Treatment with different second-generation antipsychotic agents, including risperidone, olanzapine, quetiapine, and aripiprazole, is associated with differing profiles of 5-HT2A and 5-HT6 receptor availability. A first-of-its-kind in vivo study was conducted in men to examine 5-HT2A and 5-HT6 receptor availability in patients with schizophrenia who were receiving chronic treatment with a second-generation antipsychotic agent compared with unmedicated, age-matched healthy male controls. Results of the analysis were published in the journal Psychiatry Research: Neuroimaging.

A total of 9 men with schizophrenia (mean age: 40.2±11.2 years; range: 21 to 53 years) and 9 healthy controls (mean age: 40.2±10.1 years; range: 23 to 52 years) were enrolled in the study. All of the patients underwent a comprehensive screening assessment and complete physical examination that included a medical history, routine blood tests, blood chemistry, electrocardiogram, and urine toxicology.

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Patients with schizophrenia were admitted to an inpatient research unit for 1 week in order to ensure adherence to antipsychotic medication monotherapy. They all needed to have been on a stable dose of an antipsychotic agent for ≥4 weeks prior to enrollment and not to be on any depot medications. The dose of the antipsychotic agent and number of patients taking each were: quetiapine 600 mg to 800 mg: n=2; risperidone 4 mg: n=2; olanzapine 15 mg: n=3; and aripiprazole 15 mg to 20 mg: n=2. For maintenance of psychotic symptoms in clinical practice, all of the antipsychotic agents were administered at their recommended doses.

Patients with schizophrenia underwent 1 structural magnetic resonance imaging (MRI) scan, 1 positron emission tomography (PET) scan with [11C]GSK215083 prior to the morning dose of antipsychotic on day 7 (ie, a trough scan), and a second PET scan that coincided with peak antipsychotic serum concentrations (ie, a peak scan). All healthy controls were age-matched for each subgroup according to type of antipsychotic agent, and underwent 1 structural MRI and 1 PET scan with [11C]GSK215083.


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Treatment with olanzapine was associated with significantly lower [11C]GSK215083 non-displaceable binding potential (BPND) values in the ventral striatum, putamen, caudate, and frontal cortex at both trough and peak scans (P <.05 for all). Treatment with quetiapine was also associated with significantly lower BPND values in the putamen on both trough and peak scans (P <.05). In contrast, risperidone was associated with significantly lower [11C]GSK215083 BPND in the frontal cortical region of interest at both trough and peak scans (P <.05). No significant differences were reported in [11C]GSK215083 BPND with aripiprazole in either the frontal cortex or the striatal regions.

Differences in 5-HT6 availability in the antipsychotic group vs the demographically matched healthy controls were greatest with olanzapine (–86%), quetiapine (–40%), risperidone (–31%), and aripiprazole (–27%) at the trough scan. Differences at the peak scan were olanzapine (–87%), aripiprazole (–55%), quetiapine (–52%), and risperidone (–15%).

Differences in 5-HT2A availability in the antipsychotic group vs the demographically matched healthy controls were greatest with olanzapine (–53%), risperidone (–34%), quetiapine (–32%), aripiprazole (–13%) at the trough scan. Differences at the peak scan were: olanzapine (–70%), quetiapine (–32%), aripiprazole (–41%), risperidone (–25%).

The investigators concluded that their findings are especially relevant to studies that explore the usefulness of 5-HT6 agonists as adjunctive therapy to antipsychotic agents. In particular, the >85% lower 5-HT6 availability with olanzapine implies that the degree to which the prognostic effects of 5-HT6 antagonists can be shown may be limited when olanzapine is the primary antipsychotic being used.

Reference
Radhakrishnan R, Matuskey D, Nabulsi N, et al. In vivo 5-HT6 and 5-HT2A receptor availability in antipsychotic treated schizophrenia patients vs. unmedicated healthy humans measured with [11C]GSK215083 PET. Psychiatry Res Neuroimaging. 2019;295:111007.