Recent publications have documented that a proportion of COVID-19 patients develop psychiatric symptoms during or after acute infection¹. We investigated this risk in the context of the National COVID Cohort Collaborative (N3C) – a centralized, harmonized, high-granularity electronic health record (EHR) repository² – using the largest retrospective cohort reported to date.

Two previous large-scale EHR studies examined psychiatric sequelae 90 and 180 days after COVID-19 diagnosis. A cohort of 44,779 individuals with COVID-19 was propensity score-matched to control cohorts with conditions such as influenza and other respiratory tract infections (RTI). In the 90 days following the initial presentation, the incidence proportion of new-onset psychiatric conditions was 5.8% in the COVID-19 group vs. 2.5% to 3.4% in the control groups³. A follow-up study also included individuals with a prior history of mental illness and similarly showed an increased risk of psychiatric conditions in the six months following initial presentation⁴.

To validate these findings, we leveraged data from N3C, which at our cutoff date of October 20, 2021 had 1,834,913 COVID-19 positive patients and 5,006,352 comparable controls. Our data set was drawn from 51 distinct clinical organizations. We included patients in the COVID-19 cohort if they had a confirmed diagnosis of SARS-CoV-2 infection by polymerase chain reaction or antigen test after January 1, 2020. Controls were selected from patients with a diagnosis of a RTI other than COVID-19. We excluded from this analysis patients with a history of any mental illness prior to 21 days after COVID-19 diagnosis, as well as patients without a medical record extending back a year prior to COVID-19. There were 245,027 COVID-19 positive individuals available for propensity matching.

Each COVID-19 patient was matched with a control patient from the same institution whose age differed by no more than 5 years. Propensity score matching was done on 34 factors using a logistic regression model including main effect terms, resulting in 46,610 matched patient pairs. Multivariable Cox regression was performed to compare the incidence of new-onset mental illness for all psychiatric conditions, mood disorders and anxiety disorders for 21 to 365 days following initial presentation. We additionally considered dyspnea as a positive control.

We tested the Cox regression proportional hazard assumption for comparisons of COVID-19 patients and controls⁵. Schoenfeld residual analysis yielded a significant p-value and led us to reject the null hypothesis of a constant proportional hazard over the full time period of 21-365 days. We therefore separated the cohort into two time intervals (before and after 120 days) in which the proportional hazard assumption was not violated.

We identified a statistically significant difference in the hazard rate of new-onset psychiatric sequelae between COVID-19 and RTI in the early post-acute phase (from 21 to 120 days), but not in the late post-acute phase (from 121 to 365 days). The estimated incidence proportion (as modeled on the log-hazard scale over time) of a new-onset psychiatric diagnosis in the early post-acute phase for the COVID-19 group was 3.8% (95% CI: 3.6-4.0), significantly higher than the 3.0% (95% CI: 2.8-3.2) for the RTI group, with a hazard ratio (HR) of 1.3 (95% CI: 1.2-1.4). The HR for new-onset mental illness in the late post-acute phase was not significant in the COVID-19 compared to the RTI group (HR: 1.0; 95% CI: 0.97-1.1).

Similar findings were obtained for anxiety disorders, but not for mood disorders. The estimated incidence proportion of a new-onset anxiety disorder diagnosis was significantly increased for COVID-19 patients (2.0%; 95% CI: 1.8-2.1) compared to RTI patients (1.6%; 95% CI: 1.5-1.7) in the early post-acute phase (HR: 1.3; 95% CI: 1.1-1.4). However, the estimated incidence proportion of a new-onset mood disorder diagnosis in the same period was not significantly increased for COVID-19 patients (1.2%; 95% CI: 1.1-1.3) in comparison to RTI patients (1.1%; 95% CI: 1.0-1.2).

New-onset anxiety and mood disorders were not significantly increased in the interval of 121-365 days following initial presentation (HR: 1.0, 95% CI: 0.91-1.1; and HR: 1.1, 95% CI: 0.97-1.2, respectively). In contrast, the HR for dyspnea, a known post-acute COVID-19 sequela¹, increased in both time periods (1.4, 95% CI: 1.2-1.5; and 1.2, 95% CI: 1.0-1.3, respectively).

We reasoned that patients might be followed more closely after COVID-19 as compared with other RTIs, and that a higher visit frequency might increase the probability of a mental illness being recorded in the EHR. To assess this, we repeated our analysis but added the frequency of visits 21 days or more after initial presentation as a factor to the Cox regression. The HR for any mental illness in the early post-acute phase was still significant (p<0.0001), but reduced to 1.2 (95% CI: 1.1-1.3).

Our results confirm the conclusion of the above-cited study³ that patients are at significantly increased risk of psychiatric conditions after a COVID-19 diagnosis. However, the degree of increased risk documented in our study is substantially lower than previously found.

There are several potential reasons for the differences between our results and those of the above-mentioned study. The previous study included data from January 20, 2020 (first recorded COVID-19 case in the US) to August 1, 2020, while our study includes data through October 20, 2021. It is conceivable that perceptions of COVID-19 by patients have shifted or that clinical practice has changed in the intervening time. It is possible that improved treatment options available later in the pandemic have reduced the risk of psychiatric illness. Finally, COVID-19 vaccination may reduce rates of anxiety and depression and alleviate symptoms in persons with post-acute sequelae^{6, 7}. Thus, the increasing availability of vaccines might have reduced the rate of mental illness following COVID-19. The data available in N3C do not include comprehensive information about vaccination status, so we could not test this hypothesis.

Many cohort studies have documented a high prevalence of mental illness in individuals with long COVID. For instance, in our recent analysis, the prevalence of depression was 21.1% (median reported percentage in 25 studies) and that of anxiety was 22.2% (median over 24 studies)¹. However, it is possible that the reported prevalence of these and other conditions was in­flated by a sampling bias toward long COVID patients who joined support groups or chose to participate in cohort studies⁸. This, and the fact that inclusion criteria for long COVID studies vary, has made it difficult to characterize the natural history of psychiatric manifestations of long COVID. Our study did not fo­cus specifically on long COVID, but instead investigated a cohort of patients following a diagnosis of acute COVID-19. It is difficult to know what proportion of these patients went on to develop long COVID; the recent introduction of ICD-10 codes for long COVID⁹ may enable studies on this topic in the future.

In summary, we support previously published reports of an increased risk of new-onset psychiatric illness following acute COVID-19 infection. In contrast to the nearly doubled risk identified by the earlier study, we found the relative risk to be increased by only about 25% (3.8% vs. 3.0% following other RTI). We did not find a significant difference in risk in the late post-acute phase, suggesting that the increased risk of new-onset psychiatric illness is concentrated in the early post-acute phase.

Our results have important implications for understanding the natural history of psychiatric manifestations of COVID-19. If confirmed by independent studies, our findings suggest that health services should consider mental health screening efforts early in the post-COVID clinical course.

最近的出版物记录了一部分 COVID-19 患者在急性感染期间或之后出现精神症状¹。我们在国家 COVID 队列协作 (N3C) 的背景下调查了这种风险——一个集中的、协调的、高粒度的电子健康记录 (EHR) 存储库^2——使用迄今为止报告的最大的回顾性队列。

之前的两项大规模 EHR 研究检查了 COVID-19 诊断后 90 天和 180 天的精神疾病后遗症。一个由 44,779 名 COVID-19 患者组成的队列与患有流感和其他呼吸道感染 (RTI) 等疾病的对照组进行了倾向得分匹配。在初次就诊后的 90 天内，COVID-19 组新发精神疾病的发病率比例为 5.8%，而对照组为 2.5% 至 3.4% ³。一项后续研究还包括有精神疾病病史的个体，同样显示，在初次就诊后的六个月内，患精神疾病的风险增加⁴。

为了验证这些发现，我们利用了 N3C 的数据，截至 2021 年 10 月 20 日截止日期，该数据有 1,834,913 名 COVID-19 阳性患者和 5,006,352 名可比对照。我们的数据集来自 51 个不同的临床组织。如果患者在 2020 年 1 月 1 日之后通过聚合酶链反应或抗原检测确诊为 SARS-CoV-2 感染，我们将他们纳入 COVID-19 队列。对照组选自诊断为除 COVID-19 以外的 RTI 的患者。 19. 我们从该分析中排除了在 COVID-19 诊断后 21 天之前有任何精神疾病病史的患者，以及在 COVID-19 之前一年没有病历的患者。有 245,027 名 COVID-19 阳性个体可用于倾向匹配。

每个 COVID-19 患者都与来自同一机构的对照患者相匹配，其年龄相差不超过 5 岁。使用包括主效应项的逻辑回归模型对 34 个因素进行倾向评分匹配，得到 46,610 对匹配的患者对。进行多变量 Cox 回归以比较所有精神疾病、情绪障碍和焦虑障碍在初次就诊后 21 至 365 天内新发精神疾病的发生率。我们还考虑将呼吸困难作为阳性对照。

我们测试了 Cox 回归比例风险假设，用于比较 COVID-19 患者和对照⁵。Schoenfeld 残差分析产生了显着的 p 值，并导致我们拒绝了在 21-365 天的整个时间段内恒定比例风险的零假设。因此，我们将队列分为两个时间间隔（120 天之前和之后），其中不违反比例风险假设。

我们发现 COVID-19 和 RTI 在急性后期早期（从 21 到 120 天）的新发精神疾病后遗症风险率存在统计学显着差异，但在急性后期后期（从 121 到365 天）。COVID-19 组在急性后期早期新发精神疾病诊断的估计发病率比例（根据时间对数风险量表建模）为 3.8%（95% CI：3.6-4.0），显着高于 RTI 组的 3.0% (95% CI: 2.8-3.2)，风险比 (HR) 为 1.3 (95% CI: 1.2-1.4)。与 RTI 组相比，COVID-19 在急性后期晚期新发精神疾病的 HR 不显着（HR：1.0；95% CI：0.97-1.1）。

对焦虑症也有类似的发现，但对情绪障碍则没有。与 RTI 患者（1.6%；95% CI：1.5-1.7）相比，COVID-19 患者新发焦虑症诊断的估计发病率显着增加（2.0%；95% CI：1.8-2.1）。急性后期早期（HR：1.3；95% CI：1.1-1.4）。然而，与 RTI 患者（1.1%；95%）相比，COVID-19 患者（1.2%；95% CI：1.1-1.3）在同一时期新发情绪障碍诊断的估计发病率没有显着增加CI：1.0-1.2)。

新发焦虑症和情绪障碍在初次就诊后的 121-365 天内没有显着增加（分别为 HR：1.0，95% CI：0.91-1.1；和 HR：1.1，95% CI：0.97-1.2） . 相比之下，呼吸困难（一种已知的急性 COVID-19 后遗症¹ ）的 HR在两个时间段内均有所增加（分别为 1.4，95% CI：1.2-1.5；和 1.2，95% CI：1.0-1.3）。

我们推断，与其他 RTI 相比，在 COVID-19 之后可能会更密切地跟踪患者，并且更高的访问频率可能会增加 EHR 中记录精神疾病的可能性。为了评估这一点，我们重复了我们的分析，但将首次展示后 21 天或更长时间的访问频率作为 Cox 回归的一个因素。急性后期早期任何精神疾病的 HR 仍然显着（p<0.0001），但降至 1.2（95% CI：1.1-1.3）。

我们的结果证实了上述研究³的结论，即患者在确诊 COVID-19 后患精神疾病的风险显着增加。然而，我们研究中记录的风险增加程度大大低于先前发现的。

我们的结果与上述研究结果之间的差异有几个潜在的原因。先前的研究包括 2020 年 1 月 20 日（美国首次记录的 COVID-19 病例）至 2020 年 8 月 1 日的数据，而我们的研究包括截至 2021 年 10 月 20 日的数据。可以想象，患者对 COVID-19 的看法已经在此期间发生了变化或临床实践发生了变化。大流行后期可用的改进治疗方案有可能降低了患精神疾病的风险。最后，COVID-19 疫苗接种可降低急性后遗症患者的焦虑和抑郁发生率并缓解症状^6、7. 因此，疫苗供应的增加可能降低了 COVID-19 后精神疾病的发病率。N3C 中可用的数据不包括有关疫苗接种状态的全面信息，因此我们无法检验这一假设。

许多队列研究记录了长期 COVID 患者的精神疾病患病率很高。例如，在我们最近的分析中，抑郁症的患病率为 21.1%（25​​ 项研究的中位数报告百分比），焦虑症的患病率为 22.2%（24 项研究的中位数）¹。然而，这些和其他疾病的报告患病率可能因对加入支持小组或选择参加队列研究的长期 COVID 患者的抽样偏差而被夸大了⁸. 这一点，以及长期 COVID 研究的纳入标准各不相同的事实，使得很难描述长期 COVID 的精神表现的自然史。我们的研究没有特别关注长期 COVID，而是调查了一组被诊断为急性 COVID-19 的患者。很难知道这些患者中有多少比例继续发展为长期 COVID；最近为长 COVID ⁹引入的 ICD-10 代码可能会促进未来对该主题的研究。

总之，我们支持先前发表的关于急性 COVID-19 感染后新发精神疾病风险增加的报告。与早期研究确定的几乎翻倍的风险相比，我们发现相对风险仅增加了约 25%（3.8% 与其他 RTI 后的 3.0%）。我们没有发现急性后期晚期的风险存在显着差异，这表明新发精神疾病的风险增加集中在急性后期早期。

我们的研究结果对了解 COVID-19 精神症状的自然史具有重要意义。如果得到独立研究的证实，我们的研究结果表明，卫生服务应在 COVID 后的临床过程中尽早考虑心理健康筛查工作。