Lublin H, Eberhard J, Levander S. Current therapy issues and unmet clinical needs in the treatment of schizophrenia: a review of the new generation antipsychotics. Int Clin Psychopharmacol 20: 183-198
This review discusses the atypical antipsychotics, focusing on the possibility of symptom reduction with a minimum of side-effects. A selective review of clinically relevant reports, studies and meta-analyses is presented. The results from clinical trials suggest that atypical agents improve negative and affective symptoms, and cognitive functioning more than typical antipsychotics, but that the pattern of effects on these domains, as well as on suicidality, appears to differ. In clinical trials, the newer drugs generally have less extrapyramidal side-effects (EPS) than typical antipsychotics. However, amisulpride, risperidone, olanzapine and ziprasidone still show evidence of a dose-related increase in EPS, whereas clozapine, quetiapine, sertindole and aripiprazole do not. Weight gain, increased blood lipids/cholesterol, and insulin resistance/type 2 diabetes are emerging as significant treatment-associated concerns, particularly for clozapine and olanzapine. Sedation has been reported for all the newer compounds except sertindole. The considerable variation in benefit/risk profiles of the atypical compounds can help the clinician to select the most appropriate treatment for individual patients.
Available from: Andries Kalsbeek
- "Atypical antipsychotic drugs (AAPDs) are increasingly replacing the use of typical antipsychotics due to their decreased risk for extrapyramidal side-effects  and their higher efficacy in the treatment of negative symptoms of schizophrenia –. However, some AAPDs are associated with unfavorable metabolic side-effects such as weight gain and insulin resistance , . Epidemiologic studies showed that Olanzapine is one of the AAPDs that causes the most pronounced weight gain . "
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ABSTRACT: Atypical antipsychotic drugs such as Olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying the metabolic side-effects of these centrally acting drugs are still unknown to a large extent. We compared the effects of peripheral (intragastric; 3 mg/kg/h) versus central (intracerebroventricular; 30 µg/kg/h) administration of Olanzapine on glucose metabolism using the stable isotope dilution technique (Experiment 1) in combination with low and high hyperinsulinemic-euglycemic clamps (Experiments 2 and 3), in order to evaluate hepatic and extra-hepatic insulin sensitivity, in adult male Wistar rats. Blood glucose, plasma corticosterone and insulin levels were measured alongside endogenous glucose production and glucose disappearance. Livers were harvested to determine glycogen content. Under basal conditions peripheral administration of Olanzapine induced pronounced hyperglycemia without a significant increase in hepatic glucose production (Experiment 1). The clamp experiments revealed a clear insulin resistance both at hepatic (Experiment 2) and extra-hepatic levels (Experiment 3). The induction of insulin resistance in Experiments 2 and 3 was supported by decreased hepatic glycogen stores in Olanzapine-treated rats. Central administration of Olanzapine, however, did not result in any significant changes in blood glucose, plasma insulin or corticosterone concentrations nor in glucose production. In conclusion, acute intragastric administration of Olanzapine leads to hyperglycemia and insulin resistance in male rats. The metabolic side-effects of Olanzapine appear to be mediated primarily via a peripheral mechanism, and not to have a central origin.
Available from: Gregory M Rose
- "More significantly, these CPZ-induced morphological and behavioral changes responded well to some antipsychotic drugs co-administered to mice while they consumed a CPZ-containing diet (Xu et al., 2010). With these previous results, the data presented in this study may be considered to be in good accordance with the clinical observations that positive symptoms in schizophrenic patients respond well to antipsychotic drugs while social dysfunction is difficult to treat (Lublin et al., 2005). "
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ABSTRACT: Recent animal and human studies have suggested that the cuprizone (CPZ, a copper chelator)-fed C57BL/6 mouse may be used as an animal model of schizophrenia. The goals of this study were to see the recovery processes of CPZ-induced behavioral changes and damaged white matter and to examine possible effects of antipsychotic drugs on the recovery processes. Mice were fed a CPZ-containing diet for 5 weeks then returned to normal food for 3 weeks, during which period mice were treated with different antipsychotic drugs. Various behaviors were measured at the end of CPZ-feeding phase as well as on the 14th and 21st days after CPZ withdrawal. The damage to and recovery status of white matter in the brains of mice were examined. Dietary CPZ resulted in white matter damage and behavioral abnormalities in the elevated plus-maze (EPM), social interaction (SI), and Y-maze test. EPM performance recovered to normal range within 2 weeks after CPZ withdrawal. Alterations in SI showed no recovery. Antipsychotics did not alter animals' behavior in either of these tests during the recovery period. Altered performance in the Y-maze showed some recovery in the vehicle group; atypical antipsychotics, but not haloperidol, significantly promoted this recovery process. The recovery of damaged white matter was incomplete during the recovery period. None of the drugs significantly promoted the recovery of damaged white matter. These results suggest that CPZ-induced white matter damage and SI deficit may be resistant to the antipsychotic treatment employed in this study. They are in good accordance with the clinical observations that positive symptoms in schizophrenic patients respond well to antipsychotic drugs while social dysfunction is usually intractable.
Available from: David Feifel
- "However, establishing predictive validity for cognitive deficits of schizophrenia is not a straightforward matter since the benefits of antipsychotics are modest and somewhat controversial. For example, while it is generally accepted that atypical antipsychotics such as clozapine improve cognitive deficits of schizophrenia, there is conflicting evidence regarding whether typical antipsychotics such as haloperidol produce improvements in cognitive deficits of schizophrenia (Green et al, 2002; Harvey et al, 2005; Keefe et al, 2006; Mishara and Goldberg, 2004; Remillard et al, 2005; Rollnik et al, 2002; Medalia et al, 1988; Stip et al, 2005; Lublin et al, 2005). Haloperidol is not effective in some animal models of cognitive deficits of schizophrenia, namely those based on PCP-induced deficits, whereas it does ameliorate the deficits in other preclinical cognitive deficits of schizophrenia models (e.g. "
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ABSTRACT: Cognitive deficits in schizophrenia are a major source of dysfunction for which more effective treatments are needed. The vasopressin-deficient Brattleboro (BRAT) rat has been shown to have several natural schizophrenia-like deficits, including impairments in prepulse inhibition and memory. We investigated BRAT rats and their parental strain, Long-Evans (LE) rats, in a social discrimination paradigm, which is an ethologically relevant animal test of cognitive deficits of schizophrenia based upon the natural preference of animals to investigate conspecifics. We also investigated the effects of the atypical antipsychotic, clozapine, and the putative antipsychotic, PD149163, a brain-penetrating neurotensin-1 agonist, on social discrimination in these rats. Adult rats were administered saline or one of the three doses of clozapine (0.1, 1.0, or 10 mg/kg) or PD149163 (0.1, 0.3, or 1.0 mg/kg), subcutaneously. Following drug administration, adult rats were exposed to a juvenile rat for a 4-min learning period. Animals were then housed individually for 30 min and then simultaneously exposed to the juvenile presented previously and a new juvenile for 4 min. Saline-treated LE rats, but not BRAT rats, exhibited intact social discrimination as evidenced by greater time spent exploring the new juvenile. The highest dose of clozapine and the two highest doses of PD149163 restored social discrimination in BRAT rats. These results provide further support for the utility of the BRAT rat as a genetic animal model relevant to schizophrenia and drug discovery. The potential of neurotensin agonists as putative treatments for cognitive deficits of schizophrenia was also supported.
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