The high symptomatic and biological heterogeneity of major depressive disorder (MDD) makes it very difficult to find broadly efficacious treatments that work against all symptoms. Concentrating on single core symptoms that are biologically well understood might consist of a more viable approach. The Research Domain Criteria (RDoC) framework is a trans-diagnostic dimensional approach that focuses on symptoms and their underlying neurobiology. Evidence is accumulating that psychedelics may possess antidepressant activity, and this can potentially be explained through a multi-level (psychobiological, circuitry, (sub)cellular and molecular) analysis of the cognitive systems RDoC domain. Cognitive deficits, such as negative emotional processing and negativity bias, often lead to depressive rumination. Psychedelics can increase long-term cognitive flexibility, leading to normalization of negativity bias and reduction in rumination. We propose a theoretical model that explains how psychedelics can reduce the negativity bias in depressed patients. At the psychobiological level, we hypothesize that the negativity bias in MDD is due to impaired pattern separation and that psychedelics such as psilocybin help in depression because they enhance pattern separation and hence reduce negativity bias. Pattern separation is a mnemonic process that relies on adult hippocampal neurogenesis, where similar inputs are made more distinct, which is essential for optimal encoding of contextual information. Impairment in this process may underlie the negative cognitive bias in MDD by, for example, increased pattern separation of cues with a negative valence that can lead to excessive deliberation on aversive outcomes. On the (sub) cellular level, psychedelics stimulate hippocampal neurogenesis as well as synaptogenesis, spinogenesis and dendritogenesis in the prefrontal cortex. Together, these effects help restoring resilience to chronic stress and lead to modulation of the major connectivity hubs of the prefrontal cortex, hippocampus, and amygdala. Based on these observations, we propose a new translational framework to guide the development of a novel generation of therapeutics to treat the cognitive symptoms in MDD.

重度抑郁症 (MDD) 的高症状和生物学异质性使得很难找到针对所有症状的广泛有效的治疗方法。专注于生物学上很好理解的单一核心症状可能包括一种更可行的方法。研究领域标准（RDoC）框架是一个跨- 诊断维度方法，侧重于症状及其潜在的神经生物学。越来越多的证据表明迷幻药可能具有抗抑郁活性，这可以通过认知系统 RDoC 域的多层次（心理生物学、电路、（亚）细胞和分子）分析来解释。认知缺陷，例如消极情绪处理和消极偏见，通常会导致抑郁性反刍。迷幻药可以增加长期的认知灵活性，导致消极偏见的正常化和反刍的减少。我们提出了一个理论模型来解释迷幻药如何减少抑郁症患者的消极偏见。在心理生物学层面，我们假设 MDD 中的消极偏见是由于模式分离受损并且迷幻药如psilocybin有助于抑郁症，因为它们增强了模式分离，从而减少了消极偏见。模式分离是一个依赖于成人海马神经发生的记忆过程，其中相似的输入变得更加明显，这对于上下文信息的最佳编码至关重要。此过程中的损害可能是 MDD 中负面认知偏差的基础，例如，通过增加具有负效价的线索的模式分离可能导致对厌恶结果的过度审议。在（亚）细胞水平上，迷幻剂刺激海马神经发生以及前额叶皮层中的突触发生、脊柱发生和树突发生。总之，这些影响有助于恢复对慢性压力的恢复能力，并导致前额叶皮层主要连接枢纽的调节，海马体和杏仁核。基于这些观察，我们提出了一个新的转化框架来指导新一代疗法的发展，以治疗 MDD 的认知症状。