Semi-mechanistic computer simulation of psychotic symptoms in schizophrenia with a model of a humanized cortico-striatal-thalamocortical loop.

Despite new insights into the pathophysiology of schizophrenia and clinical trials with highly selective drugs, no new therapeutic breakthroughs have been identified. We present a semi-mechanistic Quantitative Systems Pharmacology (QSP) computer model of a biophysically realistic cortical-striatal-thalamo-cortical loop. The model incorporates the direct, indirect and hyperdirect pathway of the basal ganglia and CNS drug targets that modulate neuronal firing, based on preclinical data about their localization and coupling to voltage-gated ion channels. Schizophrenia pathology is introduced using quantitative human imaging data on striatal hyperdopaminergic activity and cortical dysfunction. We identified an entropy measure of neuronal firing in the thalamus, related to the bandwidth of information processing that correlates well with reported historical clinical changes on PANSS Total with antipsychotics after introduction of their pharmacology (42 drug-dose combinations, r2=0.62). This entropy measure is further validated by predicting the clinical outcome of 28 other novel stand-alone interventions, 14 of them with non-dopamine D2R pharmacology, in addition to 8 augmentation trials (correlation between actual and predicted clinical scores r2=0.61). The platform predicts that most combinations of antipsychotics have a lower efficacy over what can be achieved by either one; negative pharmacodynamical interactions are prominent for aripiprazole added to risperidone, haloperidol, quetiapine and paliperidone. The model also recapitulates the increased probability for psychotic breakdown in a supersensitive environment and the effect of ketamine in healthy volunteers. This QSP platform, combined with similar readouts for motor symptoms, negative symptoms and cognitive impairment has the potential to improve our understanding of drug effects in schizophrenia patients.