Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia

Atypical antipsychotics have been linked to a higher risk for glucose intolerance, and consequentially the development of type 2 diabetes mellitus (DM2). We have therefore set out to investigate the acute effects of oral administration of olanzapine and ziprasidone on whole body insulin sensitivity in healthy subjects. Using the standardized hyperinsulinemic euglycemic clamp technique we compared whole body insulin sensitivity of 29 healthy male volunteers after oral intake of either olanzapine 10 mg/day (n ¼ 14) or ziprasidone 80 mg/day (n ¼ 15) for 10 days. A significant decrease (po0.001) in whole body insulin sensitivity from 5.7 ml/h/kg ( ¼ mean, SM ¼ 0.4 ml/h/kg) at baseline to 4.7 ml/h/kg ( ¼ mean, SM ¼ 0.3 ml/h/kg) after oral intake of olanzapine (10 mg/day) for 10 days was observed. The ziprasidone (80 mg/day) group did not show any significant difference (5.2 ± 0.3 ml/h/kg baseline vs 5.1 ± 0.3 ml/h/kg) after 10 days of oral intake. Our main finding demonstrates that oral administration of olanzapine but not ziprasidone leads to a decrease in whole body insulin sensitivity in response to a hyperinsulinemic euglycemic challenge. Our finding is suggestive that not all atypical antipsychotics cause acute direct effects on glucose disposal and that accurate determination of side effect profile should be performed when choosing an atypical antipsychotic.

Section: Discussionmentioning

confidence: 99%

Effects of Olanzapine and Ziprasidone on Glucose Tolerance in Healthy Volunteers

Sacher

Mossaheb

Spindelegger

et al. 2007

“…Patients with schizophrenia often discontinue their antipsychotic medications despite the high efficacy of these drugs (Lieberman et al, 2005). Non-adherence to antipsychotic medications is a primary reason for psychotic relapse and rehospitalization (Perkins, 2002).…”

Section: Introductionmentioning

confidence: 99%

D2 Receptor Occupancy of Olanzapine Pamoate Depot Using Positron Emission Tomography: An Open-label Study in Patients with Schizophrenia

Mamo

Kapur

Keshavan

et al. 2007

A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D 2 receptor occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine were switched to OP depot 300 mg by intramuscular injection every 4 weeks for 6 months. No visitwise within-group significant changes were found in Brief Psychiatric Rating Scale Total or Clinical Global Impressions-Severity of Illness scores, although seven patients received oral olanzapine supplementation during the first four injection cycles. To minimize impact on D 2 occupancy, positron emission tomography (PET) scans were not completed during injection cycles that required supplemental oral olanzapine. Two patients reported transient injection site adverse events, which did not result in discontinuation. The most frequently reported treatmentemergent adverse events were insomnia, aggravated psychosis, and anxiety. Mean striatal D 2 receptor occupancy, as measured by [ 11 C]-raclopride PET, was 69% on oral olanzapine (5-20 mg/day) and 50% (trough) on OP depot at steady state. Following an initial decline, occupancy returned to 84% of baseline oral olanzapine occupancy after six injections. Over the study period, D 2 receptor occupancy and plasma olanzapine concentrations were significantly correlated (r ¼ 0.76, Pp0.001). OP depot resulted in mean D 2 receptor occupancy of approximately 60% or higher at the end of the 6-month study period, a level consistent with antipsychotic efficacy and found during treatment with oral olanzapine. However, supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles.

“…In the recent Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study initiated by the NIMH to compare effectiveness of antipsychotic drugs, olanzapine appeared to be more effective than the other drugs studies, but it was associated with greater weight gain and other metabolic changes implicated in the development of metabolic syndrome (Lieberman et al, 2005). Although the negative public health implications of the weight gain and other metabolic adverse effects of olanzapine have become a matter of concern to both the psychiatry and endocrinology communities (American Diabetes Association, 2004), olanzapine continues to be widely prescribed.…”

Section: Introductionmentioning

confidence: 99%

Olanzapine-Induced Weight Gain and Increased Visceral Adiposity is Blocked by Melatonin Replacement Therapy in Rats

Raskind

Burke

Crites

et al. 2006

The atypical antipsychotic drug olanzapine increases body weight and visceral adiposity in schizophrenia. In rats, aging-associated increased body weight and visceral adiposity are reversed by administration of the pineal hormone melatonin. We asked if melatonin similarly would reverse olanzapine-induced increased weight and visceral adiposity in rats. Four groups (n ¼ 11/group) of female rats (240-250 g) were treated for 8 weeks with olanzapine, melatonin, olanzapine + melatonin, or vehicle alone in drinking water. Body weight and food and water consumption were determined weekly, locomotor activity at weeks 3 and 6, and nocturnal plasma melatonin concentration at week 7. At week 8, the rats were killed and visceral (perirenal, retroperitoneal, omental, and mesenteric) fat pads dissected and weighed. Olanzapine treatment reduced nocturnal plasma melatonin by 55% (po0.001), which was restored to control levels by olanzapine + melatonin. Body weight increased 18% in rats treated with olanzapine alone, but only 10% with olanzapine + melatonin, 5% with melatonin alone, and 7% with vehicle control. Body weight and visceral fat pad weight increases in rats treated with olanzapine alone were greater than in each of the other three groups (all po0.01), which were not significantly different. These results suggest that olanzapine-induced increases in body weight and visceral adiposity may be at least in part secondary to olanzapine-induced reduction of plasma melatonin levels, and that melatonin may be useful for the management of olanzapine-induced weight gain in humans.