Dcycloserine Augmentation of Cognitive Behavioral Therapy for Delusions

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DESCRIPTION (provided by applicant): Antipsychotic-resistant delusions are common in schizophrenia and are frequently responsible for incarceration and self injury. Converging evidence from cognitive neuroscience suggests that delusions persist due to an inability to extinguish or "unlearn" the false belief; a failure to activate ventromedial prefrontal cortex durig memory consolidation appears to play a role in this deficit. D-cycloserine is a highly potent full agonist at a subpopulation of NMDA receptors involved in memory consolidation and robustly enhances memory consolidation in fear extinction models and when combined with CBT in anxiety disorders. We have demonstrated improvement of memory consolidation with D-cycloserine in schizophrenia and, in a pilot trial, demonstrated a large effect on delusional severity and distress when combined with two sessions of CBT employing an alternative beliefs exercise. We now propose a parallel-group, placebo-controlled trial of once-weekly D-cycloserine augmentation of a 12 session CBT treatment for persistent delusions in 60 schizophrenia subjects with follow-up at 3 and 6 months. In addition to assessing and characterizing response of delusions, this study will clarify time course of effect and examine cognitive factors that may mediate D-cycloserine's effect, including enhancement of memory consolidation and of cognitive flexibility. This study will provide data necessary to design and implement a larger, definitive trial that could fundamentally alter the treatment approach to refractory delusions while providing an important clinical test for a compelling new model for delusions.