Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary.
Molecular Pharmacology Research Group, Szentágothai János Research Centre, University of Pécs, Pécs, Hungary.
Br J Pharmacol. 2022 Mar;179(6):1146-1186. doi: 10.1111/bph.15753. Epub 2022 Jan 26.
Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment-resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic biomarkers. Here, we review novel drug targets and drug candidates currently investigated in Phase I-III clinical trials. The most promising approaches are inhibition of glutamatergic neurotransmission by NMDA and mGlu receptor antagonists, modulation of the opioidergic system by κ receptor antagonists, and hallucinogenic tryptamine derivates. The only registered drug for TRD is the NMDA receptor antagonist, S-ketamine, but add-on therapies with second-generation antipsychotics, certain nutritive, anti-inflammatory and neuroprotective agents seem to be effective. Currently, there is an intense research focus on large-scale, high-throughput omics and neuroimaging studies. These results might provide new insights into molecular mechanisms and potential novel therapeutic strategies.
重度抑郁症是全球范围内导致残疾的主要原因。由于常规疗法对许多患者无效，因此需要新的策略来克服治疗抵抗性抑郁症（TRD）。在过去几十年中，药物开发的限制因素是缺乏（1）对病理生理学的了解，（2）转化动物模型和（3）客观的诊断生物标志物。在这里，我们回顾了目前处于 I 期至 III 期临床试验阶段的新型药物靶点和候选药物。最有前途的方法是通过 NMDA 和 mGlu 受体拮抗剂抑制谷氨酸能神经传递，通过 κ 受体拮抗剂调节阿片系统，以及致幻色胺衍生物。唯一注册用于 TRD 的药物是 NMDA 受体拮抗剂 S-氯胺酮，但添加第二代抗精神病药、某些营养、抗炎和神经保护剂的治疗似乎有效。目前，人们高度关注大规模、高通量的组学和神经影像学研究。这些结果可能为分子机制和潜在的新治疗策略提供新的见解。
