REGIONAL CEREBRAL BLOOD FLOW IN INITIALLY ANTIPSYCHOTIC-NAIVE PATIENTS WITH SCHIZOPHRENIA OR PSYCHOSIS: EFFECTS OF PARTIAL D2 RECEPTOR AGONISM AND ASSOCIATION WITH SYMPTOM IMPROVEMENT

Abstract Background Schizophrenia is suggested to stem from dysfunction of cortico-striato-thalamo-cortical networks. Supporting this, we have recently found increased glutamate levels in thalamus in antipsychotic-naïve patients with schizophrenia or psychosis. Moreover, higher baseline glutamate levels were related to less improvement of psychotic symptoms after treatment. Other groups have reported that striatal dopaminergic function in patients with psychosis is increased and associated with psychotic symptoms. Regional cerebral blood flow (rCBF) is considered a marker of neuronal activity and can be used to study the cortico-striato-thalamo-cortical networks. Here, we investigated rCBF in a large group of initially antipsychotic-naïve patients with schizophrenia or psychosis before and after treatment and related the findings to changes in psychotic symptoms. Methods rCBF was acquired in 49 initially antipsychotic-naïve patients and 50 matched healthy controls at baseline, and in 32 patients and 53 healthy controls after 6 weeks with the pseudo-Continuous Arterial Spin Labelling (pCASL) sequence. Patients were treated with a partial dopamine D2 receptor agonist (aripiprazole) as monotherapy (mean dose: 10.6±5.4mg). Primary regions of interest of rCBF were thalamus, limbic- and associative striatum. In explorative analyses, we estimated rCBF in sensorimotor striatum, hippocampus-amygdala, and frontal lobe. Psychopathology was assessed with the positive and negative syndrome scale (PANSS). A linear mixed model was used to test if the change in rCBF was different in patients compared with healthy controls (significant interaction) with adjustment for age, sex, and whole brain rCBF. Post hoc tests evaluated possible group differences at baseline and after 6 weeks. In a general linear model, we investigated associations between baseline rCBF in striatum and thalamus and improvement in psychotic symptoms. Results rCBF changed over 6 weeks in all striatal regions (associative striatum: p=0.023; limbic striatum: p=0.004; sensorimotor striatum: p=0.004). Post hoc tests of associative striatum indicated no baseline group differences in rCBF (SCZ/HC: 63.4/65.1 mL/100g/min, p=0.59), however rCBF was higher in patients after 6 weeks (SCZ/HC: 68.8/63.2 mL/100g/min, p=0.049). Post hoc tests of limbic striatum indicated no baseline group differences in rCBF (SCZ/HC: 62.7/65.3 mL/100g/min, p=0.25) and no group differences rCBF after 6 weeks (SCZ/HC: 69.3/63.3 mL/100g/min, p=0.12). Post hoc tests of sensorimotor striatum indicated no baseline group differences in rCBF (SCZ/HC: 72.6/71.2 mL/100g/min, p=0.18), however, rCBF was significantly higher in patients after 6 weeks (SCZ/HC: 80.0/67.2 mL/100g/min, p<0.001). There were no group differences in the rCBF changes in thalamus (p=0.09), hippocampus-amygdala (p=0.24), frontal lobe (p=0.90), and the whole brain (p=0.14). In patients, higher baseline rCBF in limbic striatum was associated with less improvement in PANSS positive symptoms (p=0.025). We found no other associations between rCBF and psychopathy. Discussion The findings suggest that treatment with a partial dopamine D2 agonist increases rCBF in associative and sensorimotor striatum in initially antipsychotic-naïve patients and that higher rCBF in limbic striatum at baseline is related to poorer treatment outcome. Future studies should investigate the associations between different neurotransmitters and rCBF in vivo. This could further characterize disturbances in cortico-striato-thalamo-cortical networks in schizophrenia or psychosis as well as the effect of treatment.