 mg/d, of the highest dose 16.7 mg/d. Mean olanzapine plasma levels amounted to 47.8 (T 24.1) ng/mL (n = 84) by week 6 and 42.2 (T 24.8) ng/mL by week 24 (responders only, n = 56). The mean BPRS total score decreased from BL to week 6 by 17.0 (T 14.4; P G 0.001; N = 96), with a mean improvement of 43.1% (T 32.1%). No sex differences in mean change of BPRS total and positive and negative subscores were observed. A total of 62.5% of the patients (n = 60/96) met response criteria; rates were 60.3 (m), and 67.9% (f; m/f;P 9 0.20). The rate of patients assessed as markedly ill or worse (CGI-S) declined from 83.3% (BL) to 37.5% (week 6; P G 0.001). There were no m/f differences in various CGI-S parameter changes (allP 9 0.20). The SWN total scores increased from BL to week 6 (by 7.5 T 16.4; P G 0.001) both in males (P G 0.001) and in females (P G 0.07). By week 24, mean SWN changes amounted to 11.9 (T 20.6; m) and 13.8 (T 20.0; f; m/f; P 9 0.50). Significant correlations were observed (week 6), that is, investigatorrated BPRS total andCGI-S scores, r= 0.73 (P G 0.001); BPRS total and patient-rated SWN total scores, r = j0.24 (P = 0.032); and CGI-S and SWN total scores, r =j0.24 (P = 0.029). There were 519 TEAEs documented in 89 (92.7%) patients; 268 (51.9%) were considered to be possibly related to olanzapine treatment. Most commonly reported TEAEs were weight gain (30.2%, 29/96) and increased prolactin (PRL) levels (25.0%, 24/96). Serious AEs were observed in 3 males (all Bnot related[). The TEAEs led to early discontinuation in 3 patients. No deaths were reported. Few significant m/f differences were found (UKU items, by week 6): females reported more Borthostatic dizziness[ (P G 0.01), more of a reduction of Bdepression[ and Btension headache[ (both P G 0.05); males reported more weight gain (P G 0.10). Findings for changes in hematology and metabolic and liver function parameters have been published. Higher than normal BL serum PRL levels (Covance laboratory upper limit of normal range; Table 1) were found in 28.1% (27/96) of the patients, in 23.5% (m) and 32.1% (f; m/f; P 9 0.20). By week 6, 70.8% showed elevated PRL levels and (responders only) 13.3% (8/60) by week 24. The respective m/f rates were 70.6% and 71.4% (by week 6, m/f; P 9 0.20) and 12.2% and 15.8% (by week 24, P 9 0.20). The maximum single PRL levels were 58 (m) and 104 Kg/L (f; both found at week 6). For mean serum PRL levels, changes over time, and (selected) m/f results, cf. Table 1. The TEAEs (COSTART terms; N = 96) possibly associated with elevated PRL LETTERS TO THE EDITORS