Although precise estimations of the absolute risk are still difficult to provide, it is clear that depression and anxiety are predominant symptoms in post-acute COVID-19, and that they are more pronounced in patients who have been hospitalized for COVID-19 than in those hospitalized for other respiratory tract infections¹. Also, cognitive impairment has been reported in several people who have had symptomatic COVID-19 infection, which can manifest as difficulties with concentration, memory, receptive language and/or executive function¹. Psychiatric symptoms and cognitive impairment can develop and persist months after the infection and are therefore part of what is called the “Long COVID” condition, of which fatigue is another paramount manifestation.

The development of depression and anxiety symptoms and of cognitive impairment after COVID-19 may partly be the result of somatic, functional or psychosocial consequences of the disease. Coronaviruses can also induce cognitive, emotional, neurovegetative and behavioral dysregulation due to direct neurological injury through hypoxic damage and neuroinvasion. In addition to this, the systemic immune activation seen in COVID-19 can contribute significantly to the mental health toll even months after the initial disease.

COVID-19 disease has been characterized as a cytokine release syndrome². Elevated serum concentrations of interleukin-6 and other inflammatory cytokines are hallmarks, and correlate in a dose-response manner with respiratory failure, adverse respiratory distress syndrome, and other clinical outcomes. Immuno-inflammatory dysregulation can contribute importantly to acute and post-acute psychiatric and cognition symptoms in COVID-19 patients.

To illustrate, various lines of research indicate a link between immune activation and depression. First, manipulation of the immune system through endotoxin, interferon-alpha or typhoid vaccine interventions induces sickness behavior involving depressive symptoms such as fatigue, low mood and hypersomnia. Second, large-scale studies confirmed that persons with auto-immune conditions, e.g. rheumatoid arthritis, or with inflammation-inducing conditions, e.g. obesity, have an increased risk to subsequently develop depression. Third, meta-analyses of biomarker studies indicate that levels of inflammatory markers, including cytokines – such as tumor necrosis factor, interleukin-1 beta and interleukin-6 – and acute phase proteins – such as C-reactive protein (CRP) – are significantly elevated in depressed patients compared to healthy controls. Low-grade systemic inflammation has also been shown to induce robust pathophysiological abnormalities in the endocrine systems of stress and arousal regulation that further augment neuroimmune reactivity. In addition, human and animal studies indicate that peripheral immune activation is able to induce brain inflammation, and increased inflammatory responses have been indeed reported in post-mortem brain samples of depressed individuals.

Moreover, large-scale genome-wide DNA and RNA studies indicate that depressed persons have more genetic variants and enriched gene expression pathways involved in immune signaling. Such genetic pleiotropy between immuno-inflammatory dysregulation and depression may indicate a genetic vulnerabil­ity that might partly explain why persons with a mood disorder history have a higher risk of unfavorable COVID-19 disease outcomes as compared to persons without a psychiatric history³. Fi­nally, anti-inflammatory medication approaches have demonstrated efficacy in reducing depression symptoms.

Of note, findings suggesting a pathophysiological link to the immune system have also been reported for other dimensions relevant to COVID-19, such as cognitive impairment and fatigue. In a population-representative cross-sectional analysis of >40,000 adults, a higher CRP level was associated with poorer executive functioning, which was especially true in the presence of depression and even existed in early adulthood⁴. Longitudinally, high levels of inflammatory markers have been linked to long-term cognitive decline, involving deterioration of memory and executive function⁵. A proteome-wide association study of older-adult brain donors indicated increased inflammation in brains of cognitively impaired persons as compared to those of cognitive stable persons⁶.

For fatigue, illustration of immune system involvement comes most strongly from studies of chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME), a condition characterized by persistent, unexplained fatigue that is not alleviated by rest. Although CFS/ME has long been indicated as a mystery illness, recent studies suggest that inflammation is central to its pathogenesis in at least a considerable proportion of patients, as suggested by higher levels of inflammatory markers that show a dose-response relationship to disease severity⁷.

If even low-grade systemic immune activity increases the risk of depression, cognitive impairment and fatigue, it is obvious that we need to be aware of the role that immune activation can play in the mental health consequences of COVID-19, which involves a massive cytokine storm. A dose-response relationship has been indeed documented between the severity of immune-inflammatory dysregulation in COVID-19 patients and depressive symptomatology three months later⁸. The same study also reported that high baseline inflammation load in COVID-19 patients predicted neurocognitive impairment – involving reduced processing speed, verbal memory and fluency – after three months.

How long the impact of immune activation in COVID-19 patients persists remains to be clarified. However, for infections involving hospital contact, the maximum behavioral effects can take over a year post-infection to fully develop. This suggests that, next to the immediate impact, there may also be priming whereby immune activation triggered by infection (i.e., first hit) may progressively increase sensitivity to common pro-inflammatory stimuli (i.e., second hit), which include other mild infections, concussions, airborne allergen and pollutant exposure, as well as psychosocial stressors.

Future research goals are to examine how to best monitor, prevent and treat psychiatric, behavioral and cognitive consequences of COVID-19. For clinicians treating depression in patients with SARS-CoV-2 infection, a thorough history and clinical examination are paramount. There is evidence that immune-inflammatory dysregulation is limiting the efficacy of antidepressants, as high plasma levels of CRP and interleukins have been found to be predictors of poor treatment response⁹. Consequently, whether antidepressants are effective in treating COVID-19-related depression deserves specific confirmation.

In the meantime, we can assume that any major advances in vaccines and antiviral treatments targeting SARS-CoV-2, as well as immune targeted therapies (such as anti-cytokines and cytokine receptor blockers), will not only prevent severe illness but also benefit the brain and mental health.

尽管仍然难以提供对绝对风险的精确估计，但很明显抑郁和焦虑是急性后 COVID-19 的主要症状，并且在因 COVID-19 住院的患者中比在那些住院的患者中更为明显因其他呼吸道感染住院¹．此外，据报道，一些有症状的 COVID-19 感染者出现认知障碍，这可能表现为注意力不集中、记忆力、接受性语言和/或执行功能¹困难。精神症状和认知障碍可在感染后数月出现并持续存在，因此是所谓的“长 COVID”病症的一部分，其中疲劳是另一种最重要的表现。

COVID-19 后出现抑郁和焦虑症状以及认知障碍可能部分是该疾病的躯体、功能或社会心理后果的结果。由于缺氧损伤和神经侵袭引起的直接神经损伤，冠状病毒还可以引起认知、情绪、神经植物和行为失调。除此之外，在 COVID-19 中看到的全身免疫激活甚至在初始疾病数月后也会对心理健康造成重大影响。

COVID-19 疾病的特征是细胞因子释放综合征²。白细胞介素 6 和其他炎性细胞因子的血清浓度升高是标志，并且以剂量反应方式与呼吸衰竭、不良呼吸窘迫综合征和其他临床结果相关。免疫炎症失调可能对 COVID-19 患者的急性和急性后精神和认知症状产生重要影响。

为了说明这一点，各种研究表明免疫激活和抑郁之间存在联系。首先，通过内毒素、干扰素-α 或伤寒疫苗干预来操纵免疫系统会诱发疾病行为，包括疲劳、情绪低落和嗜睡等抑郁症状。其次，大规模研究证实，患有自身免疫疾病（如类风湿性关节炎）或炎症诱发疾病（如肥胖）的人随后患抑郁症的风险增加。第三，生物标志物研究的荟萃分析表明炎症标志物的水平，包括细胞因子——如肿瘤坏死因子、白细胞介素 1β 和白细胞介素 6——和急性期蛋白——如 C 反应蛋白 (CRP)——显着与健康对照组相比，抑郁症患者升高。低度全身性炎症也已被证明会在压力和唤醒调节的内分泌系统中引起强烈的病理生理异常，从而进一步增强神经免疫反应性。此外，人类和动物研究表明，外周免疫激活能够诱发脑部炎症，并且确实在抑郁个体的死后脑部样本中报告了炎症反应的增加。

此外，大规模的全基因组 DNA 和 RNA 研究表明，抑郁症患者具有更多的遗传变异和丰富的参与免疫信号传导的基因表达途径。免疫炎症失调和抑郁症之间的这种遗传多效性可能表明存在遗传脆弱性，这可能部分解释了为什么有情绪障碍病史的人与没有精神病史的人相比，发生不利的 COVID-19 疾病结果的风险更高³。最后，抗炎药物方法已证明可有效减轻抑郁症状。

值得注意的是，还报告了与 COVID-19 相关的其他维度（例如认知障碍和疲劳）与免疫系统存在病理生理联系的发现。在对 > 40,000 名成年人进行的具有代表性的人口横断面分析中，较高的 CRP 水平与较差的执行功能相关，这在存在抑郁症时尤其如此，甚至在成年早期就存在⁴。纵向来看，高水平的炎症标志物与长期的认知能力下降有关，包括记忆力和执行功能的恶化⁵。一项针对老年脑供体的全蛋白质组关联研究表明，与认知稳定者相比，认知障碍者大脑中的炎症增加⁶.

对于疲劳，免疫系统受累的例证来自慢性疲劳综合征 (CFS) 或肌痛性脑脊髓炎 (ME) 的研究，这种情况的特征是持续的、无法解释的疲劳，休息不能缓解。尽管 CFS/ME 长期以来一直被认为是一种神秘的疾病，但最近的研究表明，炎症是至少相当一部分患者发病机制的核心，正如更高水平的炎症标志物所表明的那样，这些标志物显示出与疾病严重程度的剂量反应关系⁷ .

如果即使是低级别的全身免疫活动也会增加抑郁、认知障碍和疲劳的风险，那么很明显我们需要意识到免疫激活在 COVID-19 的心理健康后果中可能发挥的作用，这涉及大量细胞因子风暴。COVID-19 患者免疫炎症失调的严重程度与三个月后的抑郁症状之间确实存在剂量反应关系⁸。同一项研究还报告说，COVID-19 患者的高基线炎症负荷预测了三个月后的神经认知障碍——包括处理速度、语言记忆和流畅性降低。

免疫激活对 COVID-19 患者的影响持续多久仍有待澄清。然而，对于涉及医院接触的感染，最大的行为影响可能需要在感染后一年多才能完全发展。这表明，除了直接影响之外，还可能存在启动，由此感染触发的免疫激活（即第一次打击）可能会逐渐增加对常见促炎刺激（即第二次打击）的敏感性，其中包括其他轻度感染，脑震荡、空气传播的过敏原和污染物暴露，以及社会心理压力。

未来的研究目标是研究如何最好地监测、预防和治疗 COVID-19 的精神、行为和认知后果。对于治疗 SARS-CoV-2 感染患者的抑郁症的临床医生来说，全面的病史和临​​床检查至关重要。有证据表明免疫炎症失调限制了抗抑郁药的疗效，因为已发现高血浆水平的 CRP 和白细胞介素是治疗反应不佳的预测因素⁹。因此，抗抑郁药是否能有效治疗 COVID-19 相关的抑郁症值得特别确认。

与此同时，我们可以假设，针对 SARS-CoV-2 的疫苗和抗病毒治疗以及免疫靶向治疗（如抗细胞因子和细胞因子受体阻滞剂）的任何重大进展，不仅可以预防严重疾病，还可以受益大脑和心理健康。