A strategy to predict psychotic risks of drug candidates using auditory steady-state response

It is difficult to predict the psychiatric adverse effects of drug candidates from preclinical observations especially when the mechanism of actions is novel. Recently, auditory steady-state response (ASSR) in gamma band frequency has been reported as a translational biomarker for psychotic disorders and is thought to reflect the cortical functionality for neuronal oscillations. To investigate its potential for preclinical risk assessment, we evaluated the effects of the psychotogenic drugs, a non-competitive NMDA antagonist MK-801, a dopamine transporter inhibitor methylphenidate and a 5HT2 agonist DOI, on high gamma ASSR from rat auditory cortex using a chirp-modulated tone whose modulation frequency change from 1 to 120 Hz or from 120 to 1 Hz. The effect of MK-801 was very robust that it attenuated the ASSR (83 % reduction in power (p < 0.0001) and 47 % reduction in phase-locking factor (PLF. p < 0.001)) at 1 mg/kg dose. The effect of methylphenidate on ASSR in power was relatively mild while it significantly attenuated PLF by 36 % at 50 mg/kg. The effect of DOI was somewhat different: The administration of 3 mg/kg did not attenuate the ASSR amplitude, but instead increased the chirp-frequency independent high gamma band (power 322 % of control, p < 0.05). These observations resemble the attenuation of phase-locked response and augmentation of non-phase-locked response in schizophrenia patients. In baseline period, the administration of 1 mg/kg of MK-801 or 50 mg/kg of methylphenidate enhanced spontaneous high gamma power (181 % of control for MK-801, p < 0.001, 183 % of control for methylphenidate, p < 0.05), which is also observed in human psychosis. Together with the clinical reports examining the drug effects on ASSR and with pharmacokinetic models from the literatures, our results suggest that ASSR and the related EEG response in high gamma band is a promising translational biomarker for the drug-induced psychosis, and that the use of chirp tone enables the clear discrimination of modulation frequency-dependent and -independent effects.