The Mental Health Priority Area of the Wellcome Trust recently posited that sleep and circadian rhythm disturbances (SCRDs) are a plausible nexus for linking aspects of the biology, phenomenology, course and treatment of major mood, anxiety and psychotic disorders¹. This emphasis fits well with the currently spreading trend to develop more effective and scalable forms of indicated prevention, early intervention, and secondary prevention (of both primary illness progression and physical illness).

This focus on SCRDs also aligns with broader studies as to why some specific periods of life (e.g., adolescence, postnatal, menopause, late life), accompanied by large shifts in the 24-hour patterns of the sleep-wake cycle, are also associated with elevated risk of major mood disorders². Along the same line, several research groups have now prioritized understanding of chronobiology to advance the management of all phases of major mood disorders (e.g., the Chronobiology Task Force of the International Society for Bipolar Disorders)³.

Developments in this area have been greatly assisted by increased understanding of the basic biology of the homeostatic circadian system – recognized by the Nobel Prize in Medicine or Physiology in 2017. Of note has been the delineation of the molecular architecture of the core circadian clock, along with the revelation that the circadian system's stability is fundamentally regulated by common environmental factors, such as the timing, intensity and spectrum of light exposure⁴. It appears that there are specific brain circuits in mammals by which light regulates mood, learning and activity, which are not wholly dependent on mediation by the master circadian timekeeper (the suprachiasmatic nucleus), including a recently identified region in the perihabenular nucleus.

The discovery of new light-sensitive brain circuits is of extreme interest to clinical psychiatry and psychiatric epidemiology. An intriguing finding from over 80,000 adults in the UK Biobank was that more exposure to artificial light at night was associated not only with increased rates of major depression, but also with an increased incidence of several other mental disorders, including bipolar disorder, generalized anxiety disorder and post-traumatic stress disorder, as well as with higher rates of self-harm behavior and psychosis-like experiences⁴. As predicted on the basis of the evidence that day-time light exposure is the primary synchronizer of the circadian clock in mammals, as well as the success of bright light therapy in the treatment of mood disorders, more light exposure during the day was also associated with lower rates of mental disorders⁴. Triangulation of evidence from animal models, experimental studies in humans, and epidemiology has provided strong evidence for a major role of daily light exposure to good mental health.

A focus on a possible causative role of SCRDs in the etiology and pathophysiology of at least some major mood disorders may surprise those who think of these disturbances as epiphenomena that accompany most mental disorders. However, recent discoveries regarding the regulation of many physiologic and behavioral parameters by the circadian system^{2, 3}, alongside major developments in longitudinal psychiatric epidemiology⁵, have challenged that assumption. Indeed, it is now strongly established by studies across clinical, laboratory and field-based settings that mood disorders such as bipolar disorder are related to SCRD-relevant features, including stable trait-like profiles of delayed sleep phase, long sleep time, and preference for eveningness^{2, 3}; delayed melatonin and core body temperature rhythms; and abnormal time relationships between circadian phase markers and the 24-hour sleep-wake cycle⁶.

Accumulating evidence suggests that circadian dysregulation is likely to be cross-diagnostic rather than disorder-specific³, and to be especially related to key mood (e.g., affective instability), behavioral (e.g., impulsivity), cognitive (e.g., disinhibition), and immune-metabolic (e.g., insulin resistance, raised C-reactive protein blood levels) phenotypes².

Empirical advances regarding the predictive significance of prior SCRDs for the first major episode have been most evident in the mood disorders domain. SCRD-related factors such as preference for eveningness and dysregulation of social rhythms are observed in at-risk groups (e.g., offspring of a parent with bipolar disorder) as well as in youth with early bipolar disorder, and meta-analytic evidence from prospective studies suggests that a pre-existing SCRD is associated with a 40% higher risk of onset of bipolar disorder⁷. A study of over 2,000 adolescents and young adults seeking help from early-intervention clinics found that prior circadian disturbance predicted the transition from an earlier to a later clinical stage of major mood, anxiety or psychotic disorders⁸.

Studies focusing on intensive longitudinal measurement of within- and between-day dynamics of mood, sleep and motor activity in adults with mood disorders – which appear to be more dysregulated and cross-reactive than those of control populations – have highlighted the need to investigate biological interfaces linking these systems, of which the homeostatic circadian system is one plausible candidate³.

The circadian system appears to be a potentially important target for more personalized treatment of at least a major subgroup of those with mood disorders. The discovery that treatments such as selective serotonin reuptake inhibitors (SSRIs) may increase sensitivity to light, and thereby destabilize the circadian system in at-risk individuals, is a major concern⁹. This finding requires urgent replication and extension to an examination of the possible positive or negative impacts of exposures to other common interventions, such as behavioral activation, sleep restriction, mood stabilizers, antipsychotic agents, and other antidepressants. Some new agents (e.g., orexin antagonists, melatonin-based antidepressants) and older pharmacotherapies (e.g., lithium) do appear to enhance the stabilization of these systems in several animal models as well as in small studies of patients with mood disorders³. Further testing of the circadian effects of such medications, and the potential for treatment-relevant subtyping, is highly warranted^{2, 9}.

There are major hurdles to the wider application of these new insights. Accurate, real-time, and repeated detection of the true timing of the internal circadian clock, and its alignment with the external light-dark cycle, remains a major goal. Current measures are largely limited to either intensive, expensive, in-lab methods, or indirect inferences from wearable recordings of the 24-hour patterns of motor activity and sleep. Hence, a clear research focus is the development of novel methods based on 24-hour patterns of gene expression, metabolic activity, and peripheral blood or urinary markers. More sophisticated modelling techniques, based on tracking symptom clusters and objective markers earlier in the course of illness, and then longitudinally, are also required to unpick the direction of causation between these phenomena.

Increased and coordinated global investment in this research area is timely, and may well lead to genuine new therapeutic insights.

威康信托基金会的心理健康优先领域最近提出，睡眠和昼夜节律紊乱 (SCRD) 可能是连接主要情绪、焦虑和精神障碍的生物学、现象学、病程和治疗方面的一个合理的联系¹。这一重点非常符合当前发展更有效和可扩展形式的指示性预防、早期干预和二级预防（原发性疾病进展和身体疾病）的趋势。

这种对 SCRD 的关注也与更广泛的研究相一致，即为什么某些特定的生命时期（例如青春期、产后、更年期、晚年）伴随着 24 小时睡眠-觉醒周期模式的巨大转变也与此相关。患有严重情绪障碍的风险较高² . 沿着同样的思路，一些研究小组现在优先考虑对时间生物学的理解，以推进对主要情绪障碍所有阶段的管理（例如，国际双相情感障碍学会的时间生物学工作组）³。

对稳态昼夜节律系统基础生物学的深入了解极大地促进了这一领域的发展，该系统荣获 2017 年诺贝尔医学或生理学奖。值得注意的是核心昼夜节律钟的分子结构的描绘，以及研究发现，昼夜节律系统的稳定性从根本上受到常见环境因素的调节，例如光照的时间、强度和光谱⁴。哺乳动物中似乎存在特定的大脑回路，通过光来调节情绪、学习和活动，这些回路并不完全依赖于昼夜节律主宰者（视交叉上核）的调节，包括最近在缰核周围核中发现的一个区域。

新的光敏感脑回路的发现引起了临床精神病学和精神病流行病学的极大兴趣。英国生物银行超过 80,000 名成年人的一项有趣发现是，夜间更多地接触人造光不仅与重度抑郁症的发病率增加有关，而且还与其他几种精神疾病的发病率增加有关，包括双相情感障碍、广泛性焦虑症和创伤后应激障碍，以及自残行为和类似精神病经历的发生率较高⁴。正如根据白天光照是哺乳动物生物钟的主要同步器的证据以及强光疗法在治疗情绪障碍方面的成功所预测的那样，白天更多的光照也与此相关。精神障碍发生率较低⁴．来自动物模型、人类实验研究和流行病学的证据的三角测量为日常光照对良好心理健康的重要作用提供了强有力的证据。

关注 SCRD 在至少一些主要情绪障碍的病因学和病理生理学中可能的致病作用可能会让那些认为这些障碍是伴随大多数精神障碍的附带现象的人感到惊讶。然而，最近关于昼夜节律系统调节许多生理和行为参数的发现^{2, 3}以及纵向精神病学流行病学⁵的重大发展，对这一假设提出了挑战。事实上，现在通过临床、实验室和现场环境的研究已经充分证实，双相情感障碍等情绪障碍与 SCRD 相关特征有关，包括延迟睡眠阶段、长睡眠时间和偏好等稳定的特征特征。晚上^2、3；褪黑激素和核心体温节律延迟；昼夜节律相位标记与 24 小时睡眠-觉醒周期之间的异常时间关系⁶。

越来越多的证据表明，昼夜节律失调可能是交叉诊断的，而不是特定于疾病的³，并且尤其与关键情绪（例如，情感不稳定）、行为（例如，冲动）、认知（例如，去抑制）和情绪相关。免疫代谢（例如胰岛素抵抗、血液 C 反应蛋白水平升高）表型²。

关于既往 SCRD 对第一次主要发作的预测意义的实证进展在情绪障碍领域最为明显。在高危人群（例如父母患有双相情感障碍的后代）以及患有早期双相情感障碍的青少年中观察到了与 SCRD 相关的因素，例如对晚上的偏好和社会节奏失调，以及来自前瞻性研究的荟萃分析证据表明预先存在的 SCRD 与双相情感障碍发病风险增加 40% 相关⁷。一项针对 2,000 多名向早期干预诊所寻求帮助的青少年和年轻人的研究发现，先前的昼夜节律紊乱预示着主要情绪、焦虑或精神障碍从早期临床阶段向晚期临床阶段的转变⁸。

研究重点是对患有情绪障碍的成年人的情绪、睡眠和运动活动的日内和日间动态进行密集纵向测量（这些情绪障碍似乎比对照人群更加失调和交叉反应），这些研究强调了研究生物学研究的必要性。连接这些系统的接口，其中稳态昼夜节律系统是一个可能的候选者³。

昼夜节律系统似乎是对情绪障碍患者的至少一个主要亚群进行更个性化治疗的潜在重要目标。选择性血清素再摄取抑制剂 (SSRI) 等治疗可能会增加对光的敏感性，从而破坏高危个体的昼夜节律系统的稳定性，这一发现是一个主要问题⁹。这一发现需要紧急复制和扩展，以检查暴露于其他常见干预措施（例如行为激活、睡眠限制、情绪稳定剂、抗精神病药物和其他抗抑郁药物）可能产生的积极或消极影响。在一些动物模型以及针对情绪障碍患者的小型研究中，一些新药物（例如食欲素拮抗剂、褪黑激素类抗抑郁药）和较旧的药物疗法（例如锂）似乎确实增强了这些系统的稳定性³。非常有必要进一步测试此类药物的昼夜节律影响以及治疗相关亚型的可能性^{2, 9}。

这些新见解的更广泛应用存在重大障碍。准确、实时和重复检测内部生物钟的真实时间及其与外部明暗周期的一致性仍然是一个主要目标。目前的测量方法很大程度上局限于密集、昂贵的实验室方法，或者通过可穿戴设备记录的 24 小时运动活动和睡眠模式进行间接推断。因此，一个明确的研究重点是开发基于 24 小时基因表达模式、代谢活动以及外周血或尿液标记物的新方法。还需要更复杂的建模技术，基于在病程早期跟踪症状群和客观标记，然后纵向跟踪，以揭示这些现象之间的因果关系。

在这一研究领域增加和协调的全球投资是及时的，并且很可能带来真正的新的治疗见解。