While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or
positive symptoms of schizophrenia, there is no satisfactory medication for the negative and cognitive symptoms of
schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class
of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent
development of glycine transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy
stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction
of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of
GlyT1 reduces clearance of extra-cellular glycine near NMDA receptor-containing synapses, and thereby increases
baseline occupancy of the glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of
channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to
boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity
associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin
(a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the
glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing.
The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the
therapeutic potential of GlyT1 inhibition or down-regulation.
Keywords: Antipsychotics, Bitopertin, Glycine, GlyT1, NMDA receptor, RG1678, RO-4917838, Schizophrenia.
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