Background: Dysregulation of N-methyl D-aspartate (NMDA) receptor
signaling is strongly implicated in schizophrenia. Based on the ketamine model of
NMDA receptor hypoactivity, therapeutic approaches designed to maintain a
sustained increase in agonist activity at the glycine site of the NMDA receptor have
produced promising, although inconsistent, efficacy for negative symptoms.
Methods: A review of the published literature on D-cycloserine (DCS) pharmacology
in animal models and in clinical studies was performed. Findings relevant to DCS
effects on memory and plasticity and their potential clinical application to schizophrenia
Results: Studies in animals and clinical trials in patients with anxiety disorders have demonstrated that
single or intermittent dosing with DCS enhances memory consolidation. Preliminary trials in patients
with schizophrenia suggest that intermittent dosing with DCS may produce persistent improvement of
negative symptoms and enhance learning when combined with cognitive behavioral therapy for delusions
or with cognitive remediation. The pharmacology of DCS is complex, since it acts as a “super agonist” at
NMDA receptors containing GluN2C subunits and, under certain conditions, it may act as an antagonist
at NMDA receptors containing GluN2B subunits.
Conclusions: There are preliminary findings that support a role for D-cycloserine in schizophrenia as a
strategy to enhance neuroplasticity and memory. However, additional studies with DCS are needed to
confirm these findings. In addition, clinical trials with positive and negative allosteric modulators with
greater specificity for NMDA receptor subtypes are needed to identify the optimal strategy for enhancing
neuroplasticity in schizophrenia.