Instructor of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
Medical student, Washington University School of Medicine, St. Louis, Missouri.
Mo Med. 2023 Jul-Aug;120(4):292-298.
The 21 century has brought novel therapies and new therapeutic targets for major depressive disorder (MDD). Until recently all antidepressant medications targeted monoamines-serotonin, norepinephrine, and dopamine- and their regulatory systems. But growing evidence has suggested that individuals who fail to respond to a monoaminergic treatment are likely to fail to respond to other monoaminergic options. The emergence in recent years of treatment targets beyond the monoaminergic systems (e.g. κ-opioid antagonists, ketamine and other NMDA modulators, neurosteroids) has cultivated hopes for not only greater efficacy in treating depression, but also improved precision in targeting specific phenotypes and symptoms. Concurrently, an expanding repertoire of diagnostic and assessment tools-such as smartphone-based experience sampling and brain imaging-is moving the field toward more reliable and symptom-specific measurement with greater descriptive and prescriptive power. Taken together, these diagnostic tools and treatment options herald a new era of "precision psychiatry"-the selection and implementation of an optimal treatment for an individual patient's particular needs. Anhedonia offers an example of the new precision psychiatry. Anhedonia has moved from merely one among several criteria for depression to a transdiagnostic psychopathology which can be understood neurobiologically, assessed quantitatively, and centered as a primary target in research and development of novel pharmacotherapies. We describe functional testing of reward circuits in the development of kappa-opioid antagonists for anhedonia. This offers a lens for understanding how and under what circumstances other novel treatments, such as psychedelics, might find a place in the future landscape of precision psychiatric care.
21 世纪为重度抑郁症（MDD）带来了新的治疗方法和新的治疗靶点。直到最近，所有的抗抑郁药物都针对单胺类物质——血清素、去甲肾上腺素和多巴胺及其调节系统。但越来越多的证据表明，对单胺能治疗无反应的个体很可能对其他单胺能治疗方案无反应。近年来，除单胺能系统之外的治疗靶点（如κ-阿片受体拮抗剂、氯胺酮和其他 NMDA 调节剂、神经甾体）的出现，不仅为治疗抑郁症的疗效提供了更大的希望，而且为针对特定表型和症状的精准治疗提供了更好的选择。与此同时，诊断和评估工具的范围不断扩大——例如基于智能手机的体验采样和脑成像——正在推动该领域朝着更可靠和更具症状特异性的测量方向发展，具有更大的描述性和规定性。综上所述，这些诊断工具和治疗方案预示着“精准精神病学”的新时代——为个体患者的特定需求选择和实施最佳治疗方案。快感缺失就是新的精准精神病学的一个例子。快感缺失已经从抑郁症的几个标准之一转变为一种跨诊断的精神病理学，可以从神经生物学上进行理解，可以进行定量评估，并作为新型药物治疗的研究和开发的主要目标。我们描述了在开发用于快感缺失的κ-阿片受体拮抗剂过程中对奖赏回路的功能测试。这为理解其他新型治疗方法（如迷幻药）在未来的精准精神护理领域中可能发挥作用的方式和情况提供了一个视角。
