Singewald N, Schmuckermair C, Whittle N, Holmes A, Ressler K J
Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
Pharmacol Ther. 2015 May;149:150-90. doi: 10.1016/j.pharmthera.2014.12.004. Epub 2014 Dec 27.
Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L-DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery.
病理性恐惧和焦虑极具致残性，尽管心理治疗和药物治疗取得了显著进展，但许多创伤后应激障碍、恐惧症、惊恐障碍及其他焦虑症患者的病情仍未得到充分治疗。越来越多的临床前和临床证据表明，包括认知增强剂在内的药物治疗作为心理治疗方法（包括基于消退的暴露疗法的认知行为疗法）的辅助手段时，可提高治疗效果，而使用苯二氮䓬类等抗焦虑药作为辅助手段则可能破坏长期治疗效果。本综述的目的是概述相关文献，展示针对包括5-羟色胺、多巴胺、去甲肾上腺素、组胺、谷氨酸、γ-氨基丁酸、大麻素、神经肽（催产素、神经肽Y和S、阿片类物质）以及其他靶点（神经营养因子脑源性神经营养因子和碱性成纤维细胞生长因子2、糖皮质激素、L型钙通道、表观遗传修饰）及其下游信号通路的神经递质系统的药物干预，如何在临床前模型中增强恐惧消退并持续强化消退记忆。文中讨论了特别有前景的方法对恐惧消退特定方面的影响，即获得、巩固和提取，包括长期预防恐惧复发（如自发恢复、恐惧重现和更新）等现象。我们还强调了临床前研究有前景的转化价值以及用例如d-环丝氨酸、育亨宾、皮质醇和左旋多巴靶向某些神经化学系统的临床潜力。当前的研究成果揭示了恐惧消退的神经生物学和神经化学方面的重要新见解，并为药物增强心理治疗带来了重大希望，这是一种更有效、更持久地治疗创伤和焦虑相关疾病的改进方法，可促进症状缓解和康复。
