REVIEW

CURRENT
OPINION A systematic review of neuropsychological and
psychiatric sequalae of COVID-19: implications
for treatment
William Michael Vanderlind a,b,, Beth B. Rabinovitz a,b,c,, Iris Yi Miao d,
Lauren E. Oberlin a,c, Christina Bueno-Castellano a,c, Chaya Fridman a,b,
Abhishek Jaywant a,b,e, and Dora Kanellopoulos a,b,c

Purpose of review
COVID-19 impacts multiple organ systems and is associated with high rates of morbidity and mortality.
Pathogenesis of viral infection, co-morbidities, medical treatments, and psychosocial factors may contribute
to COVID-19 related neuropsychological and psychiatric sequelae. This systematic review aims to
synthesize available literature on psychiatric and cognitive characteristics of community-dwelling survivors
of COVID-19 infection.
Recent findings
Thirty-three studies met inclusion/exclusion criteria for review. Emerging findings link COVID-19 to
cognitive deficits, particularly attention, executive function, and memory. Psychiatric symptoms occur at
high rates in COVID-19 survivors, including anxiety, depression, fatigue, sleep disruption, and to a lesser
extent posttraumatic stress. Symptoms appear to endure, and severity of acute illness is not directly
predictive of severity of cognitive or mental health issues. The course of cognitive and psychiatric sequelae
is limited by lack of longitudinal data at this time. Although heterogeneity of study design and sociocultural
differences limit definitive conclusions, emerging risk factors for psychiatric symptoms include female sex,
perceived stigma related to COVID-19, infection of a family member, social isolation, and prior psychiatry
history.
Summary
The extant literature elucidates treatment targets for cognitive and psychosocial interventions. Research
using longitudinal, prospective study designs is needed to characterize cognitive and psychiatric
functioning of COVID-19 survivors over the course of illness and across illness severity. Emphasis on
delineating the unique contributions of premorbid functioning, viral infection, co-morbidities, treatments,
and psychosocial factors to cognitive and psychiatric sequelae of COVID-19 is warranted.
Keywords
cognition, COVID-19, neuropsychology, psychiatric disorders, SARS-CoV-2, Severe Acute Respiratory Syndrome
Coronavirus 2

INTRODUCTION
The novel coronavirus (SARS-CoV-2) that causes
a
coronavirus disease (COVID-19) impacts multiple Department of Psychiatry, Weill Cornell Medicine, bNewYork-Presbyte-
organ systems [1]. Mortality rates are staggering, rian Hospital/Weill Cornell Medical Center, New York, cNewYork-Pres-
byterian Hospital/Westchester Behavioral Health Center, White Plains,
and morbidity trends have been the focus of numer- d
Department of Psychology, New School for Social Research and
ous investigations. Persisting symptoms following e
Department of Rehabilitation Medicine, Weill Cornell Medicine, New
infection are increasingly reported, including psy- York, New York, USA
chiatric symptoms and cognitive concerns [2,3], Correspondence to Beth B. Rabinovitz, PhD, Department of Psychiatry,
which are likely salient contributors to morbidity Weill Cornell Medicine/New York-Presbyterian Hospital, New York
and disability. Although the etiology is still largely 10605, New York, USA. E-mail: [email protected]

unknown, cognitive deficits may arise from stroke, These authors contributed equally to this work.
meningitis, hypoxia, and inflammatory injury [4–8] Curr Opin Psychiatry 2021, 34:420–433
or from the invasive interventions required to treat DOI:10.1097/YCO.0000000000000713

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 Neuropsychological and psychiatric sequalae Vanderlind et al.

were used to identify original research articles. Case

KEY POINTS reports, studies with a sample size of N < 10, and
 Neuropsychological weaknesses are not uncommon studies examining acute psychiatric and cognitive
among COVID-19 survivors, particularly in the domains consequences of infection, with data exclusively
of attention and executive functioning. collected during hospitalization, were excluded.
Titles were initially screened by five reviewers.
 COVID-19 is associated with high rates of psychiatric
Abstracts were then independently examined by
symptoms, including anxiety, depression, fatigue, sleep
disruption, and posttraumatic stress, and consistent risk two reviewers, and two additional independent
factors for psychiatric symptoms include the history of a reviewers evaluated full-text articles to verify inclu-
psychiatric disorder and female gender. sion eligibility (Fig. 1). Differences were reconciled
by consensus conference. We extracted sample char-
 Rates of anxiety and depression are similar, if not
acteristics, study design, assessment measures, pri-
higher, among patients who were never hospitalized
compared to those who required inpatient mary outcomes, and study limitations (Table 1).
hospitalization, whereas rates of posttraumatic stress
appear higher among previously hospitalized patients.
RESULTS
 Literature on neuropsychological functioning in COVID-
19 is scarce, and the heterogeneity of patient samples, Neuropsychological and cognitive sequelae
methods, and timeframe of assessment limit the
characterization of neuropsychological and psychiatric
sequelae among COVID-19 survivors. Objective neuropsychological assessment
Abnormal cognitive performance was documented
 There is a pressing need for prospective research in approximately 15.0–40.0% of participants 10–
studies that recruit large patient populations and & &

comparison samples, comprehensively define medical

105 days following hospital discharge [11 ,12 ,
&& &&

and treatment course, and utilize gold-standard 13 ,14 ,15–17]. Comparison of cognitive function
measures to characterize cognitive and psychiatric in COVID-19 patients to matched controls found
functioning across specific domains over time. significant differences in performance on measures
&&
of sustained attention [13 ], executive function and
&
visuospatial processing [11 ], attention, memory,
&
and language [12 ]. Notably, most studies relied
severe illness from COVID-19 [9]. Psychiatric illness on cognitive screening measures (e.g., Montreal
may arise from a combination of biological, psycho- Cognitive Assessment, Mini Mental State Exam,
social, and environmental factors. Early findings on Telephone Interview for Cognitive Status).
COVID-19 are consistent with existing literature on Executive dysfunction was implicated in patients
patients with severe and unexpected illness who who were treated in the intensive care unit (ICU) and
experience psychiatric symptoms related to medical oxygen therapy was associated with lower scores in
illness, functional disability, and psychosocial the domains of memory, attention, working mem-
stressors [10]. ory, processing speed, executive function, and global
Here, we review the nascent literature on the &&
cognition [14 ]. Specific COVID-19 related symp-
neuropsychological and psychiatric sequelae of toms were associated with differential patterns of
COVID-19 among community-dwelling individu- cognitive performance. Neurological symptoms were
als. We included studies that reported on postacute associated with lower working memory scores, head-
infection, including individuals who were never ache with lower scores on memory coding, attention,
hospitalized and those who were previously hospi- complex working memory, processing speed, execu-
talized. We highlight trends, discuss treatment tive function, and global cognition, diarrhea with
implications, and provide a roadmap for further lower scores in delayed visual memory, working
research on long-term psychiatric and cognitive memory, and complex working memory [14 ]. Poor
&&

impairment after COVID-19. cognitive performance was associated with increased

&&
inflammatory markers in one study [13 ]. Brain
Magnetic Resonance Imaging in one study was not
METHODS indicative of severe neurological injury in patients 2–
A systematic literature search of articles published in 3 months post recovery in comparison to healthy
English between December 2019 and February 2021 controls. However, recovered patients demonstrated
was conducted according to PRISMA standards increased bilateral thalamic T2 signal on susceptibil-
using PubMed. Medical Subject Headings and key- ity-weighted imaging and increased mean diffusivity
words pertaining to cognitive and psychiatric symp- in the posterior thalamic radiations and sagittal stri-
toms in community-dwelling adults with COVID-19 atum, suggesting possible increased burden of

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Provision of services to people with mental illnesses

4,932 Records identified

through database searching

48 Duplicates removed

4,884 Titles screened

4,581 Records excluded

303 Abstracts screened

59 Full-text articles assessed for

eligibility
26 Full-text articles excluded, with reasons
13 Patients hospitalized or in
inpatient rehabilitation at time of
assessment
7 No neuropsychological or
psychiatric assessment data
3 Without confirmed COVID-19
2 Abstract-only articles
1 Sample size 10

33 Studies included in
qualitative synthesis

FIGURE 1. Flowchart of study selection.

microvascular events. Notably these findings were Psychiatric sequalae of COVID-19

associated with markers of inflammation but not In addition to general mental health difficulties
&
cognitive performance [11 ]. [22,23], there are elevated rates of depression, anxi-
ety, Post Traumatic Stress (PTS), fatigue, and sleep
Self-reported cognitive functioning
difficulties among COVID-19 survivors.
Self-report or observer report of cognitive difficulties
was collected 4–15 weeks post discharge from
hospital or recovery from COVID-19. Memory com- Depression
& & &&
plaints were reported in 19.5–34.0% of participants In 19 of 33 studies assessing depression [2,11 ,12 ,13 ,
&& &
and attention difficulties were reported in 24.4– 14 ,16,17,20,24,28,29 ,30,31–34], symptom rates
28.0% of participants [18,19]. de Graaf [20] reported ranged from 10.0 to 68.5%. Previously hospitalized
cognitive complaints in 25.0% of participants. patients experienced high rates of depression both in
Medical comorbidities were associated with more the near- and long-term following hospital discharge.
frequent report of concentration difficulties and In the month following hospitalization, many
memory loss [19]. Observation of patients from patients endorsed subclinical levels of depression
& &&
home healthcare workers indicated general [12 ,14 ,26], and 10.0–19.0% of patients reported
improvements in cognitive status 1 month post moderate to severe depression [28,30]. Two to three
hospital discharge [21]. months following discharge, rates of moderate to

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 Table 1. Overview of cited studies
Study Population Age (in years) Race/ethnicity Time of assessment Measures Findings Limitations

Almeria et al. 35 patients without a history M ¼ 47.6 Not listed 10–35 days post TAVEC: list learning, 34.3% of the patients reported cognitive Small sample size
(2020) of prior cognitive SD ¼ 8.9 discharge from interference, complaints Older individuals were excluded to avoid
impairment, psychiatric Range ¼ 24-60 hospital recognition No differences in neuropsychological performance age-related cognitive impairment.
illness, or other CNS WMS-IV: Visual between patients who reported cognitive Assessed shortly after discharge home
disease reproduction complaints compared to those who did not Some data was extracted from the EMR
Barcelona, Spain Digit Span endorse cognitive complaints rather than being assessed directly
45.7% male Letters and Numbers Higher levels of anxiety and depression were
TMT found among individuals who endorsed
SDMT cognitive complaints
Stroop Neurological symptoms such as headache as well
Verbal fluency as loss of smell and taste were strongly
BNT associated with impaired attention, memory,
HADS and executive function
Bellan et al. 238 previously hospitalized Median ¼ 61 Not listed 3–4 months post IES-R Most patients did not endorse posttraumatic Only contacted patients who necessitated
(2021) patients Range ¼ 50-71 discharge from stress: 57.1% were within normal range, 25.6% inpatient hospitalization
Italy hospital reported mild symptoms, 11.3% reported High rate of patients declining participation
59.7% male moderate, and 5.9% reported severe symptoms Evaluation was limited to assessment of
Male sex was the only factor independently posttraumatic stress
associated with the presence of moderate to
severe PTS symptoms
Bonazza et al. 261 previously hospitalized M ¼ 58.9 Not listed 2 months post discharge HADS High prevalence of patients reported anxiety Participants assessed within quarantine
(2020) patients (35.2% received SD ¼ 13.3 from hospital IES-R (28%), depression (16%), as well as setting
intensive care) posttraumatic stress (36.4%) Underlying reasons for high endorsement
Italy Psychological distress was associated with female of PTS remains unclear
68.2% male gender. Younger patients are more likely to
have anxiety
No correlations were found between duration of
hospitalization or the intensity of care, and

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psychological outcomes
Bowles et al. 1409 hospitalized patients M ¼ 67 27% White; 28% Black; Not listed OASIS-D1 mandatory Improvements in cognitive functioning and Information on rehospitalization and death
(2020) New York, US SD ¼ 15 35% Hispanic; 9% assessment tool anxiety usually within one month post hospital after hospital discharge was not
51% male other discharge available
16% increase in cognitive functioning and 35%
decrease in anxiety
Cai et al. 126 hospitalized patients M ¼ 45.7 Not listed Not listed Self-report of PTSD 54% reported psychiatric distress 23 participants had prior history of
(2020) Shenzhen, China SD ¼ 14 Self-report of depression Comorbidity of clinically significant stress psychiatric illness
47.6% male Self-report of anxiety response, anxiety and depression was 11.9% All patients were discharged from hospital
31% had clinically significant stress response; into a mandatory quarantine facility,
22.2% had clinical anxiety; 38.1% had clinical and were assessed while in quarantine
depression
Older survivors (over age 60) reported lower levels
of stress response than younger individuals
Significantly higher rates of psychiatric symptoms
than seen following previous major disasters
Daher et al. 33 hospitalized patients not M ¼ 64 Not listed 6 weeks post EQ-5D-5L Most common endorsement was mild depression Patients had multiple medical
(2020) requiring mechanical SD ¼ 3 discharge from PHQ-9 and anxiety comorbidities, and did not identify
ventilation hospital GAD-7 On quality-of-life measures, patients reported slight premorbid psychiatric disorders

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Germany to moderate difficulties with mobility, Primary outcome was respiratory function;
67% male self-care, completing ADLs as well as elevated assessment of psychiatric concerns was
levels of pain/discomfort and anxiety/ secondary aim
depression

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Neuropsychological and psychiatric sequalae Vanderlind et al.

423
 424
Table 1 (Continued)
Study Population Age (in years) Race/ethnicity Time of assessment Measures Findings Limitations

de Graaf et al. 81 hospitalized patients M ¼ 60.8 Not listed 6 weeks post GAD-7 17% reported elevated symptoms of depression; Small Sample size
(2021) (42% requiring ICU SD ¼ 13 discharge from PHQ-9 5% endorsed elevated anxiety; 10% met Less than 50% of sample were admitted to
admission); only 59 Range ¼ 27-88 hospital PCL-5 criteria for PTSD the hospital participated in the study
completed psychological Cognitive Failures 40% reported previous mental health treatment Lack of baseline data
assessments Questionnaire 25% of patients endorsed cognitive impairments
Netherlands IQ Code-N semi
51% male structured clinical
interview
De Lorenzo 185 patients (68.1% M ¼ 57 90.8% European; 8.6% Median of 23 days WHOQOL-BREF Cognitive impairment was observed in 25% of Lack of objective assessment of cognition
et al. (2020) requiring inpatient Range ¼ 48-67 Hispanic; 0.5% African- post discharge from IES-R patients despite no history of cognitive Use of unstructured clinical interviews
hospitalization) American hospital STAI-Y disorder Only previously hospitalized patients were
Italy WHIIRS 22.2% of patients met criteria for PTSD recruited

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66.5% male Unstructured clinical
interview
Garrigues 129 hospitalized patients M ¼ 63.2 Not listed Mean of 110.8 EQ-5D-5L Most patients reported persistent symptoms of Exclusive use of self-reported measures
et al. France SD ¼ 15.7 (SD ¼ 11.1) days post Brief phone interview of fatigue (55%), memory loss (34%) Lack of baseline functioning
(2020) 75% male admission clinical symptoms concentration difficulties (24%), and sleep Only previously hospitalized patients were
disorders (30.8%) recruited
Guo et al. 259 patients < 18 ¼ 1.6% Not listed One month post SF-36 Role limitations due to emotional problems were High rate of attrition across follow-up
(2020) China 18–46 ¼ 53.1% discharge from related to male sex and positive nucleic acid period
46.9% male 46–49 ¼ 43.3% hospital duration Lack of standardized, granular mental
> 69 ¼ 2% Significant differences were found in vitality and assessment
Provision of services to people with mental illnesses

mental health of patients aged 46–69 with Only previously hospitalized patients were
positive nucleic acid duration longer than 14 recruited
days
Huang et al. 1733 patients M ¼ 57 Not listed Median of 184 mMRC 23% of reported depression or anxiety Lack of baseline functioning
(2021) China (Range ¼ 175– EQ-5D-5L 63% reported fatigue/muscle weakness Exclusion of patients with mild symptoms
52% male 199) days after EQ-VAS 25% reported sleep difficulties
symptom onset
Islam et al. 1002 patients (21% were M ¼ 34.7 Bangladeshi Not listed PHQ-9 30.4% endorsed minimal symptoms of Time of assessment was not provided
(2021) previously hospitalized) SD ¼ 13.9 Self-report treatment history depression, 21.5% endorsed mild symptoms, Diagnostic status determined by self-report
Bangladesh Range ¼ 18-81 Assessment of fear of 24.2% endorsed moderate symptoms, 19.4% rather than utilization of PCR test
57.9% male reinfection endorsed moderate-severe symptoms, 4.6%
endorsed severe symptoms
52.2% reported sleep disturbance
Lower SES, poor health, sleep disturbance,
asthma/respiratory problems, and fear of
reinfection were associated with moderate-
severe depression
Janiri et al. 61 patients who were > 60 Italian Mean of 41 days TEMPS-A-39 Small sample size
(2020) referred to postacute care (SD ¼ 19) post Difficulties in Emotion High likelihood of psychological distress was Statistical models in (ANCOVA with 7
clinic (9% previously discharge from Regulation Scale associated with female gender, Cyclothymic covariates) in light of sample size
required ICU admission) hospital Kessler Questionnaire-10 and Depressive scales of TEMPS, self-reported
Italy impulse control difficulties and lack of emotional
59% male clarity scales of DERS

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Jeong et al. 234 patients who were M ¼ 37.78 South Korean Not listed HADS During first week of quarantine, 19.8% endorsed Small sample size
(2020) admitted to nonhospital SD ¼ 15.57 mild depression or anxiety symptoms Clinical outcomes of all the patients were
facilities for isolation and At 1 week follow-up, 14% reported depression or not included
monitoring (28.2% were anxiety symptoms; significant decline in Mental health data was collected via
asymptomatic and 71.8% anxiety but not depression mobile-phone based survey. Patients
were mildly symptomatic) 20% of the asymptomatic group endorsed mood without access was contacted by
South Korea difficulties physicians via direct questioning
39.7% male Anxiety and depression levels positively associated
with quarantine durations

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 Table 1 (Continued)
Study Population Age (in years) Race/ethnicity Time of assessment Measures Findings Limitations

Liu et al. 675 previously hospitalized Median ¼ 55 Not listed Mean of 36.75 days PHQ-9 12.4% of patients were provisionally diagnosed Cross-sectional study which limits causal
(2020) patients (21.5% had mild Range ¼ 41-66 post discharge from GAD-7 with clinically significant PTSD symptoms inference
symptoms, 60.1% had hospital PCL-5 10.4% were categorized as having moderate to Mental health outcomes were cut off based
moderate symptoms, 5-item Perceived severe anxiety symptoms, with 32.3% reporting on sum-score of diagnostic criteria,
17.2% had severe discrimination mild symptoms presenting potential threat to validity
symptoms, 1.2% were scale 19% were categorized as having moderate to Medical comorbidities were not examined
critically ill) severe depression symptoms, with 46.7% directly
Wuhan, China reporting mild symptoms Lack of baseline psychological data
47% male Perceived discrimination, disease severity, living
with children, and death of family member were
predictors of mental health symptoms;
mechanical ventilation was not associated with
mental health outcomes
Liu et al. 324 patients: 6% Asymptomatic: Not listed Not listed Not listed Rates of anxiety was as follows: 11.94% among Anxiety measure was not reported,
(2021) asymtomatic, 73% had M ¼ 23.44 patients with mild/moderate symptoms, 10% outcome was subsequently described as
mild or moderate Mild/moderate: among patients with severe/critical symptoms ’anxiety/depression’
symptom 19% had M ¼ 38.61 Rates of headache or insomnia were: 8.96% Timing of anxiety assessment remains
severe/critical symptoms Severe/critical: among patients with mild/moderate symptoms unclear
Shenzhen, China M ¼ 57 and 22.5% among patients with severe/critical
47.8% male Total: symptoms
Range ¼ 0.3–86
Mandal et al. 384 previously hospitalized M ¼ 59.9 43% ethnic minority Median of 54 days PHQ-2 14.6% of patients endorsed depression Abbreviated measure of depressive
(2020) patients (14.5% required SD ¼ 16.1 post discharge from a median of 54 days post discharge symptoms
ICU admission) hospital
UK
62% male
Mannan et al. 1021 patients (10.9% were 0–9: N ¼ 18 Not listed Received negative PCR Phone interview Most prevalent postrecovery complications Measures used to assess cognitive and
(2021) asymptomatic and 89.1% 10–19: N ¼ 50 result at least 4 weeks included sleep disturbance (32%), weakened psychological functioning were not

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were symptomatic) 20–29: N ¼ 248 prior to the study attention span (24.4%), anxiety and depression reported
384 previously hospitalized 30–39: N ¼ 309 (23.1%), memory loss (19.5%), and
patients (14.5% required 40–49: N ¼ 171 complications with mobility (17.7%)
ICU admission) 50–59: N ¼ 126 Patients with medical comorbidity were found to be
Bangladesh > 60: N ¼ 96 more likely to experience mobility problem
75% male (26%), weakness and problems performing
usual activities (14%), anxiety and depression
(28.5%), sleep disturbances (41.3%),
concentration difficulties (28.5%), and memory
loss (24.6%) than those without any comorbid
conditions
Mazza et al. 402 patients who were M ¼ 57.8 Not listed Mean of 31.29 IES-R Rates of clinically significant psychopathology Cross-sectional study
(2020) presented to ED (74.6% Range ¼ 18-87 (SD ¼ 15.7) days PCL-5 based on self-report: 28% for PTSD, 31% for
were admitted for post discharge from BDI-13 depression, 42% for anxiety, 20% for
inpatient hospitalization hospital, or mean of STAI-Y obsessive-compulsive symptoms, and 40% for
and 25.4% were 28.56 (SD ¼ WHIIRS insomnia
discharged home) 11.73) days after ED Obsessive-Compulsive 55.7% endorsed clinical levels on at least 1
Milan, Italy admision Inventory psychopathological dimension, with 36.8%
65.7% male Zung Depression endorsing clinical levels across 2 dimensions,

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Scale 20.6% across 3 dimensions, and 10% across 4
Medical Outcomes dimensions
Study Sleep Scale Female patients with a previous psychiatric history,
and patients who were discharged home

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reported greater difficulties on most measures
Neuropsychological and psychiatric sequalae Vanderlind et al.

425
 426
Table 1 (Continued)
Study Population Age (in years) Race/ethnicity Time of assessment Measures Findings Limitations

Park et al. 10 patients M ¼ 62.6 Not listed 1 month post discharge PHQ-9 50% endorsed depressive symptoms during Small sample size
(2020) South Korea SD ¼ 14.9 from hospital GAD-7 treatment
80% male (median ¼ 25 days, IES-R 100% of patients denied significant anxiety after
range ¼ 13–50 days) discharge
At 1 month postdischarge, 10% endorsed
symptoms of depression and PTSD
Patients with high perceived stigma reported
higher levels of PTSD symptoms
Patients with a history of prior psychiatric treatment
reported higher levels of PTSD symptoms,
whereas levels of depression and anxiety did
not differ as a function of treatment history

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Raman et al. 58 hospitalized patients M ¼ 55.4 77.6% White, 22.4% Median of 2.3 months PHQ-9 Executive/visuospatial impairments were greater Small sample size
(2021) (95% required SD ¼ 13.2 Nonwhite from disease-onset, GAD-7 among patients compared to controls. Cross-sectional assessment
mechanical ventilation, median of 1.6 months SF-36 Severity of illness did not predict levels of Lack of correction for multiple comparisons
36% required ICU post discharge from MoCA depression or anxiety Given that controls were not hospitalized,
admission) hospital MRC At 2–3 months from disease-onset, patients group differences may not be specific to
30 uninfected matched Fatigue Severity reported significantly reduced quality of life and COVID-19 infection
controls Scale endorsed greater levels of depression, anxiety,
UK and fatigue than controls did
58.6% male
Soldati et al. Soldati et al. (2021) M ¼ 53.6 Not listed Ranged 43–136 days TICS 60.9% of patients fell within normal limits on Lack of control group
Provision of services to people with mental illnesses

(2021) 23 patients who were SD ¼ 11.7 post discharge from EuroQol cognitive assessments
previously treated in the hospital 13% met criteria for MCI
ICU MCI diagnosis was negatively associated with
Brazil EuroQol scores
78.3% male No one exhibited severe levels of cognitive
impairment on TICS
Quality of education was inversely associated with
cognitive functioning
Speth et al. 114 patients M ¼ 44.6 Not listed M ¼ 12.3 days (SD ¼ 7.2, PHQ-2 Depressed mood and anxiety were positively Cross-sectional assessment
(2020) Switzerland SD ¼ 16.1 range ¼ 0–31) following GAD-2 associated with chemosensory dysfunction but Utilization of retrospective report
45.6% male onset of COVID-19 not positively associated with symptoms of Lack of objective measures of olfactory
symptoms fever, cough and shortness of breath dysfunction
Older age and preexisting depressive and anxiety
symptoms were positively associated with levels
of depression and anxiety across disease course
Sykes et al. 134 hospitalized patients M ¼ 59.6 91% White, 1.5% Black, Median of 113 days MRC 86% reported at least one residual symptom, Severity of persistent symptoms was not
(2021) (87% required SD ¼ 14 6% Asian, 1.5% (range: 46–167) post EQ-5D-5L with the most frequently reported complaint assessed
supplemental oxygen or Mixed/other discharge from hospital being fatigue
respirator support, 20% Illness severity was not associated with self-
required ICU admission) reported symptom burden
UK Female sex was positively correlated with level of
65.7% male residual symptoms, particularly anxiety and
fatigue
Persistent COVID-related complications may not be

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directly attributable to SARS-CoV2 infection but,
rather, the neuropsychiatric sequelae of the
virus

Volume 34  Number 4  July 2021

 Table 1 (Continued)
Study Population Age (in years) Race/ethnicity Time of assessment Measures Findings Limitations

Tomasoni et al. 105 hospitalized patients Median ¼ 55 Not listed 1–3 months (Median ¼ 46 HADS Among 25 patients who completed MMSE, 40% Small sample size
(2021) (72% received minimal days) after virological MMSE indicated cognitive impairment, which ranged Only included patients with confirmed
oxygen therapy whereas clearance from mild to severe virological recovery, patients with
22% were treated with Many patients continued to endorse anxiety (29%) persistent positive PCR after clinical
CPAP, NIV or OTI) and depression (11%) 1–3 months after recovery were excluded
Milan, Italy virological clearance Lack of baseline psychological data
73.3% male Clinical levels of HADS-A/D scores were positively
associated with physical complaints
Townsend 128 patients (55.4% were M ¼ 49.5 Not listed Outpatients: at least Chalder Fatigue Scale Mean psychological fatigue was 4.72 (SD ¼ 1.99) Cross-sectional assessment
et al. (2020) hospitalized, 44.6% SD ¼ 15 6 weeks after abatement Treatment factors (hospitalization status, need for
were outpatients) of acute COVID-19 respiratory treatments) were not associated with
Dublin, Ireland symptoms fatigue levels
46.1% male Hospitalized patients: date of Fatigue was positively associated with preexisting
discharge depression and use of antidepressant
medications
Van den borst 124 patients (21.7% with M ¼ 59 Not listed Outpatients: M ¼ 13.0 weeks HADS Approximately 33% exhibited cognitive difficulties Skewed distribution of prior health
et al. (2020) mild disease, 41.1% with SD ¼ 14 (SD ¼ 2.2) symptom onset TICS or atypical mental status difficulties across disease severity
moderate, 20.9% with PCL-5 Disease severity grade was not associated with groups; participants with mild disease
severe, 16.1% with critical Hospitalized patients: IES-R mental or cognitive status in this study had longstanding health impairments
disease); 78.2% required M ¼ 9.1 weeks (SD ¼ 1.6) SF-36 Many patients reported chronic, and severe, Diagnostic status not confirmed by PCR test
inpatient hospitalization after discharge home Cognitive Failures problems across health domains for all participants
Nijmegen, Netherlands Questionnaire Referred mild disease patients displayed a female
60% male Nijmegen Clinical predominance and reported more frequently
Screening Instrument severe problems than moderate-to-critical
disease, in the domains of physical functioning,
quality of life, and energy
Wang, et al. 215 hospitalized patients Not listed Not listed Not listed PTSD-5 57% screened positive for PTSD, anxiety, or Utilization of self-report to characterize
(2020) Cleveland, US GAD-7 depression. Specific rates were as follows: 34% psychiatric history

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CES-D10 for PTSD, 24% for anxiety, and 42% for Not all patients were initially hospitalized
depression due to COVID-19
Among patients without a prior psychiatric history,
42% screened positive for one psychiatric
disorder
Among patients with a prior psychiatric history,
78% screened positive for one disorder
Weerhandi 152 hospitalized patients Median ¼ 62 44.1% White, 21.7% Median of 37 days (range: the PROMIS Global Poorer physical health and mental health were Strict exclusion criteria
et al. (2021) (45.3% required ICU Range ¼ 50–67 Hispanic, 9/9% Asian, 30–43) post discharge Health-10 reported after hospital discharge compared to
admission, 36.7% 11.2% Black, 8.7% from hospital baseline functioning
required mechanical Mixed/other, 4.4%
ventilation) unknown
New York, US
62.7% male
Woo et al. 18 patients with mild to M ¼ 42.2 Not listed Median of 85 days TICS-M Patients exhibited greater difficulties on TICS-M Small sample size
(2020) moderate disease (61% SD ¼ 14.3 (Range ¼ 20–105 days) PHQ-9 as compared to healthy controls in the areas Screening measure of cognitive functioning
required inpatient after recovery Fatigue Assessment of short-term memory, attention, concentration/
hospitalization) Scale language
10 age-matched healthy 50% reported attention deficits, 44.4% reported

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controls short-term memory deficits, 27.8% reported
Hamburg, Germany word-finding difficulties, 16.7% reported
42.1% male fatigue, 11.1% reported mood swings, and
5.6% reported fatigue, phonophobia, or

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incoherent thoughts
Cognitive functioning was not associated with
somatic symptoms
Disease severity and treatment factors were not
Neuropsychological and psychiatric sequalae Vanderlind et al.

427
associated with cognitive impairments
 428
Table 1 (Continued)
Study Population Age (in years) Race/ethnicity Time of assessment Measures Findings Limitations

Zarghami 50 outpatients with mild M ¼ 43.62 Not listed During home quarantine PHQ-9 17.3% patients had prior history of psychiatric Small sample size
et al.(2020) symptomatology SD ¼ 15.81 GAD-7 disorders
Fasa City, Iran PSS-14 Based on self-report measure, 34.6% endorsed
Semi-structured depressive symptoms, 32.7% endorsed anxiety,
psychiatric interview and mean score for PSS-14 is 11.8 (scores

www.co-psychiatry.com
range from 0–56)
Based on clinical interview, 18.8% met criteria for
a psychiatric disorder; specific rates were as
follows: 5.8% for GAD, 21.2% for insomnia,
3.8% for MDD, and 9.6% for an adjustment
disorder
Zhou et al. 29 recovered patients M ¼ 47 Chinese Han 2–3 weeks after infection TMT Cognitive impairments among patients with Small sample size
(2020) 29 healthy controls SD ¼ 10.54 Digit Span SARS-CoV-2 were mild and most prominent in Participants excluded if they received fewer
Zhejiang, China Range ¼ 30-64 Sign Coding Test the domain of sustained attention than nine years of education
62% male CPT No significant difference between patient and
Provision of services to people with mental illnesses

GAD-7 healthy controls in TMT, SCT, or DST

PHQ-9
Zhu et al. 432 previously hospitalized Median ¼ 49, Chinese Han and Tibetan Not listed Lawton IADL scale 36.8% of patients reported at least one IADL Lack of baseline data
(2020) patients range ¼ 35-60 Barthel Index limitation, with 16.4% reporting moderate Lack of control group
China Zung’s self-reported dependence and 5.6% reporting severe Reliance on self-report measures
51% male anxiety scale dependence Cross-sectional assessment
28.7% of patients met criteria for a probable
anxiety disorder diagnosis
Disease severity was associated with greater
prevalence of disability and anxiety and was an
independent risk factor for all outcomes

BDI-13, Beck’s Depression Inventory; BNT, Boston Naming Test; CESD-10, Center for Epidemiological Studies Depression Scale; CPT, Continuous Performance Test; EQ-5D-5L, Euro Quality of Life-5 Dimensions-5 Levels;
EQ-VAS, Euro Quality of Life- Visual Analogue Scale; GAD-7, Generalized Anxiety Disorder Scale; HAD, Hospital Anxiety and Depression Scale; IES-R, Impact of Event Scale–Revised; IQ Code-N, Informant
Questionnaire on Cognitive Functioning in the Elderly; mMRC, modified British Medical Research Council dyspnea scale; MoCA, Montreal Cognitive Assessment; PCL, Posttraumatic Stress Disorder Checklist; PHQ-9,
Patient Health Questionnaire 9; PSS-14, Perceived Stress Scale-14; SDMT, Symbol Digit Modalities Test; SF-36, 36-Item Short Form Survey; STAI-Y, State-Trate Anxiety Inventory form Y; TAVEC, Test de Aprendizaje
Verbal España-Complutense; TEMPS, Temperament Evaluation of Memphis, Pisa, Paris, and San Diego; TICS, Telephone Interview of Cognitive Status; TMT, Trail Making Test A and B; WHIIRS, Women’s Health Initiative
Insomnia Rating scale; WHOQOL-BREF, World Health Organization Quality of Life; WMS , the Wechsler Memory Scale.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Volume 34  Number 4  July 2021
 Neuropsychological and psychiatric sequalae Vanderlind et al.

severe depression endured and ranged from 10.0 to months from symptom onset [31,34,37]. Risk fac-
& & &&
42.0% [2,11 ,16,24,25,28,29 ,32,33]. Survivors with tors for anxiety included illness severity [36 ],
higher depression severity endorsed greater perceived medical comorbidities [19], reduced quality of life
& &&
stigma related to COVID-19 [28,30], had a prior psy- and persistent dyspnea [11 ], younger age [14 ],
&
chiatric history [29 ,33], and underwent quarantine having close relatives with COVID-19 [25], prior
posthospitalization [25]. psychiatric history [33], and decreased sense of
In contrast, fewer studies focus on nonhospital- smell [31].
ized COVID-19 survivors. Prevalence of depression
&
in this group ranged from 15.0 to 68.5% [29 ,31,34]. Acute and posttraumatic stress
Among mixed samples of previously hospitalized Eleven studies reported on acute stress reaction or
and never-hospitalized patients, prevalence rates PTS symptoms. One study found that, among adults
ranged from 12.0 to 48.0% [17,27]. The wide range in quarantine facilities in China, the prevalence rate
of prevalence rates are reflective of differences in of acute stress symptoms was 31.0% [25]. PTS prev-
assessment methods (e.g., screening questionnaires, alence among patients not held in a quarantine
clinical interview, self-report online surveys), used facility ranged from 7.0 to 36.4% [17,20,24,28,29 ,
&

to capture symptoms of depression, differences in 30,33–35,41]. On average, 10.0–28.0% survivors

follow-up time frames, and global diversity of sam- endorsed symptoms consistent with acute stress
ples. Risk factors for depression in those with milder &
reaction [28,29 ,30,35]. Risk factors for greater sever-
&
illness included female gender [29 ], older age, and ity of stress response included a history of psychiat-
decreased sense of smell [31]. ric disorders, female gender, and COVID-19
infection of a close family member, whereas retire-
Anxiety ment status and older age were related to lower
Of 33 studies, 25 included anxiety assessments. psychological distress [25].
Estimates of clinical anxiety among patients with Among studies that evaluated Post Traumatic
COVID-19 were broad and ranged from 5.0 to Stress Disorder (PTSD), prevalence rates of 10.0%
& && && &
55.2% [11 ,13 ,14 ,16– 21,24 –26,28,29 ,30– were reported 6 weeks postdischarge [20], whereas
&&
35,36 ,37– 40]. Among hospitalized survivors, others reported rates of 36.4% 2 months posthospi-
rates of anxiety ranged from 5.0 to 47.8% postdi- talization [24]. Three to four months posthospital-
scharge, while some reported only subclinical ization, 25.6% of survivors endorsed symptoms
symptoms of anxiety [26]. In the near term consistent with mild PTSD, 11.3% endorsed moder-
(<2months) following hospital discharge, anxiety ate symptoms, and 5.9% endorsed severe symptoms
rates were somewhat lower than in nonhospital- [41]. Among never-hospitalized patients with
ized survivors. In a sample of 402 COVID-19 sur- mild illness, 7.0% met the criteria for clinically
vivors, 32.3% of previously hospitalized patients significant PTSD while 10.0% endorsed acute stress
endorsed moderate to severe anxiety, whereas symptoms [17].
44.2% of never-hospitalized patients endorsed sim-
ilar levels one month after initially presenting to an Fatigue
&
emergency room in Italy [29 ]. Others confirm Rates of fatigue- as measured both by formal assess-
&
greater rates of anxiety among never-hospitalized ment (i.e., Fatigue Assessment Scale [12 ], Chalder
&
patients in the near term after infection [35]. Nota- Fatigue Scale or CFQ-11 [42 ], Fatigue Severity Scale
&
bly, those who were never hospitalized tend to be [11 ], SF-36 energy/fatigue subscale [17] and Borg
younger patients who have to return to family and Rating Scale of Extreme Exhaustion [26], and by
&&
work responsibilities shortly after recovery and the patient report of symptoms [2,14 ,17,18,28,32,
&&
these demands may exacerbate anxiety within this 36 ]ranged from 12.7 to 88.6% across 11 studies. In
group. However, further, follow-up including pro- one study, 10–35 days posthospitalization, 88.6% of
&&
spective studies can confirm this finding and per- patients endorsed fatigue [14 ], however, two other
haps elucidate the etiology of higher rates of studies report much lower rates (12.7–16.7%)
&
anxiety in nonhospitalized survivors. 1 month after discharge [12 ,28]. Six weeks after
Two to four months posthospitalization, survi- symptom abatement or hospital discharge, 52.3%
vors reported ongoing anxiety, with rates ranging of COVID-19 survivors experienced fatigue, and
&
from 14.0 to 47.8% [11 ,16,32]. The longest follow- 31.0% of those patients had not returned to work
up study to date (6 months postdischarge) indi- despite being medically cleared of COVID-19 related
&
cated that 23.0% of previously hospitalized illness [42 ].
&&
patients experienced anxiety or depression [36 ]. Two to three months after hospital discharge,
Never-hospitalized patients experienced moderate 40.0–69.0% of COVID-19 survivors endorsed ongo-
to severe anxiety, at rates of 14.0– 55.2%, up to four ing fatigue that interfered with activities of daily

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Provision of services to people with mental illnesses

&
living and quality of life [2,11 ,17,18,26]. Sixty- characterization of cognitive functioning within
three percentage of COVID-19 survivors endorsed specific domains. Studies inconsistently excluded
ongoing fatigue or muscle weakness at six individuals with prior cognitive impairment. Not-
&&
months [36 ]. Risk factors for persistent fatigue withstanding, most studies included here indicate
included female sex and prior history of depression some degree of cognitive impairment among
&
or anxiety [32,42 ]. There was generally no associa- patients with previous diagnosis of COVID-19.
tion between fatigue and inflammatory markers or Though rates vary, a substantial portion of survivors
&
COVID-19 disease severity [32,42 ]; however, one exhibit poor cognitive performance in the domains
study reported that patients with moderate or severe of attention, executive function, and memory. Our
illness endorsed worse fatigue than did those with findings have several important implications for
mild illness [17]. further research, clinical management, and treat-
ment of COVID-19 survivors.
Sleep difficulties
Estimates of sleep disturbance ranged from 26.0 to
&&
52.2% across five studies [18,19,27,32,36 ]. Those
Implications for further research
with multiple medical comorbidities were more Limited assessment of psychiatric symptoms to date
likely to experience sleep disturbance (41.3%) than does not allow for granular examination of psychi-
those without (32.0%) four weeks after hospital atric symptom range and acuity. Most studies to
discharge [19]. Sleep disturbance was higher among date use screening instruments to categorize and
women, and increased depression risk [32]. Further, determine the severity of psychiatric disorders.
sleep disturbance appeared to persist in 26.0% of Examination of patterns of symptoms or transdiag-
survivors, 6 months postdischarge [36 ].
&&
nostic processes (e.g., increased negative affect,
decreased reward, rumination) may elucidate com-
mon underlying features of psychiatric sequelae
DISCUSSION post-COVID-19 to clarify mechanisms of psychiatric
In a systematic review of 33 studies evaluating the symptoms and inform treatment targets.
neuropsychological and psychiatric sequelae of There is a need for prospective research studies
community-dwelling patients recovering or recov- that recruit large patient populations and compari-
ered from COVID-19, we found high rates of depres- son samples, comprehensively define medical and
sion, anxiety, fatigue, and sleep disruption, and treatment course, and utilize gold-standard mea-
somewhat lower, but still significant, rates of PTS. sures to characterize cognitive and psychiatric func-
Similar rates of depression and anxiety appear tioning across specific domains over time. Sample
among patients who were previously hospitalized characteristics in the extant literature vary widely
or never hospitalized; some studies even suggest and often fail to characterize participants’ medical
these symptoms may be higher in never hospitalized comorbidities, premorbid cognitive functioning,
survivors possibly due to the younger age range of and prior psychiatric and treatment history. Few
these cohorts which developmentally may coincide studies examine the association between known
with competing work/life responsibilities which COVID-19 risk factors (e.g., hypertension, diabetes,
older adults may not face. In contrast, rates of PTS cardiovascular disease) and cognition or psychiatric
appear higher among hospitalized patients. Fatigue symptoms, and studies do not consistently control
is the most prevalent and persistent symptom at for the impact of treatments.
longer-term follow-up time points and may contrib- There are few studies including nonhospitalized
ute to difficulties returning to preillness roles. COVID-19 survivors. Elevated rates of psychiatric
Though longitudinal studies are scarce, cross-sec- symptoms among patients who did not warrant
tional studies at different time points postinfection hospitalization, as compared to those who did, sug-
suggest that psychiatric symptoms may be endur- gest that, for some patients, environmental and
ing. Consistent risk factors for psychiatric symptoms psychological factors may contribute more to psy-
include history of psychiatric disorder and female chiatric sequalae than do disease characteristics or
gender. Additional risk factors are infection of a medical treatments. Identifying factors that contrib-
family member, isolation, perceived stigma, and ute to psychiatric sequalae among never-hospital-
medical comorbidity. Findings on age as a risk factor ized COVID-19 survivors is needed. Relatedly,
are inconsistent. prospective studies on populations that are quaran-
Overall, few studies have formally assessed tined per government directive may help to clarify
neuropsychological sequelae of COVID-19, and the role of mood dysfunction stemming from
the substantial heterogeneity of study samples COVID-related illness as compared to protracted
and methods undermine comprehensive isolation and perceived stigma.

430 www.co-psychiatry.com Volume 34  Number 4  July 2021

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 Neuropsychological and psychiatric sequalae Vanderlind et al.

This review did not focus on acute COVID-19 performed routinely in COVID-19, with referral
infection and treatment, and studies included here for more comprehensive neuropsychological assess-
were predominantly conducted within the first few ment as indicated.
months of symptom abatement or hospital dis- Among studies that use objective measures of
charge. Longitudinal assessment across the course cognition, memory was occasionally impaired
of viral infection/progression, treatment, and recov- whereas attention and executive functions appear
ery is needed to document the nature of COVID- to be commonly impaired. Cognitive remediation
related cognitive and psychiatric difficulties over that introduces and practices strategies designed to
time. Such work will aid in the selection of appro- support attention and executive functions may be
priate interventions across stages of recovery. helpful. Given the prevalence of COVID-19 infec-
Most studies relied on retrospective self-report tion and the varied rates of impairment, scalable
assessment measures, which are susceptible to interventions (e.g., digital therapeutics) that can be
reporting biases [43]. Relatedly, neuropsychological widely disseminated will be paramount in this pop-
functioning was often assessed using screening mea- ulation [44].
sures, thereby limiting the granular measurement of Cognitive-behavioral (CBT) and mindfulness-
cognition. Future studies should utilize gold-stan- based approaches targeting depression, anxiety,
dard measures of specific cognitive and psychiatric and sleep difficulties are likely to be beneficial for
domains, which will help to elucidate specific survivors. Cognitive restructuring and mindfulness
treatment targets. focused on self-compassion can target perceived dis-
This review should be considered in the context crimination while modified forms of behavioral acti-
of temporal and cultural factors that may limit vation can ameliorate depression symptoms. CBT for
generalizability. Many studies included in this anxiety may be especially useful for individuals with
review were conducted at the height of the pan- ongoing shortness of breath postdischarge from the
demic, when understanding of the virus, its treat- hospital. Activity pacing and graded increase in activ-
ment, and the nature of the pandemic at large was ities, together with medical management, may help
limited. Prevalence rates of neuropsychological and those with fatigue symptoms. Sleep hygiene and CBT
psychiatric difficulty during the first peak of the for insomnia are recommended to address ongoing
pandemic may differ from those observed across sleep difficulties. Cognitive processing therapy or
subsequent waves of viral infection. Further, cul- prolonged exposure therapy may be beneficial for
tural differences, including stigma, quarantine pro- ICU survivors who experience PTS symptoms. Given
cedures, access to, and the nature of, treatment, may the rates of psychiatric symptoms reported to date,
underlie differing prevalence rates of neuropsycho- mechanisms for broad dissemination of interven-
logical and psychiatric symptoms across countries tions should be considered [45].
and regions.
Finally, given that COVID-19 disproportion-
ately affects marginalized and ethnic minority com- Limitations
munities, there is a critical need to explore factors Limitations of this review include a limited time
that may contribute to increased risk of morbidity frame (December 2019 to February 2021). Given the
and mortality among this population. Treatment surge of research on COVID-19, timeframe restric-
modalities may require modification according to tions on literature searches notably limit the inclu-
the ethnocultural preferences of patients, to ensure sion of emerging data on the topic. Further, this
treatment compliance, optimal recovery, and review excluded studies with samples of hospital-
better outcomes. ized patients to minimize the review of neuropsy-
chological and psychiatric sequelae stemming from
factors related to inpatient hospitalization. In doing
Clinical assessment and treatment so, however, this review could not document cog-
Psychiatric symptoms should be considered highly nitive and psychiatric deficits among acutely, and
common, distressing, and debilitating sequelae of often critically, ill patients. Although outside the
COVID-19 that can be endure, contribute to poor scope of the current paper, greater understanding of
adherence to medical treatments, and require assess- the nature of neuropsychological and psychiatric
ment and treatment. Survivors of COVID-19 should functioning across hospitalization course is needed.
routinely be screened for psychiatric symptoms, and Indeed, delirium is common in patients treated in
providers should not assume that those with milder the ICU, which can cause severe and persistent
forms of COVID-19 or those who were never hospi- cognitive dysfunction [46–48], and depression, anx-
talized will not manifest psychiatric symptoms or iety, and PTSD are frequently experienced by survi-
cognitive deficits. Cognitive screening should be vors of critical illness [49,50].

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Provision of services to people with mental illnesses

13. Zhou H, Lu S, Chen J, et al. The landscape of cognitive function in recovered

CONCLUSION && COVID-19 patients. J Psychiatr Res 2020; 129:98–102.
This systematic review highlights cognitive deficits This study utilized a comprehensive battery of neuropsychological measures and
compared compared performance between participants recovered from COVID-
and psychiatric symptoms associated with COVID- 19 and healthy controls. Patients with less than nine years of education were
19. Cognitive and psychiatric dysfunction has the excluded.
14. Almeria M, Cejudo JC, Sotoca J, et al. Cognitive profile following COVID-19
potential to negatively impact survivors’ social and && infection: clinical predictors leading to neuropsychological impairment. Brain
occupational functioning during and after recovery. Behav Immun Health 2020; 9:100163.
This study attempted to control for prior cognitive impairment and psychiatric
Primary findings from this paper shed light on illness. The authors utilized a relatively comprehensive battery of neuropsycholo-
important treatment targets for this population. gical measures and sought to discriminate between various COVID-19 related
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