Dcycloserine Augmentation of Cognitive Behavioral Therapy for Delusions

描述（由申请人提供）：抗精神病药物抗性妄想在精神分裂症中很常见，经常导致监禁和自残。来自认知神经科学的越来越多的证据表明，错觉之所以持续存在，是因为无法消除或“忘记”错误的信念；在记忆巩固过程中未能激活腹内侧前额叶皮层似乎在这种缺陷中发挥了作用。d -环丝氨酸是一种高度有效的NMDA受体亚群的完全激动剂，参与记忆巩固，并在恐惧消退模型中强有力地增强记忆巩固，当与CBT联合治疗焦虑症时。我们已经证明了使用d -环丝氨酸可以改善精神分裂症患者的记忆巩固，并在一项试点试验中证明，当与使用替代信念练习的两次CBT相结合时，对妄想严重程度和痛苦有很大的影响。我们现在提出了一项平行组，安慰剂对照试验，每周一次d -环丝氨酸增加12次CBT治疗60名精神分裂症患者的持续性妄想，随访3个月和6个月。除了评估和表征妄想的反应外，本研究还将阐明效果的时间过程，并检查可能介导d -环丝氨酸效果的认知因素，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更大规模、更明确的试验提供必要的数据，从根本上改变难治性妄想的治疗方法，同时为令人信服的妄想新模型提供重要的临床试验。

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.