The glycine site of NMDA receptors: A target for cognitive enhancement in psychiatric disorders

Bahareh Peyrovian; Joshua D Rosenblat; Zihang Pan; Michelle Iacobucci; Elisa Brietzke; Roger S McIntyre

doi:10.1016/j.pnpbp.2019.02.001

The glycine site of NMDA receptors: A target for cognitive enhancement in psychiatric disorders

Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jun 8:92:387-404. doi: 10.1016/j.pnpbp.2019.02.001. Epub 2019 Feb 6.

Authors

Bahareh Peyrovian¹, Joshua D Rosenblat², Zihang Pan³, Michelle Iacobucci¹, Elisa Brietzke⁴, Roger S McIntyre⁵

Affiliations

¹ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
² Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
³ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
⁴ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, Federal University of São Paulo (Unifesp), São Paulo, SP, Brazil.
⁵ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada. Electronic address: Roger.McIntyre@uhn.ca.

PMID: 30738126
DOI: 10.1016/j.pnpbp.2019.02.001

Abstract

Cognitive dysfunction is a principal determinant of functional impairment in major depressive disorder (MDD) and often persists during periods of euthymia. Abnormalities in the glutamate system, particularly in N-methyl-d-aspartate receptors (NMDARs) activity, have been shown to contribute to both mood and cognitive symptoms in MDD. The current narrative review aims to evaluate the potential pro-cognitive effects of targeting the glycine site of NMDARs in the treatment of psychiatric disorders, with a special focus on how these results may apply to MDD. Literature databases were searched from inception to May 2018 for relevant pre-clinical and clinical studies evaluating antidepressant and pro-cognitive effects of NMDAR glycine site modulators in both MDD and non-MDD samples. Six glycine site modulators with pro-cognitive and antidepressant properties were identified: d-serine (co-agonist), d-cycloserine (partial agonist), d-alanine (co-agonist), glycine (agonist), sarcosine (co-agonist) and rapastinel (partial agonist). Preclinical animal studies demonstrated improved neuroplasticity and pro-cognitive effects with these agents. Numerous proof-of-concept clinical trials demonstrated pro-cognitive and antidepressant effects trans-diagnostically (e.g., in healthy participants, MDD, schizophrenia, anxiety disorders, major neurocognitive disorders). The generalizability of these clinical studies was limited by the small sample sizes and the paucity of studies directly evaluating cognitive effects in MDD samples, as most clinical trials were in non-MDD samples. Taken together, preliminary results suggest that the glycine site of NMDARs is a promising target to ameliorate symptoms of depression and cognitive dysfunction. Additional rigorously designed clinical studies are required to determine the cognitive effects of these agents in MDD.

Keywords: Cognitive enhancement; Glutamate; Glycine site; Ketamine; Major depressive disorder (MDD); N-methyl-d-aspartate (NMDA).

Publication types

Review

MeSH terms

Animals
Antidepressive Agents / therapeutic use*
Cognition Disorders / complications
Cognition Disorders / drug therapy*
Depressive Disorder, Major / complications
Depressive Disorder, Major / drug therapy*
Humans
Nootropic Agents / therapeutic use*
Protein Binding / drug effects*
Receptors, N-Methyl-D-Aspartate / agonists*

Substances

Antidepressive Agents
Nootropic Agents
Receptors, N-Methyl-D-Aspartate