Neuropsychiatric Disorders Following SARS-CoV-2 Infection

Paul J. Harrison; Maxime Taquet

Brain. 2023;146(6):2241-2247.

Abstract and Introduction

Abstract

Several large-scale electronic health records studies have reported increased diagnostic rates for neuropsychiatric disorders following Coronavirus disease 2019 [COVID-19 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 infection)], but many questions remain. To highlight the issues, we selectively review this literature, focusing on mood disorder, anxiety disorder, psychotic disorder, and cognitive impairment ('brain fog'). Eight key questions are addressed, comprising: (i) the nature and magnitude of the risks; (ii) their association with severity of infection; (iii) their duration; (iv) whether the risks differ between adults and children, or between men and women; (v) whether prior vaccination protects against them; (vi) the risk profile associated with different SARS-CoV-2 strains; (vii) what the underlying mechanisms might be; and (viii) whether the sequelae can be predicted. We consider the major unknowns, the limitations of electronic health records for research in this area, and the use of additional approaches to help characterize and understand the neuropsychiatric burden of COVID-19.

Introduction

Early concerns that Coronavirus disease 2019 [COVID-19 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 infection)] might confer an increased risk of psychiatric and neurological disorders^[1] have largely been borne out.^[2,3] The findings have emerged from electronic health records (EHRs),^[4–6] claims databases,^[7] and self-report surveys,^[8] and are broadly consistent in reporting increased risks of many psychiatric and neurological symptoms and syndromes in the weeks and months after infection, as part of a broader post-acute COVID-19 syndrome.^[9] These risks are in addition to effects of the pandemic itself on mental health.^[10–12] However, many key questions about the links between COVID-19 infection and subsequent mental and brain health remain unanswered.

Here we address several of these questions, focusing on a limited number of disorders that highlight the issues: mood, anxiety and psychotic disorders, as well as cognitive impairment ('brain fog'). Other neuropsychiatric sequelae of COVID-19 are covered elsewhere.^[13,14] We consider primarily the findings from our studies that have used the USA-based TriNetX Analytics EHR network (www.trinetx.com) to investigate risks for a broad range of psychiatric, neurological and cerebrovascular disorders. The value of EHRs in the context of the COVID-19 pandemic is that they provide large and up-to-date datasets with detailed demographic and biomedical data and standardized measures (e.g. ICD-10 diagnoses). EHR networks lend themselves to analyses whereby diagnostic rates after COVID-19 can be compared to matched cohorts experiencing other health events to generate relative risks as well as incidence figures—and with enough statistical power to look at subgroups, rare diagnoses, and time trends.

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Next Section

Table 1. Selected neuropsychiatric disorders following SARS-CoV-2 infection
	Mood disorder	Anxiety disorder	Psychotic disorder	Brain fog
HR at 6 months versus other RTI (95% CI)	1.08 (1.06–1.11)	1.13 (1.11–1.15)	1.27 (1.18–1.37)	1.36 (1.33–1.39)
Incidence at 6 months (95% CI), %	2.95 (2.91–3.00)	4.98 (4.92–5.04)	0.20 (0.19–0.21)	2.65 (2.61–2.69)
Absolute risk increase at 6 months, %	0.15	0.37	0.036	0.64
Risk horizon, days	43	58	>730	>730
Time to equal incidence, days	457	417	>730	>730

Figures refer to first recorded diagnosis (i.e. people who had no diagnosis of that condition prior to infection). Incidence, hazard ratio (HR) and absolute risk increase are shown at 6 months compared to other respiratory tract infections (RTI). Risk horizon = the time at which the HR returns to 1. Time to equal incidence = the time when the cumulative number of diagnoses in the COVID-19 cohort is the same as the cumulative number of diagnoses in the comparator cohort. Diagnoses are ICD-10 codes: psychotic disorder (F20-F29), mood disorder (F30-F39), anxiety disorder (F40-F48). 'Brain fog' is a composite category²⁰ of diagnostic codes for dementia (F01-F03, G30, G31.0, G31.83), mild cognitive impairment (G31.84), delirium (F05), encephalopathy (G93.40), and R codes for symptoms and signs of attentional or cognitive dysfunction (R40, R41, R48); the majority of people in the brain fog category had the R41 code, 'other cognitive symptoms'.¹⁵ The 95% CIs are shown in parentheses. Data are from Taquet et al.^15,20

Table 2. Relationship of post-COVID-19 neuropsychiatric disorders with hospitalization and ICU admission
	Mood disorder	Anxiety disorder	Psychotic disorder	Brain fog
Hospitalized versus non-hospitalized COVID-19
HR at 6 months (95% CI)	1.53 (1.33–1.75)	1.49 (1.34–1.65)	2.77 (1.99–3.85)	2.24 (2.12–2.35)
Incidence in hospitalized cases at 6 months, %	4.49 (4.05–4.99)	6.91 (6.38–7.47)	0.89 (0.72–1.09)	16.66 (16.14–17.17)
Incidence in non-hospitalized cases at 6 months, %	3.86 (3.60–4.14)	6.81 (6.47–7.16)	0.25 (0.19–0.33)	4.91 (4.71–5.11)
ICU versus non-ICU COVID-19
HR at 6 months (95% CI)	2.06 (1.57–2.71)	2.22 (1.82–2.71)	1.77 (0.98–3.20)	2.54 (2.32–2.74)
Incidence in ICU cases at 6 months, %	5.82 (4.86–6.97)	9.79 (8.65–11.06)	0.70 (0.46–1.06)	27.75 (26.58–28.91)
Non-hospitalized COVID-19 versus non-hospitalized other RTIs
HR at 6 months (95% CI)	1.37 (1.27–1.47)	1.37 (1.30–1.45)	1.49 (1.15–1.93)	N/A

Incidence and HR in hospitalized versus non-hospitalized COVID-19 (n = 45 167 in each cohort, except n = 52 597 for brain fog); in cohorts of COVID-19 admitted or not admitted to ICU (n = 8942 in each cohort), and in non-hospitalized COVID-19 versus non-hospitalized other respiratory infections (RTIs; n = 183, 731 in each cohort). Matched cohorts used for HRs; complete cohort used for incidences. See Table 1 legend for diagnostic categories. Data from Taquet et al.,¹³ except for brain fog.²⁰ These studies excluded children younger than 10 years old.

Table 3. Risks of neuropsychiatric disorders after COVID-19 across the lifespan
	Mood disorder	Anxiety disorder	Psychotic disorder	Brain fog
HR at 6 months (95% CI)
Children	1.02 (0.94–1.10)	1.00 (0.94–1.06)	2.00 (1.26–3.19)	1.20 (1.09–1.33)
Adults	1.06 (1.04–1.09)	1.13 (1.11–1.15)	1.18 (1.08–1.29)	1.35 (1.31–1.40)
Older adults	1.17 (1.11–1.22)	1.16 (1.11–1.20)	1.39 (1.21–1.59)	1.41 (1.36–1.46)
Incidence at 6 months, % (95% CI)
Children	1.50 (1.41–1.59)	2.63 (2.51–2.75)	0.04 (0.029–0.052)	1.02 (0.95–1.09)
Adults	3.20 (3.14–3.26)	5.62 (5.54–5.71)	0.20 (0.18–0.21)	2.09 (2.05–2.13)
Older adults	3.20 (3.09–3.30)	4.68 (4.55–4.81)	0.31 (0.28–0.34)	5.98 (5.84–6.11)
Absolute risk increase at 6 months, %
Children	−0.054	−0.13	0.018	0.11
Adults	0.11	0.44	0.022	0.52
Older adults	0.38	0.43	0.088	1.56
Risk horizon, days
Children	–	–	75	75
Adults	44	65	86	>730
Older adults	36	44	>730	>730
Time to equal incidence, days
Children	–	–	>730	491
Adults	330	466	657	>730
Older adults	>730	463	>730	>730

Table shows incidence, HR, absolute risk increase, risk horizon and time to equal incidence for selected psychiatric disorders in children (<18 years; n = 185 748), adults (18–64 years; n = 856 588) and older adults (≥65 years; n = 242 101). See Table 1 legend for diagnostic categories. Data from Taquet et al.¹⁵

Table 4. Some limitations of electronic health records for COVID-19 research, and how they may impact on the relative risk and incidence of neuropsychiatric disorders
Limitation	Effect on relative risk of NPD	Effect on incidence of NPD after COVID-19	Comments and implications
Undocumented COVID-19 infection (in comparator cohort)	Decreased	Unaffected	Some subjects in comparator cohorts will have had COVID-19
People with asymptomatic COVID-19 under-represented	Unaltered if comparator cohort has a similar limitation (e.g. other respiratory infection). Increased if comparator cohort does not have a similar limitation (e.g. general population or all people testing negative for COVID-19) and if NPDs are less common after asymptomatic COVID-19	Increased, if NPDs are less common after asymptomatic COVID-19	Using multiple comparator cohorts can help better characterize relative risk. Prospective studies specifically targeting asymptomatic COVID-19 cases can help determine the incidence of NPDs in that subgroup.
NPD might have started before the index event but not diagnosed till afterwards	Unlikely	Increased	Could lead to misattribution of causality to COVID-19 or other index event
NPD present but not yet diagnosed (e.g. because of diagnostic delay or because affected individual does not seek medical attention)	Unlikely	Decreased	The effect on incidence will tend to counter the over-estimation arising from the limitation above.Active follow-up in prospective studies is required to detect these cases
Incomplete past health records	Unlikely	First-onset diagnostic rates increased if previous episodes had occurred but were not recorded	Less of a problem in countries where people have a single health record
Lack of information on viral strain	Could be increased, decreased or unchanged	Could be increased, decreased or unchanged	Effects depend on whether the strain affects risk of NPD and, if so, the timing and design of the study
SARS-CoV-2 could affect patient or physician behaviour and thence diagnostic behaviour	Could be increased, decreased or unchanged	Could be increased, decreased or unchanged	Direction of effect depends on what (if anything) COVID-19 does to health-seeking or physician behaviour. Difficult limitation to overcome.
People making no further contact with health services considered lost to follow-up	Could be increased, decreased, or unchanged	Decreased when using Kaplan–Meier estimator, unchanged when using total counts	Prospective studies with active follow-up and low attrition can address this limitation
Unknown NPD severity, course, and outcome	None	None	Difficult to assess using conventional EHR data. Although risk and incidence unaffected, these factors have implications for treatment and services