Resolving the heterogeneity of dopamine subsystems dysfunction in schizophrenia: a PET meta-analysis

The "dopamine hypothesis" of schizophrenia suggests the imbalance of the brain dopamine system plays a crucial role in the development of this disorder. Although this hypothesis has been partly supported by early studies, the brain region-specific abnormalities of different dopamine subsystems, and the influential factors on the heterogeneity of dopamine dysfunction of schizophrenia are still unknown. To address these issues, we carried out random-effect meta-analyses by collecting 49 in vivo PET studies (692 patients and 730 controls). Patients exhibited significant regional and population heterogeneity in D_2/3 receptor availability, primarily manifesting as a moderate increased in the striatum of only drug-off patients (Cohen's d = 0.56, 95%CI [0.16; 0.97]), whereas only drug-on patients showed a large decrease in D_2/3 receptor availability in the thalamus, limbic lobe, substantia nigra, and temporal lobe (Cohen's d < -1.40). Drug-off patients also had a small increase in dopamine synthesis in the striatum (Cohen's d = 0.38, 95%CI[0.06; 0.69]), with no replicable dysfunctions in drug-on patients or other brain regions. D₁ receptor availability and DAT showed high heterogeneity but no consistent significances. Finally, Meta-regression indicated that elevated striatal D_2/3 levels correlated with a higher proportion of males, older patients, longer duration and worse symptoms predicted more severe D₁ deficits in the striatum and prefrontal cortex. This study suggests that different dopamine subsystems in schizophrenia are selectively involved across brain regions; moreover, medication status, sex, age, illness duration and symptom diversity have significant impacts on the dysfunctions of dopamine subsystems in schizophrenia.