Anhedonia—the loss of pleasure or lack of reactivity to pleasurable stimuli—remains a formidable treatment challenge across neuropsychiatric disorders. In major depressive disorder, anhedonia has been linked to poor disease course, worse response to psychological, pharmacological, and neurostimulation treatments, and increased suicide risk. Moreover, although some neural abnormalities linked to anhedonia normalize after successful treatment, several persist—for example, blunted activation of the ventral striatum to reward-related cues and reduced functional connectivity involving the ventral striatum. Critically, some of these abnormalities have also been identified in unaffected, never-depressed children of parents with major depressive disorder and have been found to prospectively predict the first onset of major depression. Thus, neural abnormalities linked to anhedonia may be promising targets for prevention. Despite increased appreciation of the clinical importance of anhedonia and its underlying neural mechanisms, important gaps remain. In this overview, the author first summarizes the extant knowledge about the pathophysiology of anhedonia, which may provide a road map toward novel treatment and prevention strategies, and then highlights several priorities to facilitate clinically meaningful breakthroughs. These include a need for 1) appropriately controlled clinical trials, especially those embracing an experimental therapeutics approach to probe target engagement; 2) novel preclinical models relevant to anhedonia, with stronger translational value; and 3) clinical scales that incorporate neuroscientific advances in our understanding of anhedonia. The author concludes by highlighting important future directions, emphasizing the need for an integrated, collaborative, cross-species, and multilevel approach to tackling anhedonic phenotypes.

快感缺乏——快乐的丧失或对愉悦刺激缺乏反应——仍然是神经精神疾病治疗的一个巨大挑战。在重度抑郁症中，快感缺失与病程不良、对心理、药物和神经刺激治疗的反应较差以及自杀风险增加有关。此外，尽管一些与快感缺失相关的神经异常在成功治疗后恢复正常，但仍有一些异常持续存在，例如，腹侧纹状体对奖励相关线索的激活减弱以及涉及腹侧纹状体的功能连接减少。重要的是，其中一些异常现象也在父母患有重度抑郁症的未受影响、从未抑郁的孩子中被发现，并且被发现可以前瞻性地预测重度抑郁症的首次发作。因此，与快感缺失相关的神经异常可能是有希望的预防目标。尽管人们越来越认识到快感缺乏的临床重要性及其潜在的神经机制，但仍然存在重要的差距。在这篇概述中，作者首先总结了有关快感缺失病理生理学的现有知识，这可能为新的治疗和预防策略提供路线图，然后强调了促进具有临床意义的突破的几个优先事项。这些包括需要：1）适当对照的临床试验，特别是那些采用实验治疗方法来探测目标参与的临床试验；2）与快感缺失相关的新颖的临床前模型，具有更强的转化价值；3）临床量表将神经科学的进步融入我们对快感缺乏的理解中。