Mental and neurological disorders and risk of COVID-19 susceptibility, illness severity and mortality: A systematic review, meta-analysis and call for action

Abstract

Background: Coronavirus disease 2019 (COVID-19) has evolved into a worldwide pandemic, and has been found to be closely associated with mental and neurological disorders. We aimed to comprehensively quantify the association between mental and neurological disorders, both pre-existing and subsequent, and the risk of susceptibility, severity and mortality of COVID-19.

Methods: In this systematic review and meta-analysis, we searched PubMed, Web of Science, Embase, PsycINFO, and Cochrane library databases for studies published from the inception up to January 16, 2021 and updated at July 7, 2021. Observational studies including cohort and case-control, cross-sectional studies and case series that reported risk estimates of the association between mental or neurological disorders and COVID-19 susceptibility, illness severity and mortality were included. Two researchers independently extracted data and conducted the quality assessment. Based on I² heterogeneity, we used a random effects model to calculate pooled odds ratios (OR) and 95% confidence intervals (95% CI). Subgroup analyses and meta-regression analysis were also performed. This study was registered on PROSPERO (registration number: CRD 42021230832).

Finding: A total of 149 studies (227,351,954 participants, 89,235,737 COVID-19 patients) were included in this analysis, in which 27 reported morbidity (132,727,798), 56 reported illness severity (83,097,968) and 115 reported mortality (88,878,662). Overall, mental and neurological disorders were associated with a significant high risk of infection (pre-existing mental: OR 1·67, 95% CI 1·12-2·49; and pre-existing neurological: 2·05, 1·58-2·67), illness severity (mental: pre-existing, 1·40, 1·25-1·57; sequelae, 4·85, 2·53-9·32; neurological: pre-existing, 1·43, 1·09-1·88; sequelae, 2·17, 1·45-3·24), and mortality (mental: pre-existing, 1·47, 1·26-1·72; neurological: pre-existing, 2·08, 1·61-2·69; sequelae, 2·03, 1·66-2·49) from COVID-19. Subgroup analysis revealed that association with illness severity was stronger among younger COVID-19 patients, and those with subsequent mental disorders, living in low- and middle-income regions. Younger patients with mental and neurological disorders were associated with higher mortality than elders. For type-specific mental disorders, susceptibility to contracting COVID-19 was associated with pre-existing mood disorders, anxiety, and attention-deficit hyperactivity disorder (ADHD); illness severity was associated with both pre-existing and subsequent mood disorders as well as sleep disturbance; and mortality was associated with pre-existing schizophrenia. For neurological disorders, susceptibility was associated with pre-existing dementia; both severity and mortality were associated with subsequent delirium and altered mental status; besides, mortality was associated with pre-existing and subsequent dementia and multiple specific neurological diseases. Heterogeneities were substantial across studies in most analysis.

Interpretation: The findings show an important role of mental and neurological disorders in the context of COVID-19 and provide clues and directions for identifying and protecting vulnerable populations in the pandemic. Early detection and intervention for neurological and mental disorders are urgently needed to control morbidity and mortality induced by the COVID-19 pandemic. However, there was substantial heterogeneity among the included studies, and the results should be interpreted with caution. More studies are needed to explore long-term mental and neurological sequela, as well as the underlying brain mechanisms for the sake of elucidating the causal pathways for these associations.

Funding: This study is supported by grants from the National Key Research and Development Program of China, the National Natural Science Foundation of China, Special Research Fund of PKUHSC for Prevention and Control of COVID-19, and the Fundamental Research Funds for the Central Universities.

Keywords: COVID-19; illness severity; mental health; mortality; neurological disorders; susceptibility.

Figure 1

Flow chart of study selection. 13,475 records from PubMed, Web of Science, Embase, PsycINFO, and Cochrane library databases were included in the initial search and 149 articles were finally included after full-text screen.

Figure 2

Subgroup analysis of odds ratios (ORs) across variables. Mental and neurological disorders were both associated with higher COVID-19 susceptibility, illness severity and mortality. Subgroup analyses suggested that the associations of mental disorders and severity varied in subgroups by temporal relationship, geographic regions, mean age and adjustments applied to OR. The association between mental and neurological disorders and mortality differed by mean age. While, there was not statistical significance observed for other subgroup analysis.

Figure 3

Meta-regression for COVID-19 susceptibility, illness severity and death by mental and neurological disorders. Meta-regression showed that the strength of association between mental disorders and severity, and between neurological disorders and mortality decreased with age. (a). Meta-regression for mean age; (b). Meta-regression for sex ratio.

Figure 4

Funnel plot for Covid-19 susceptibility, illness severity and death. Funnel plot and Egger's test suggested that there was publication bias among studies of COVID-19 severity and mortality, but not susceptibility. (a). susceptibility; (b). severity; (c). death

Figure 5

The association of mental and neurological disorders with the risk of susceptibility and prognosis of COVID-19, and the prevention and intervention The blue arrows indicate potential associations between mental and neurological disorders and the three different outcomes, with light blue for mental disorders and dark blue for neurological disorders. The black arrows represent possible interventions for improving poor outcomes of COVID-19 susceptibility, severity and death.