d-cycloserine facilitation of cognitive behavioral therapy for delusions in schizophrenia

Glutamatergic N-methyl-d-aspartate (NMDA) receptor hypofunction has been proposed as a mechanism underlying psychosis. d-cycloserine, a partial agonist at the glycine site of the NMDA receptor, enhances learning in animal models, although tachyphylaxis develops with repeated dosing. Once-weekly dosing of d-cycloserine produces persistent improvement when combined with cognitive behavioral therapy (CBT) in anxiety disorders. Delusional beliefs can be conceptualized as a learning deficit, characterized by the failure to use contradictory evidence to modify the belief. CBT techniques have been developed with modest success to facilitate such reality-testing (or new learning) in delusional beliefs. The current study evaluated whether d-cycloserine could potentiate beneficial effects of CBT on delusional severity. Twenty-one outpatients with schizophrenia or schizoaffective disorder and moderately severe delusions were randomized in a double-blind cross-over design to receive a single-dose of either d-cycloserine 50 mg or placebo in a counterbalanced order on two consecutive weeks 1 h prior to a CBT intervention involving training in the generation of alternative beliefs. Assessments were completed at baseline, 7 days following the first study drug administration and 7 days following the second study drug administration. Contrary to prediction, there was no significant d-cycloserine treatment effect on delusional distress or severity as measured by the SAPS or PSYRATS. An unexpected finding was an order effect, whereby subjects who received d-cycloserine first had significantly reduced delusional severity, distress, and belief conviction on PSYRATS compared to subjects who received placebo first. However, this finding is consistent with animal models in which d-cycloserine enhances learning only when accompanying the first exposure to training.