Brain imaging to determine the effects of sertindole in schizophrenic patients

Sertindole, discovered and patented by H. Lundbeck (Denmark), and under development by Abbott Laboratoriesʹ Psychopharmacology Venture, is a new compound with a selective antagonistic activity at dopamine D2, serotonin 5HT2, and α1receptors. Sertindole combines a selective antagonism on mesolimbic dopamine neurons (demonstrated inin vivo animal experiments) with serotonergic antagonistic properties. Study M93-098 was a large, Phase III, double-blind, placebo-controlled, fixed dose, randomized, eight-week trial of two doses of sertindole (20mg and 24mg) and haloperidol (16mg) in hospitalized schizophrenic patients. Brain imaging with positron emission tomography (PET) of 10 patients participating at the UCI Medical Center were obtained during the placebo lead-in phase and at Week 5. 18-F deoxyglucose (FDG) PET scanning was conducted while subjects performed the degraded stimulus version of the Continuous Performance Test (CPT). The analysis of these data was combined with data collected from patients treated with clozapine, placebo, and haloperidol in a similar manner. Despite the small sample size, statistically significant decreases were seen in the metabolic activity of the basal ganglia while on sertindole therapy. These are consistent with the metabolic profile of a medication with a low propensity for causing EPS. In contrast, haloperidol increases basal ganglia metabolism and clozapine has no effect. The cortical areas affected by sertindole are associated with attention, working memory, processing of emotional content and the negative symptoms. The PET data presented here suggest that brain metabolism of sertindole-treated patients is consistent with a metabolic profile of a psychotropic drug with atypical antipsychotic properties and a low incidence of extrapyramidal symptoms.