Binding of clozapine to the GABAB receptor: clinical and structural insights

Clozapine is the gold-standard agent for treatment resistant schizophrenia but its mechanism of action remains unclear. There is emerging evidence of the potential role of the GABA(B) receptor in the pathogenesis of schizophrenia. It has been hypothesised that clozapine can mediate its actions via the GABA(B) receptor. Baclofen is currently recognised as the prototype GABA(B) receptor agonist. There are some potential clinical similarities between clozapine and baclofen. Indeed, baclofen has been previously proposed for use as an antipsychotic agent. Our analysis of the X-ray crystal structure of GABA(B) receptor along with molecular docking calculations, suggests that clozapine could directly bind to the GABA(B) receptor similar to that of baclofen. This finding could lead to a better understanding of the pharmacological uniqueness of clozapine, potential development of a biomarker for treatment resistant schizophrenia and the development of more targeted treatments leading to personalisation of treatment.