quetiapine-fumarate and altanserin

We have previously reported decreased frontal cortical serotonin2A receptor binding in 30 antipsychotic naïve first-episode schizophrenic patients and a relationship between this binding and positive psychotic symptoms. Until now, no longitudinal studies of serotonin2A receptor in first-episode antipsychotic-naïve schizophrenia patients have reported on the relationship between serotonin2A receptor occupancy and treatment effect after sustained treatment with a specific atypical antipsychotic compound.. Here, we measured serotonin2A receptor occupancy with [(18)F]altanserin PET in 15 first-episode antipsychotic-naïve schizophrenia patients before and after 6 months of quetiapine treatment. Moreover, we investigated possible relationships between clinical efficacy, oral dose, and plasma levels of quetiapine. Significant nonlinear relationships were found between serotonin2A receptor occupancy, quetiapine dose, and plasma concentration. There was a modest effect on positive symptoms up until a serotonin2A receptor occupancy level of approximately 60%. A receptor occupancy level between 60% and 70% appeared to exert the optimal serotonin2A receptor related treatment effect on positive symptoms whereas no additional serotonin2A receptor associated treatment effect was obtained above a receptor occupancy of 70%.. Taken together, the data point to a therapeutic role of the serotonin2A receptor in the treatment of subgroups of patients with schizophrenia. Specifically, the study indicates a serotonin2A receptor associated therapeutic window on positive symptoms in responding patients in the range between 60% and 70% occupancy in antipsychotic-naïve first-episode schizophrenia. We speculate that non-responding patients need higher dopamine D(2) receptor blockade. Future studies with concurrent measurement of interactions with the dopamine system are, however, warranted to clarify this.

Topics: Adult; Antipsychotic Agents; Dibenzothiazepines; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Ketanserin; Longitudinal Studies; Male; Positron-Emission Tomography; Quetiapine Fumarate; Receptor, Serotonin, 5-HT2A; Schizophrenia; Schizophrenic Psychology; Time Factors; Young Adult

Antipsychotic-induced weight gain is of major clinical importance since it is associated with severe metabolic complications and increased mortality. The serotonin2A receptor system has been suggested to be implicated in weight gain and obesity. However, no previous in vivo imaging data have related serotonin2A receptor binding to weight gain before and after antipsychotic monotherapy. Fifteen antipsychotic-naive first-episode schizophrenia patients were included and investigated before and after six months of quetiapine treatment. We examined the relationship between serotonin2A receptor binding as measured with positron emission tomography (PET) and [18F]altanserin and change in body mass index (BMI). Quetiapine was chosen because it is characterized by a moderately high affinity for the serotonin2A receptor and a fast dissociation rate from the dopamine D2 receptor. At baseline the mean BMI was 24.2 kg/m2, range 18-36 kg/m2. After six months of quetiapine treatment (mean dose: 383 mg/day) the BMI had, on average, increased by 6.7%, corresponding to an average weight gain of 5.0 kg. We found a significant positive correlation both between neocortical serotonin2A receptor binding prior to treatment and subsequent increase in BMI (rho=0.59, p=0.022). At follow-up, the serotonin2A receptor occupancy was positively correlated with BMI increase (rho=0.54, p=0.038). To our knowledge, these are the first in vivo receptor imaging data in initially antipsychotic-naive first-episode schizophrenia patients to show that the cerebral serotonin2A receptor is associated with antipsychotic-induced weight gain.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Dibenzothiazepines; Female; Follow-Up Studies; Humans; Imaging, Three-Dimensional; Ketanserin; Male; Neocortex; Positron-Emission Tomography; Predictive Value of Tests; Protein Binding; Quetiapine Fumarate; Receptor, Serotonin, 5-HT2A; Schizophrenia; Serotonin Antagonists; Weight Gain; Young Adult