Witkin Consulting Group, Carmel, Indiana, 46033, United States.
Department of Chemistry and Biochemistry, University of Wisconsin- Milwaukee, Milwaukee Wisconsin, United States.
Curr Pharm Des. 2018;24(22):2556-2563. doi: 10.2174/1381612824666180730104707.
Conventional antidepressants are thought to produce their impact on clinical symptoms by increasing the central availability of biogenic amine neurotransmitters (the monoamine hypothesis of depression). These drugs continue to be the primary medicines used in major depressive disorder. Although they have biological effects after acute dosing, full antidepressant response generally takes weeks of daily administration. Lack of rapid onset is a large limitation in antidepressant therapy (e.g., suicide, lack of medication compliance, difficulty switching medications).
The present review of the literature discusses the preclinical and clinical findings on compounds that can produce immediate symptom relief.
These compounds include ketamine, scopolamine, and mechanistically-related drugs. Newer additions to the list of potential rapid-acting agents include antagonists of metabotropic (mGlu) 2/3 receptors, negative allosteric modulators of α5-containing GABAA receptors, and psychedelic compounds. An additional benefit of these compounds is that they have demonstrated large effect sizes and, importantly, demonstrated efficacy in patient's refractory to other treatments. A drawback of some of these compounds, to date, is finding ways to expand the duration of clinical efficacy. In addition, for some compounds, the side-effect profile requires management. A primary mechanism by which rapid effects might be produced is through the amplification of excitatory neurotransmission through activation of AMPA receptors. The extracellular efflux of glutamate induced by these drugs has been documented and provides the hypothesized triggering mechanism for AMPA receptor amplification.
The preclinical and clinical literature strongly suggests that rapid-acting antidepressants are the current focus of antidepressant drug discovery. Promising clinical findings exist for several compounds including ketamine and other NMDA receptor antagonists, scopolamine, and psilocybin. Two compounds are in late stage clinical development: GLYX-13 (Rapastinel) and eskekamine.
传统的抗抑郁药被认为通过增加生物胺神经递质的中枢可用性（抑郁症的单胺假说）来产生对临床症状的影响。这些药物仍然是治疗重度抑郁症的主要药物。尽管它们在急性给药后具有生物学效应，但完全的抗抑郁反应通常需要数周的每日给药。起效缓慢是抗抑郁治疗的一个很大的局限性（例如，自杀、药物依从性差、药物更换困难）。
本文综述了关于能立即缓解症状的化合物的临床前和临床研究结果。
这些化合物包括氯胺酮、东莨菪碱和具有类似作用机制的药物。潜在的快速作用药物中新增的有代谢型谷氨酸受体 2/3（mGlu）拮抗剂、α5 型 GABA A 受体负变构调节剂和迷幻化合物。这些化合物的另一个好处是它们已经显示出了较大的效应量，并且重要的是，对其他治疗方法无效的患者也显示出了疗效。这些化合物中的一些化合物，到目前为止，找到扩大临床疗效持续时间的方法是一个挑战。此外，对于一些化合物，其副作用谱需要进行管理。快速作用的一个主要机制可能是通过激活 AMPA 受体来放大兴奋性神经传递。这些药物诱导的谷氨酸细胞外流出已被记录下来，并为 AMPA 受体放大提供了假设的触发机制。
临床前和临床文献强烈表明，快速作用的抗抑郁药是当前抗抑郁药物发现的重点。几种化合物的临床研究结果很有前景，包括氯胺酮和其他 NMDA 受体拮抗剂、东莨菪碱和裸盖菇素。两种化合物正在进行后期临床试验：GLYX-13（Rapastinel）和 Esketamine。
