altanserin and Schizophrenia

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

Here we imaged serotonin 2A receptor (5-HT2AR) binding in a very rare population of monozygotic twins discordant for schizophrenia to provide insight into trait and state components in brain 5-HT2AR patterns. In four twin pairs not medicated with drugs that target 5-HT2AR, frontal 5-HT2AR binding was consistently lower (33%) in schizophrenic- relative to their healthy co-twins. Our results strongly imply low frontal 5-HT2AR availability as a state feature of schizophrenia. If replicated, ideally in a larger sample also including dizygotic twin pairs and drug-naïve patients, this finding critically advance our understanding of the complex pathophysiology of schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Female; Fluorine Radioisotopes; Frontal Lobe; Humans; Ketanserin; Male; Positron-Emission Tomography; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Schizophrenia; Twins, Monozygotic; 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

Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT(2A) receptor (5-HT(2A)R) binding associated with the pathophysiology of schizophrenia. These studies were performed with ligands, such as ketanserin, altanserin and LSD, that may bind with high-affinity to different structural or functional conformations of the 5-HT(2A)R. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT(2A)R density by radioligand binding assays in postmortem prefrontal cortex of antipsychotic-free (n=29) and antipsychotic-treated (n=16) schizophrenics, suicide victims with other psychiatric diagnoses (n=13), and individually matched controls. [³H]Ketanserin binding, and its displacement by altanserin or the LSD-like agonist DOI, was assayed. Results indicate that the number of [³H]ketanserin binding sites to the 5-HT(2A)R was increased in antipsychotic-free (128 ± 11%), but not in antipsychotic-treated (92 ± 12%), schizophrenic subjects. In suicide victims, [³H]ketanserin binding did not differ as compared to controls. Aging correlated negatively with [³H]ketanserin binding in schizophrenia, suicide victims and controls. The fraction of high-affinity sites of DOI displacing [³H]ketanserin binding to the 5-HT(2A)R was increased in antipsychotic-free schizophrenic subjects. Functional uncoupling of heterotrimeric G proteins led to increased fraction of high-affinity sites of altanserin displacing [³H]ketanserin binding to the 5-HT(2A)R in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT(2A)R is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained.

Topics: Amphetamines; Animals; Antipsychotic Agents; Diagnostic and Statistical Manual of Mental Disorders; Frontal Lobe; Humans; Ketanserin; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurons; Prefrontal Cortex; Radioligand Assay; Receptor, Serotonin, 5-HT2A; Schizophrenia; Serotonin Antagonists; Serotonin Receptor Agonists; Suicide; Up-Regulation

Postmortem investigations and the receptor affinity profile of atypical antipsychotics have implicated the participation of serotonin(2A) receptors in the pathophysiology of schizophrenia. Most postmortem studies point toward lower cortical serotonin(2A) binding in schizophrenic patients. However, in vivo studies of serotonin(2A) binding report conflicting results, presumably because sample sizes have been small or because schizophrenic patients who were not antipsychotic-naive were included. Furthermore, the relationships between serotonin(2A) binding, psychopathology, and central neurocognitive deficits in schizophrenia are unclear.. To assess in vivo brain serotonin(2A) binding potentials in a large sample of antipsychotic-naive schizophrenic patients and matched healthy controls, and to examine possible associations with psychopathology, memory, attention, and executive functions.. Case-control study.. University hospital, Denmark.. A sample of 30 first-episode, antipsychotic-naive schizophrenic patients, 23 males and 7 females, and 30 matched healthy control subjects.. Positron emission tomography with the serotonin(2A)-specific radioligand fluorine 18-labeled altanserin and administration of a neuropsychological test battery.. Binding potential of specific tracer binding, scores on the Positive and Negative Syndrome Scale, and results of neuropsychological testing.. Schizophrenic patients had significantly lower serotonin(2A) binding in the frontal cortex than did control subjects. A significant negative correlation was observed between frontal cortical serotonin(2A) binding and positive psychotic symptoms in the male patients. No correlations were found between cognitive functions and serotonin(2A) binding.. The results suggest that frontal cortical serotonin(2A) receptors are involved in the pathophysiology of schizophrenia.. clinicaltrials.gov Identifier: NCT00207064.

Topics: Adult; Antipsychotic Agents; Brain; Case-Control Studies; Female; Fluorine Radioisotopes; Frontal Lobe; Humans; Ketanserin; Male; Neuropsychological Tests; Radionuclide Imaging; Receptor, Serotonin, 5-HT2A; Schizophrenia; Serotonin

Current perspectives on the pathophysiology of schizophrenia direct attention to serotonergic (serotonin, 5-HT) dysregulation in the prodrome or at-risk mental state (ARMS).. To study the cerebral 5-HT(2A) receptor (5-HT(2A)R) in the ARMS with [(18)F]altanserin positron emission tomography (PET) and a bolus-infusion paradigm.. We quantified the spatial distribution of 5-HT(2A)R binding potential (BP(1)') in never-medicated subjects assigned to early (n = 6) and late (n = 8) prodromal states of schizophrenia relative to healthy controls (n = 21). Five single nucleotide polymorphisms (SNPs) in the 5-HT(2A)R-encoding gene (HTR2A; 13q14-21) were genotyped to control for a potential bias in BP(1)' due to between-group differences in genotype distributions.. Group comparisons of partial-volume corrected PET data by statistical parametric mapping and confirmatory volume of interest analysis yielded a dissemination of BP(1)' decreases consistent with increasing levels of risk. An additional decrease in caudate BP(1)' was present in subjects who subsequently converted to first-episode psychosis (n = 5), but absent in non-converters (n = 9). Between-group differences were not confounded by a differential distribution of SNP genotypes.. These results suggest a progressive reduction of cortical 5-HT(2A)R density as a surrogate biological measure of increased risk for schizophrenia, irrespective of conversion. Progressive reductions of subcortical 5-HT(2A)R density could provide an indicator of illness activity and help to predict imminent conversion to schizophrenia. Moreover, our findings substantiate the rationale for establishing a phase-specific psychopharmacological intervention in the ARMS that addresses the serotonergic component of vulnerability to schizophrenia.

Topics: Adult; Brain; Brain Mapping; Cerebral Cortex; Dominance, Cerebral; Early Diagnosis; Female; Fluorine Radioisotopes; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; Ketanserin; Male; Positron-Emission Tomography; Psychiatric Status Rating Scales; Receptor, Serotonin, 5-HT2A; Schizophrenia; Schizotypal Personality Disorder

The serotonin 5-HT(2A) receptor is suspected to be involved in a number of psychiatric disorders, including schizophrenia. In particular, atypical antipsychotics have antagonistic effects on the 5-HT(2A) receptors, supporting a specific role of the 5-HT(2A) receptor in the pathophysiology of this disease. The aim of this study is to investigate cortical and subcortical 5-HT(2A) binding in neuroleptic-naive schizophrenic patients. Fifteen neuroleptic-naive patients diagnosed with schizophrenia (age 27.5+/-4.5 years), 11 men and 4 women, and 15 healthy control subjects matched for age (28.5+/-5.7 years) and gender underwent a 40 min positron emission tomography (PET) study using the 5-HT(2A) antagonist, [(18)F]altanserin, as a radioligand. PET images were co-registered to 3 T magnetic resonance images (MRIs) for each individual subject, and ROIs were applied automatically onto the individual MRIs and PET images. The cerebellum was used as a reference region. The binding potential of specific tracer binding (BP(p)) was used as the outcome measure. No significant difference was seen in cortical receptor distribution between patients and controls. An increase in 5-HT(2A) receptor binding in the caudate nucleus was detected in the group of schizophrenic patients (0.7+/-0.1) when compared to the healthy controls (0.5+/-0.3) (p=0.02). Our results confirm other in vivo findings of no difference in cortical 5-HT(2A) receptor binding between first-episode antipsychotic-naive schizophrenic patients and age- and gender-matched healthy control subjects. However, a preliminary finding of increased 5-HT(2A) binding in the caudate nucleus requires further investigation to explore the relation of subcortical and cortical 5-HT(2A) receptor binding.

Topics: Adult; Antipsychotic Agents; Binding, Competitive; Brain; Brain Chemistry; Brain Mapping; Caudate Nucleus; Cerebral Cortex; Female; Humans; Ketanserin; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Receptor, Serotonin, 5-HT2A; Schizophrenia; Serotonin; Serotonin Antagonists; Young Adult

The brain serotonin-2A receptor (5-HT(2A)R) has been implicated in both the pathology of schizophrenia and the therapeutic action of atypical antipsychotics. However, little is known about the 5-HT(2A)R status before the onset of schizophrenia and before the exposure to antipsychotics. We used [18F] altanserin and positron emission tomography (PET) in a pilot study of 6 individuals suspected to be at elevated risk for schizophrenia and seven age-matched controls to test the hypothesis that regional 5-HT(2A)R binding is altered in the prodromal stages of schizophrenia. Distribution volume ratios (DVRs) as a proxy for 5-HT(2A)R availability were significantly reduced in prefrontal cortex regions of at-risk subjects, implicating early abnormalities of serotonergic neurotransmission that antecede the onset of schizophrenia.

Topics: Adult; Brain Mapping; Case-Control Studies; Female; Fluorine Radioisotopes; Humans; Image Processing, Computer-Assisted; Ketanserin; Magnetic Resonance Imaging; Male; Pilot Projects; Positron-Emission Tomography; Prefrontal Cortex; Receptor, Serotonin, 5-HT2A; Risk Factors; Schizophrenia