Predicting treatment response in Schizophrenia: the role of stratal and frontal dopamine D2/D3 receptor binding potential

Background
One of the best validated findings in schizophrenia is an association between increased presynaptic striatal dopaminergic activity and psychotic symptoms. We have previously reported an association between positive symptoms and dopamine D2 receptor binding potentials (BPs) in frontal cortex in antipsychotic-naïve first-episode male schizophrenia patients(1). Preclinical studies suggest an inverse relationship between frontal and striatal dopamine activity. This activity can indirectly be expressed by the BP of dopamine receptors using Single Photon Emission Computed Tomography (SPECT) where low striatal BP is believed to reflect high dopamine availability. We aim to assess the association between D2 receptor BPs in antipsychotic-naïve first-episode schizophrenia patients and their response to the first treatment with an antipsychotic compound. We hypothesise that patients with low striatal BP have the best treatment response, whereas we expect an inverse correlation in the frontal cortex, where patients with high frontal BP have the best outcome. We expect the correlation to be strongest regarding positive symptoms.

Methods
We have data from two comparable cohorts of antipsychotic-naïve first-episode schizophrenia patients the IBZMcohort and the EPIcohort. Both cohorts were longitudinal studies, where patients were examined at baseline and at follow up. The examinations included structural Magnetic Resonance Imaging, SPECT and PANSS. In the IBZMcohort we included 26 patients. We used the ligand [123]IBZM (123labeled iodbenzamid) to examine the binding potential (BP) of dopamine D2/D3 receptors in striatum. Patients were treated with amisulpride for six weeks. In the EPIcohort we included 25 patients. The ligand [123I]epidepride was used for quantification of extrastriatal dopamine D2/D3 receptors. Patients were randomised to twelve weeks of treatment with either risperidone or zuclopenthixol.

Results
We found no significant differences in BP between patients and healthy controls in either cohort at baseline. In the IBZMcohort the mean PANSS total score was 79 at baseline and 65 at follow-up. There was a negative correlation between striatal BP and improvement of the PANSS total score (Rho=-0,553 P=0.009). Furthermore we found a negative correlation between striatal BP and improvement of positive symptoms among the male patients only (P=0.020). The same relationship was found at trend level for the entire group (Rho=-0,417 P=0,060). In the EPIcohort the mean PANSS total score was 70 at baseline and 48 at follow up. In the frontal cortex we found a positive correlation (Rho=0.56 P=0.003) between BP and change in positive symptom score for the whole group as well as in the subgroup treated with risperidone. We found no significant correlation between BP in frontal cortex and improvement of PANSS total score.

Discussion
Our preliminary results suggest that D2 BP in antipsychotic-naïve patients may serve as a predictor for treatment outcome and further support previous data pointing to an inverse relationship between frontal and striatal dopamine activity. Data also emphasize that there might be gender differences. The data analysis is ongoing.
(1) Glenthøj BY, Mackeprang T et al. Frontal dopamine D2/3 receptor binding in drug-naïve first-episode schizophrenic patients correlates with positive psychotic symptoms and gender. Biol Psychiatry 2006;60(6):621-9.