Do antipsychotics induce dopaminergic supersensitivity in humans? A PET/MR study in patients with schizophrenia and healthy subjects

• Applicants: Professor Dr. Gerhard Gründer; Professor Dr. Dusan Hirjak
• Subject Area: Biological Psychiatry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547113478

The aim of this project is to investigate for the first time in humans whether the long-term treatment with antipsychotics, which is now clinically common in patients with schizophrenia, leads to an upregulation of D2/3 dopamine receptors and an associated supersensitivity of these receptors. The detection of such changes and the investigation of influencing factors (especially smoking and type of medication) are of great importance for our understanding of the risk of recurrence, the development of treatment resistance and the risk of motor complications of antipsychotic pharmacotherapy. The hypothesis will be tested that chronically ill patients with schizophrenia who have received antipsychotic pretreatment have an increased D2/3 receptor availability compared to antipsychotic naïve patients with the first psychotic episode of schizophrenia. It is further intended to demonstrate that the increased D2/3 receptor availability correlates with the sensitivity of these receptors, measured as cerebral hemodynamic response, to a pharmacological dopaminergic stimulus. The dopamine receptor agonist apomorphine serves as a pharmacological stimulus. While the site of action of a drug and the receptor density of dopamine receptors can be quantified using positron emission tomography (PET), functional magnetic resonance imaging enables the effects of an applied drug on brain activity to be characterized. Simultaneous PET/MR makes it possible to quantify a relationship between dopamine receptor availability in different brain regions, the corresponding dopamine receptor occupancy by a drug and its effect on cerebral blood flow as an indicator of brain activity. Simultaneous PET/MR is therefore an excellent method to study D2/3 dopamine receptors in humans and at the same time to examine the sensitivity of these receptors to a pharmacological dopaminergic stimulus. The high-affinity [18F]fallypride, which binds selectively to D2/3 receptors, serves as the PET radioligand. In a first step, 20 healthy volunteers are examined in order to increase the statistical power of the pre-established study paradigm for further analysis. For testing the primary hypothesis, 20 first-episode, "drug-naïve" patients with schizophrenia will be examined. In a third step, 60 patients with schizophrenia who have been treated with antipsychotics of different substance classes for at least one year are examined.

• DFG Programme: Research Grants