Department of Psychiatry and Neuroscience, University of California Riverside, Riverside, CA, USA.
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
J Psychopharmacol. 2023 Mar;37(3):242-247. doi: 10.1177/02698811231158891. Epub 2023 Mar 29.
Numerous new agents with rapid onset antidepressant effects are entering clinical trials and clinical practice. Studies focus on either first-line treatment of major depressive disorder or on patients whose major depressive disorder is resistant to prior antidepressant drugs. Novel agents target three very different central nervous system sites: as antagonists of -methyl-d-aspartate (NMDA) glutamate receptors, as positive allosteric modulators (PAMs) of gamma amino butyric acid (GABA) A neurosteroid and benzodiazepine receptor sites, and as psychedelic agonists of serotonin 2A/2C receptors. Onset of antidepressant action is rapid, sometimes after only one dose whereas traditional agents for depression take several days to weeks to have an antidepressant effect. Although the direct molecular targets of these three classes of agents with rapid antidepressant onset are quite diverse and not clearly related to each other, analysis of the downstream effects of all these agents show that all are "plastogens," namely agents that trigger rapid onset of neuroplasticity that correlates with their rapid onset of antidepressant clinical action. The GABA A PAMs and some of the NMDA antagonists induce neuroplasticity without notable changes in mental status and can be designated "neuroplastogens." Some NMDA antagonists cause mental dissociation, and the psychedelics cause psychotomimetic/hallucinatory experiences and can be designated "psychoplastogens." A great debate exists whether psychoplastogens are effective because of their ability to acutely alter mental state, or whether these acute mental states are unwanted behavioral toxicity. The promise of numerous novel agents with rapid acting antidepressant action and neuroplasticity is set to transform the treatment of major depressive disorder.
许多具有快速抗抑郁作用的新型药物正在进入临床试验和临床实践。这些研究的重点要么是治疗重度抑郁症的一线药物，要么是针对那些对抗抑郁药物耐药的重度抑郁症患者。新型药物针对三个非常不同的中枢神经系统部位：作为 -甲基-D-天冬氨酸（NMDA）谷氨酸受体的拮抗剂，作为γ-氨基丁酸（GABA）神经甾体和苯二氮䓬受体的正变构调节剂（PAMs），以及作为血清素 2A/2C 受体的致幻激动剂。抗抑郁作用的发作很快，有时只需一剂，而传统的抗抑郁药物需要数天到数周才能产生抗抑郁作用。尽管这三类具有快速抗抑郁作用的药物的直接分子靶点非常不同，彼此之间也没有明显的关联，但对所有这些药物的下游效应的分析表明，它们都是“塑体药物”，即触发快速神经可塑性的药物，这与它们快速抗抑郁的临床作用有关。GABA A PAMs 和一些 NMDA 拮抗剂在不改变精神状态的情况下诱导神经可塑性，可被指定为“神经塑体药物”。一些 NMDA 拮抗剂会引起精神分离，而致幻剂会引起精神病样/幻觉体验，可被指定为“心理塑体药物”。目前存在一个很大的争议，即心理塑体药物是否因其急性改变精神状态的能力而有效，还是这些急性精神状态是不受欢迎的行为毒性。具有快速抗抑郁作用和神经可塑性的新型药物的出现，有望彻底改变重度抑郁症的治疗方法。
