Abstract
The glycine reuptake inhibitor (GRI) bitopertin (also known as RG1678 or RO-4917838), invented by Hoffmann-La Roche, was poised to make an impact on the pharmacotherapy of schizophrenia, but hope was finally dashed by the disappointing outcomes of the recently completed multi-centre phase III clinical trials. Against this backdrop, this review aims to survey the rationale and potential of GRIs to treat neuropsychiatric conditions beyond schizophrenia. Indeed, although the development of bitopertin as an anti-schizophrenia drug has since been shelved, it is still being pursued by Roche as a potential adjunctive medication for the treatment of obsessive-compulsive disorder. Several lines of research have independently indicated that the pharmacological inhibition of glycine reuptake may be relevant to the treatment of diverse clinical conditions, including depression, anxiety disorders, alcohol dependence, epilepsy, and pain. In each case, the rationale emphasizes the physiological impact of glycine reuptake inhibition on either the inhibitory glycinergic neurotransmission or the excitatory v-methyl-D- aspartate receptor-dependent glutamatergic neurotransmission. None of the proposed clinical applications, however, can readily incorporate and integrate, a priori, both expected neuropharmacological effects of GRIs. The dual action of glycine in the nervous system may be the Achilles heel in precisely predicting the outcome of the systemic effects of GRIs, which may explain why none of these approaches has yet yielded any clinic-ready GRI drug. A better understanding at the circuitry level implicated in the respective disorders would be needed to overcome this roadblock to drug discovery.
Original language | English |
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Title of host publication | Psychiatry and Neuroscience Update |
Publisher | Springer International Publishing |
Pages | 389-403 |
Number of pages | 15 |
Volume | 2 |
ISBN (Electronic) | 9783319531267 |
ISBN (Print) | 9783319531250 |
DOIs | |
Publication status | Published - 1 Jul 2017 |
Keywords
- Addiction
- Glutamate
- Glycine transporter
- NMDA receptor
- Obsessive-compulsive disorder
- Pain
- Schizophrenia
ASJC Scopus subject areas
- General Medicine
- General Neuroscience
- General Psychology