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Context Most antipsychotics are thought to have an effect on D 2 and D 3 receptors. The development of carbon 11–labeled (+)-4-propyl-9-hydroxynaphthoxazine ([ 11 C]-(+)-PHNO), the first agonist radioligand with higher affinity for D 3 than D 2 receptors, allows one to differentiate the effects of antipsychotics on high-affinity vs low-affinity sites of the D 2 receptor and on D 3 vs D 2 receptor subtypes. Objectives To examine the effects of antipsychotics (clozapine, risperidone, or olanzapine) on the high- vs high- + low-affinity sites of the D 2 and D 3 receptors by comparing the [ 11 C]-(+)-PHNO and [ 11 C]raclopride binding in the D 3 receptor–rich (globus pallidus and ventral striatum) and D 2 receptor–rich (caudate and putamen) regions. Design Two sequential studies with different participants and appropriate controls were performed. The first compared the occupancy produced by 3 antipsychotics as measured with [ 11 C]-(+)-PHNO and [ 11 C]raclopride. The second was a double-blind, placebo-controlled experiment to compare the effect of pramipexole (a D 3 receptor–preferring agonist) vs placebo on the increased [ 11 C]-(+)-PHNO signal observed in the globus pallidus of patients. Setting Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. Participants Twenty-three patients with schizophrenia and 23 healthy controls. Main Outcome Measures Antipsychotic occupancies as measured with [ 11 C]-(+)-PHNO and [ 11 C]raclopride. Results The antipsychotic-treated patients showed high occupancies with both [ 11 C]-(+)-PHNO and [ 11 C]raclopride in the dorsal striatum, with [ 11 C]raclopride occupancies about 20% higher. Most strikingly, patients did not show any occupancy with [ 11 C]-(+)-PHNO in the globus pallidus as compared with normal controls or with their own scans using [ 11 C]raclopride. This unblocked [ 11 C]-(+)-PHNO signal was displaced by a single dose of pramipexole. Conclusions Antipsychotics block both the high- and low-affinity states of the D 2 receptors across the brain, but antipsychotic treatment does not block the [ 11 C]-(+)-PHNO signal in the D 3 receptor–rich regions, despite the ongoing D 2 receptor blockade. This [ 11 C]-(+)-PHNO signal in regions such as the globus pallidus seems increased despite antipsychotic treatment and is displaceable by a D 3 receptor–preferring agonist. The radiotracer [ 11 C]-(+)-PHNO and the data open up new avenues for exploring the potential therapeutic significance of the D 3 receptor in schizophrenia.

Antipsychotic drugs produce unpleasant subjective experiences, which have been associated with high levels of dopamine D2 receptor occupancy. Aripiprazole is a partial agonist antipsychotic, which is hypothesized to produce a different subjective experience profile compared to standard D2 antagonist antipsychotics. The aim of this study was to compare the effect of D2 occupancy produced by a partial agonist antipsychotic (aripiprazole) to that of antagonist antipsychotics (risperidone or olanzapine) on the subjective well-being of patients. Subjective well-being was measured using the Subjective Well-being under Neuroleptics Scale (SWN) and was related to dopamine D2 receptor occupancy using [11C]raclopride PET. Patients that were switched to aripiprazole showed improvement in their subjective well-being from 79.80 (S.D.=16.08) to 89.90 (S.D.=15.33), an effect that was sustained for 6 months. This sustained improvement was observed despite very high levels of DA D2 occupancy (82–99%), in contrast to the effects of antagonist antipsychotics on subjective well-being., peer-reviewed

Glutamatergic dysfunction is implicated in the pathoaetiology of schizophrenia, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls, using the log coefficient of variation ratio (CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data using Hartigan’s unimodality dip test. MEDLINE and EMBASE databases were searched from inception to October 2021 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia patients compared to controls. 116 studies reporting on 7,844 patients and 7,305 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p