Early Intervention for Psychosis with N-Methyl-D-Aspartate Receptor Modulators

TO THE EDITOR Accumulating evidence suggests that patients with schizophrenia exhibit nonpsychotic, nonspecific prodromal symptoms for several years before the onset of frank psychosis. A meta-analysis demonstrated that cognitive impairment is a common feature of the prodromal state of psychosis. Accordingly, interest in the potential benefit of early intervention in psychosis is increasing. We read the recent article by Kantrowitz et al., concerning the efficacy of D-serine (an endogenous co-agonist at the N-methyl-D-aspartate receptor; NMDAR) on negative symptoms in individuals at clinical high risk of schizophrenia, with great interest. In a double-blind, placebo-controlled trial, these authors compared D-serine (n=20, 60 mg/kg) and placebo (n=24) for 16 weeks. The primary endpoint was scores on the negative subscale of the Scale of Prodromal Symptoms (SOPS). D-Serine induced a significant (35.7%) improvement in negative symptoms compared to placebo, although the number of conversions (one in the D-serine group and two in the placebo group) was too small for statistical analysis, in part due to the short duration of treatment. Nevertheless, these pilot data suggest that D-serine is an effective treatment of prodromal schizophrenia symptoms, despite the small sample size. Previously, we reported that serum D-serine levels in patients with schizophrenia were lower compared to control subjects, whereas serum L-serine levels were higher in patients than in controls. Furthermore, we reported a reduced ratio of D-serine to total serine (DL-serine) in the cerebrospinal fluid of first-episode and drug naïve schizophrenia patients, indicating decreased NMDAR neurotransmission in the brain in early phase patients. Combined, these findings suggest that disturbed NMDAR neurotransmission, due to decreased D-serine levels, plays a causative role in the pathogenesis of schizophrenia. In the brain, D-serine is synthesized from L-serine by serine racemase (SRR). A recent genome-wide association study confirmed the association between SRR and schizophrenia. Furthermore, we reported that D-serine supplementation at between 5 and 10 weeks could prevent schizophrenia-like behavioral abnormalities in adult mice (11 weeks old) after neonatal disruption of SRR, suggesting that early intervention with D-serine prevents the onset of psychosis in adults. Finally, glycine, another NMDAR co-agonist, was associated with a 10-15% reduction in negative SOPS symptoms in high-risk subjects. In conclusion, given the role of NMDAR hypofunction in prodromal symptoms (e.g., cognitive impairment) and early stage schizophrenia, NMDAR modulators, including D-serine, glycine, D-alanine, and sarcosine, may be effective early intervention for psychosis because they all occur naturally in humans.