A Placebo-Controlled Trial of D-Cycloserine Added to Conventional Neuroleptics in Patients With Schizophrenia

Abstract

RECENT EFFORTS to direct pharmacological intervention at theN-methyl-D-aspartate (NMDA) subtype of glutamate receptor have followed from evidence linking this receptor complex to schizophrenia.^1,2 For example, phencyclidine and ketamine, noncompetitive antagonists at the NMDA receptor complex, produce positive and negative symptoms, thought disorder, and cognitive symptoms that may better mimic schizophrenia than other pharmacological models.^3,4 Because of the risk of neurotoxic effects, agents at the NMDA receptor do not represent a viable therapeutic approach to correct a hypothesized hypoactivity at the NMDA receptor complex.^5,6 More promising are agents directed at the glycine modulatory site of the NMDA receptor complex that enhance activation of the NMDA-gated voltage-dependent cation channel with substantially lower risk of neurotoxic effects.⁷ Glycine acts as an obligatory co-agonist at this site, increasing the frequency of the NMDA-gated channel openings.⁸ In early open-label trials, glycine administered at doses ranging from 5 to 15 g/d produced improvement of negative symptoms in 33% to 50% of patients with schizophrenia, although results were inconsistent, possibly due to its poor penetration of the blood-brain barrier.^9-11 More recently, Javitt et al¹² reported that higher oral doses (0.4 g/kg per day or approximately 30 g/d) of glycine added to antipsychotic medication significantly improved negative symptoms (mean decrease of 15%). In a subsequent placebo-controlled crossover trial, glycine (60 g/d) was administered to 11 patients with schizophrenia for 6 weeks and produced a significant 36% mean reduction in negative symptom scores.¹³ Serum concentrations of glycine at baseline correlated inversely with the reduction in negative symptom scores (r=0.91, P<.001).