Although first-line antidepressants offer therapeutic benefit, about 35% of depressed patients are not adequately treated, creating a large unmet medical need. These medicines mostly enhance the synaptic levels of serotonin and/or norepinephrine. Evidence from preclinical and clinical studies implicate dopamine hypofunction in the pathophysiology of depression. Triple reuptake inhibitors (TRIs), which elevate dopamine in addition to serotonin and norepinephrine, may demonstrate greater efficacy, with the reversal of anhedonia and improved tolerability. Medicinal chemistry efforts have resulted in more than 10 clinical candidates, although clinical candidates have failed to demonstrate superior efficacy compared to placebo or existing antidepressants. Hence, the successful development of future TRIs for depression will demand strong translational evidence, an optimal dosing regimen, and better tolerability. TRIs also hold therapeutic potential for other indications, with four candidates under clinical development for attention deficit hyperactivity disorder, binge eating disorder, cocaine addiction, obesity, and type 2 diabetes. Clinical studies have indicated a lower abuse potential for TRIs than psychostimulants.

中文翻译：

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三重再摄取抑制剂作为抑郁症和其他疾病的潜在疗法：设计范例和发展挑战

尽管一线抗抑郁药可提供治疗益处，但约35％的抑郁症患者未得到充分治疗，从而产生了大量未满足的医疗需求。这些药物主要增强5-羟色胺和/或去甲肾上腺素的突触水平。临床前和临床研究的证据表明，多巴胺功能低下与抑郁症的病理生理有关。三重再摄取抑制剂（TRIs）不仅可以提高5-羟色胺和去甲肾上腺素的多巴胺水平，还可以显示出更高的疗效，可以逆转快感缺失和改善的耐受性。尽管与候选药物或现有抗抑郁药相比，临床候选药物未能显示出优异的疗效，但药物化学方面的努力已导致产生了十多种临床候选药物。因此，未来针对抑郁症的TRI的成功开发将需要强有力的转化证据，最佳的给药方案以及更好的耐受性。TRIs还具有治疗其他适应症的潜力，目前有四个候选药物正在临床开发中，用于注意力缺陷多动障碍，暴食症，可卡因成瘾，肥胖症和2型糖尿病。临床研究表明，与精神刺激药相比，TRIs的滥用可能性更低。