The Therapeutic Role of d-Cycloserine in Schizophrenia

The ketamine model for schizophrenia has led to several therapeutic strategies for enhancing N-methyl d-aspartate (NMDA) receptor activity, including agonists directed at the glycine receptor site and inhibitors of glycine reuptake. Because ketamine may primarily block NMDA receptors on inhibitory interneurons, drugs that reduce glutamate release have also been investigated as a means of countering a deficit in inhibitory input. These approaches have met with some success for the treatment of negative and positive symptoms, but results have not been consistent. An emerging approach with the NMDA partial agonist, d-cycloserine (DCS), aims to enhance plasticity by intermittent treatment. Early trials have demonstrated benefit with intermittent DCS dosing for negative symptoms and memory. When combined with cognitive remediation, intermittent DCS treatment enhanced learning on a practiced auditory discrimination task and when added to cognitive behavioral therapy, DCS improved delusional severity in subjects who received DCS with the first CBT session. These studies require replication, but point toward a promising strategy for the treatment of schizophrenia and other disorders of plasticity.