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.