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August 2008

High-Dose Olanzapine in Treatment-Resistant Schizophrenia
For some treatment-resistant patients with schizophrenia, high-dose olanzapine might be a better option than clozapine.

Increased Stroke Risk in Schizophrenia Patients
Patients with schizophrenia appear to have an increased risk of stroke, and the risk may be higher for women than for men.

Tamoxifen for Mania?
Through inhibition of protein kinase C, tamoxifen may benefit patients with mania and merits further study.

In Brief
Genetic Variations in Patients with Schizophrenia; Zonisamide for Weight Loss in Bipolar Disorder; Music Therapy for Stroke Recovery

NMS in Children and Adolescents
The neuroleptic malignant syndrome is a risk in children and adolescents treated with second-generation antipsychotics.

Options for SSRI-Resistant Depression in Adolescents
In a study by Brent et al, depressed adolescents who did not respond sufficiently to an SSRI benefited from switching to a different antidepressant and cognitive behavioral therapy.

High-Dose Olanzapine in Treatment-Resistant Schizophrenia

August 2008

For many years, clozapine (Clozaril and others) has been the ultimate "go-to" medication for difficult-to-treat cases of schizophrenia. Virtually all schizophrenia treatment guidelines agree on this role for clozapine, which is further supported by data from the recent Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial (BTP 2007;30:43-44).1 Meltzer et al investigated whether high doses of the pharmacologically similar compound olanzapine (Zyprexa) might be comparably efficacious to clozapine in patients for whom other antipsychotics have failed.2

In this 6-month, double-blind trial, the authors randomly assigned 40 patients with schizophrenia or schizoaffective disorder who had not experienced adequate relief from other antipsychotics to either high-dose olanzapine, 25 to 40 mg/day, or clozapine, 300 to 900 mg/day. The mean doses achieved were 34 mg/day for olanzapine and 564 mg/day for clozapine.

Both treatment groups showed "robust and significant" (P < .001) improvement in symptoms of schizophrenia—mostly occurring between 6 weeks and 6 months of treatment. There were no significant efficacy differences between the two treatment groups, except for greater improvement in global assessment of functioning in patients who took clozapine. At 6 months, 50% of the olanzapine group and 60% of the clozapine group met criteria for treatment response. There were no significant differences in extrapyramidal symptoms between the two groups. However, olanzapine-treated patients gained more weight: an average of 7.2 kg (15.9 lb) versus 1.6 kg (3.5 lb) for those treated with clozapine (P = .01).

In an accompanying commentary, Roth calls these results "provocative."3 He notes that previous studies of high-dose olanzapine in a treatment-resistant population have yielded mixed results. The editorialist offers several plausible hypotheses as to why high-dose olanzapine might be comparable in efficacy to clozapine in difficult cases of schizophrenia: (1) the two drugs share similar affinities for most relevant biogenic amine receptors; (2) some patients may rapidly metabolize olanzapine and require higher doses for optimal response; and (3) a subset of patients with treatment-resistant schizophrenia may have single nucleotide polymorphisms that interfere with olanzapine's actions and require higher than usual doses. Meltzer et al call for trials of other antipsychotics at higher than usual doses in this population.

Based on current science, clozapine remains the antipsychotic to try when other agents fail. This study, however, suggests that high-dose olanzapine may be considered, possibly before clozapine. Olanzapine does not require regular blood tests and is generally safer, although in the study by Meltzer et al, it did result in substantially higher weight gain. Olanzapine is known to cause diabetes and the metabolic syndrome, which are also associated with clozapine. In treatment-resistant schizophrenia, the prescriber must make difficult treatment decisions, weighing the pros and cons of treatment in collaboration with the patient, and ideally with family members and caregivers.

1McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK, CATIE Investigators: Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006;163:600-610.

2Meltzer HY, Bobo WV, Roy A, Jayathilake K, Chen Y, Ertugrul A, Anil Yagcioglu AE, Small JG: A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry 2008;69:274-285.

3Roth BL: High-dose olanzapine for treatment-resistant schizophrenia. J Clin Psychiatry 2008;69:176-177.