Novel Potential Therapeutics for Schizophrenia: Focus on the Modulation of Metabotropic Glutamate Receptor Function

Abstract

Schizophrenia is the most disabling psychiatric disorder and one of the world's top ten causes of long-term disability, affecting 1% of the population worldwide. The major symptoms of schizophrenia , psychosis (positive symptoms), apathy, social withdrawal (negative symptoms) and cognitive impairment, become manifest in late adolescence/early adulthood and persist thereafter, resulting in chronic disability. The pharmacotherapy of schizophrenia has evolved from typical antipsychotics (dopamine D2 receptor antagonists) to atypical antipsychotics (mixed D2 and serotonin 5-HT2A antagonists with activity at various other receptors) with improved efficacy and side effect profile. More recently, the glutamate/ N-methyl-D- aspartate glutamate receptor (NMDAR) hypothesis of schizophrenia has been formulated. This hypothesis is supported by the observation that administration of NMDAR blockers to human volunteers is psychotomimetic and administration to schizophrenic patients exacerbates pre-existing symptoms. This has generated an interest to develop novel antipsychotics focused on the identification of novel molecular targets and susceptibility genes that result in deregulation of glutamatergic , GABAergic and dopaminergic neurotransmission. In particular, metabotropic glutamate (mGlu) receptors mGlu2/3 and mGlu5 are prominently expressed in relevant forebrain regions and their activation modulates glutamatergic transmission and NMDAR function in the mammalian brain. The activity of mGlu2/3 and mGlu5 receptor agonists and more recently, the activity shown by selective mGlu2 and mGlu5 receptor allosteric potentiators in preclinical models of psychosis are promising. Further evaluation of the efficacy and side effect profile of potent, selective and brain-penetrant mGlu receptor activators may provide novel therapeutic avenues for the treatment of schizophrenia.