Institute of Pharmacy, Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck (CMBI), Leopold Franzens University Innsbruck, Innsbruck, Austria.
Institute of Pharmacy, Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck (CMBI), Leopold Franzens University Innsbruck, Innsbruck, Austria.
Pharmacol Ther. 2019 Dec;204:107402. doi: 10.1016/j.pharmthera.2019.107402. Epub 2019 Aug 27.
Current medication for anxiety disorders is suboptimal in terms of efficiency and tolerability, highlighting the need for improved drug treatments. In this review an overview of drugs being studied in different phases of clinical trials for their potential in the treatment of fear-, anxiety- and trauma-related disorders is presented. One strategy followed in drug development is refining and improving compounds interacting with existing anxiolytic drug targets, such as serotonergic and prototypical GABAergic benzodiazepines. A more innovative approach involves the search for compounds with novel mechanisms of anxiolytic action using the growing knowledge base concerning the relevant neurocircuitries and neurobiological mechanisms underlying pathological fear and anxiety. The target systems evaluated in clinical trials include glutamate, endocannabinoid and neuropeptide systems, as well as ion channels and targets derived from phytochemicals. Examples of promising novel candidates currently in clinical development for generalised anxiety disorder, social anxiety disorder, panic disorder, obsessive compulsive disorder or post-traumatic stress disorder include ketamine, riluzole, xenon with one common pharmacological action of modulation of glutamatergic neurotransmission, as well as the neurosteroid aloradine. Finally, compounds such as D-cycloserine, MDMA, L-DOPA and cannabinoids have shown efficacy in enhancing fear-extinction learning in humans. They are thus investigated in clinical trials as an augmentative strategy for speeding up and enhancing the long-term effectiveness of exposure-based psychotherapy, which could render chronic anxiolytic drug treatment dispensable for many patients. These efforts are indicative of a rekindled interest and renewed optimism in the anxiety drug discovery field, after decades of relative stagnation.
目前治疗焦虑症的药物在疗效和耐受性方面并不理想，这凸显了需要改进药物治疗。在这篇综述中，介绍了正在不同临床试验阶段研究的药物，这些药物可能对治疗恐惧、焦虑和创伤相关障碍有潜在作用。药物开发中遵循的一个策略是精制和改进与现有的抗焦虑药物靶点（如血清素能和典型的 GABA 能苯二氮䓬类）相互作用的化合物。一种更具创新性的方法是利用与病理性恐惧和焦虑相关的神经回路和神经生物学机制的不断增长的知识基础，寻找具有新型抗焦虑作用机制的化合物。在临床试验中评估的目标系统包括谷氨酸能、内源性大麻素和神经肽系统，以及离子通道和源自植物化学物质的靶点。目前在广泛性焦虑障碍、社交焦虑障碍、惊恐障碍、强迫症或创伤后应激障碍的临床开发中具有前景的新型候选药物包括氯胺酮、利鲁唑、氙气，它们具有共同的调节谷氨酸能神经传递的药理学作用，以及神经甾体 aloradine。最后，D-环丝氨酸、MDMA、L-DOPA 和大麻素等化合物已显示出在增强人类恐惧消退学习方面的疗效。因此，它们在临床试验中被作为一种增强策略进行研究，以加速和增强暴露疗法的长期疗效，这可能使许多患者不再需要长期使用抗焦虑药物治疗。这些努力表明，在经历了几十年的相对停滞之后，人们对焦虑症药物发现领域重新产生了兴趣和乐观。
