The effect of AUT00206, a Kv3 potassium channel modulator, on dopamine synthesis capacity and the reliability of [18F]-FDOPA imaging in schizophrenia

Background: Current treatments for schizophrenia act directly on dopamine (DA) receptors but are ineffective for many patients, highlighting the need to develop new treatment approaches. Striatal DA dysfunction, indexed using [F-18]-FDOPA imaging, is linked to the pathoetiology of schizophrenia. We evaluated the effect of a novel drug, AUT00206, a Kv3.1/3.2 potassium channel modulator, on dopaminergic function in schizophrenia and its relationship with symptom change. Additionally, we investigated the test-retest reliability of [F-18]-FDOPA PET in schizophrenia to determine its potential as a biomarker for drug discovery. Methods: Twenty patients with schizophrenia received symptom measures and [F-18]-FDOPA PET scans, before and after being randomised to AUT00206 or placebo groups for up to 28 days treatment. Results: AUT00206 had no significant effect on DA synthesis capacity. However, there was a correlation between reduction in striatal dopamine synthesis capacity (indexed as Ki(cer)) and reduction in symptoms, in the AUT00206 group (r = 0.58, p = 0.03). This was not observed in the placebo group (r = -0.15, p = 0.75), although the placebo group may have been underpowered to detect an effect. The intraclass correlation coefficients of [F-18]-FDOPA indices in the placebo group ranged from 0.83 to 0.93 across striatal regions. Conclusions: The relationship between reduction in DA synthesis capacity and improvement in symptoms in the AUT00206 group provides evidence for a pharmacodynamic effect of the Kv3 channel modulator. The lack of a significant overall reduction in DA synthesis capacity in the AUT00206 group could be due to variability and the low number of subjects in this study. These findings support further investigation of Kv3 channel modulators for schizophrenia treatment. [F-18]-FDOPA PET imaging showed very good test-retest reliability in patients with schizophrenia.