The serotonin deficit hypothesis explanation for major depressive disorder (MDD) has persisted among clinicians and the general public alike despite insufficient supporting evidence. To combat rising mental health crises and eroding public trust in science and medicine, researchers and clinicians must be able to communicate to patients and the public an updated framework of MDD: one that is (1) accessible to a general audience, (2) accurately integrates current evidence about the efficacy of conventional serotonergic antidepressants with broader and deeper understandings of pathophysiology and treatment, and (3) capable of accommodating new evidence. In this article, we summarize a framework for the pathophysiology and treatment of MDD that is informed by clinical and preclinical research in psychiatry and neuroscience. First, we discuss how MDD can be understood as inflexibility in cognitive and emotional brain circuits that involves a persistent negativity bias. Second, we discuss how effective treatments for MDD enhance mechanisms of neuroplasticity—including via serotonergic interventions—to restore synaptic, network, and behavioral function in ways that facilitate adaptive cognitive and emotional processing. These treatments include typical monoaminergic antidepressants, novel antidepressants like ketamine and psychedelics, and psychotherapy and neuromodulation techniques. At the end of the article, we discuss this framework from the perspective of effective science communication and provide useful language and metaphors for researchers, clinicians, and other professionals discussing MDD with a general or patient audience.

尽管没有足够的支持证据，但临床医生和公众仍然坚持用血清素缺乏假说来解释重度抑郁症（MDD）。为了应对日益严重的心理健康危机并削弱公众对科学和医学的信任，研究人员和临床医生必须能够向患者和公众传达最新的 MDD 框架：(1) 普通受众可以理解，(2) 准确将有关传统血清素能抗抑郁药疗效的现有证据与对病理生理学和治疗的更广泛和更深入的理解相结合，并且（3）能够容纳新的证据。在本文中，我们根据精神病学和神经科学的临床和临床前研究总结了 MDD 的病理生理学和治疗框架。首先，我们讨论如何将 MDD 理解为认知和情感大脑回路的不灵活性，涉及持续的消极偏见。其次，我们讨论了 MDD 的有效治疗如何增强神经可塑性机制（包括通过血清素干预），以促进适应性认知和情绪处理的方式恢复突触、网络和行为功能。这些治疗包括典型的单胺能抗抑郁药、氯胺酮和迷幻药等新型抗抑郁药，以及心理治疗和神经调节技术。在文章的最后，我们从有效的科学传播的角度讨论了这个框架，并为研究人员、临床医生和其他专业人士与普通或患者受众讨论 MDD 提供了有用的语言和隐喻。