Conclusions This is the first attempt to evaluate the efficacy of melperone in the treatment of refractory psychotic illness in a naturalistic setting. Although it may be a worthwhile option in a very few patients, our results indicate a low overall success rate with melperone in patients with treatment refractory psychotic illness. Melperone should probably not be seen as an alternative for patients for whom clozapine is not suitable. Routine ECG

monitoring should be considered at doses greater than 300 mg daily. Footnotes This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. None declared.
Clozapine is an important atypical antipsychotic used Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical in treatment-resistant schizophrenia. Despite its known efficacy, it is a medication with many well-known adverse effects. As a result, its use in the UK is limited according to strict guidelines and is closely monitored [find protocol National Institute for Health and Clinical Excellence, 2009; Taylor et al. 2009a]. As with certain other second-generation antipsychotics, there is an established relationship Inhibitors,research,lifescience,medical between clozapine and impaired glucose metabolism [Henderson et al. 2005; Koller et al. 2001]. Adverse effects seen in clozapine-treated patients range from mild glucose intolerance to diabetes. In rare cases, patients can present with diabetic ketoacidosis

(DKA) which may lead to death. The mechanism of insulin resistance is thought to be via the propensity for

clozapine to Inhibitors,research,lifescience,medical cause weight gain, which is a known risk factor in the pathogenesis of diabetes [Henderson et al. 2005; Newcomer, 2005]. Recent research however has suggested that in up to a quarter of clozapine-related cases of diabetes, the cause is independent of adiposity [Newcomer, 2005]. Other mechanisms implicated include a potential inhibitory effect of clozapine on glucose transporter Inhibitors,research,lifescience,medical proteins [Tovey et al. 2005]. Regarding the timing of presentation of diabetes, a small prospective study examining glucose control found that the majority of patients developed impairments within the first 4 months of clozapine treatment independent of insulin sensitivity only [Howes et al. 2004]. Cases of more rapid onset and life-threatening diabetic complications also tend to occur early in the course of treatment, with 61.5% of cases of DKA occurring within 3 months of starting clozapine treatment [Nihalani et al. 2007]. Irrespective of the exact diabetogenic mechanism, the first 6 months of clozapine treatment appear to be a high-risk period and this is reflected in guidelines on the safe use of the drug. In the UK, the commonly used Maudsley Prescribing Guidelines suggest a combination of pretreatment screening of patients at risk and regular monitoring for early detection of diabetes [Taylor et al. 2009a].