Dcycloserine Augmentation of Cognitive Behavioral Therapy for Delusions

描述(由申请人提供)：抗精神病药物抵抗妄想症在精神分裂症中很常见，经常导致监禁和自我伤害。来自认知神经科学的综合证据表明，妄想症之所以持续存在，是因为无法消除或忘记错误的信念；在记忆巩固期间，未能激活腹内侧额前皮质似乎在这一缺陷中起到了作用。D-环丝氨酸是参与记忆巩固的NMDA受体亚群中的一种高度有效的完全激动剂，在恐惧消退模型中以及在焦虑症中与CBT联合使用时，它能有力地增强记忆巩固。我们已经证明了D-环丝氨酸对精神分裂症患者记忆巩固的改善，并且在一项试点试验中，当与采用另类信念练习的两次CBT相结合时，证明了对妄想严重程度和痛苦的巨大影响。我们现在提出了一项平行分组的安慰剂对照试验，每周一次，对60名精神分裂症患者进行为期12个疗程的CBT治疗，并在3个月和6个月进行随访。除了评估和表征妄想症的反应外，这项研究还将阐明作用的时间进程，并检查可能介导D-环丝氨酸作用的认知因素，包括增强记忆巩固和认知灵活性。这项研究将为设计和实施一项更大规模的决定性试验提供必要的数据，这项试验可能从根本上改变顽固性妄想的治疗方法，同时为引人注目的新妄想症模型提供重要的临床测试。

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.