A Systematic Review of Neuropsychological and Psychiatric Sequalae of COVID-19

Implications for Treatment

William Michael Vanderlind; Beth B. Rabinovitz; Iris Yi Miao; Lauren E. Oberlin; Christina Bueno-Castellano; Chaya Fridman; Abhishek Jaywant; Dora Kanellopoulos


Curr Opin Psychiatry. 2021;34(4):420-433. 

In This Article


Neuropsychological and Cognitive Sequelae

Objective Neuropsychological Assessment. Abnormal cognitive performance was documented in approximately 15.0–40.0% of participants 10–105 days following hospital discharge.[11–17] Comparison of cognitive function in COVID-19 patients to matched controls found 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 on cognitive screening measures (e.g., Montreal Cognitive Assessment, Mini Mental State Exam, Telephone Interview for Cognitive Status).

Executive dysfunction was implicated in patients who were treated in the intensive care unit (ICU) and oxygen therapy was associated with lower scores in the domains of memory, attention, working memory, processing speed, executive function, and global cognition.[14] Specific COVID-19 related symptoms were associated with differential patterns of cognitive performance. Neurological symptoms were associated with lower working memory scores, headache with lower scores on memory coding, attention, complex working memory, processing speed, executive function, and global cognition, diarrhea with lower scores in delayed visual memory, working memory, and complex working memory.[14] Poor cognitive performance was associated with increased inflammatory markers in one study.[13] Brain Magnetic Resonance Imaging in one study was not indicative of severe neurological injury in patients 2–3 months post recovery in comparison to healthy controls. However, recovered patients demonstrated increased bilateral thalamic T2 signal on susceptibility-weighted imaging and increased mean diffusivity in the posterior thalamic radiations and sagittal striatum, suggesting possible increased burden of microvascular events. Notably these findings were associated with markers of inflammation but not cognitive performance.[11]

Self-reported Cognitive Functioning

Self-report or observer report of cognitive difficulties was collected 4–15 weeks post discharge from hospital or recovery from COVID-19. Memory complaints were reported in 19.5–34.0% of participants and attention difficulties were reported in 24.4–28.0% of participants.[18,19] de Graaf[20] reported cognitive complaints in 25.0% of participants. Medical comorbidities were associated with more frequent report of concentration difficulties and memory loss.[19] Observation of patients from home healthcare workers indicated general improvements in cognitive status 1 month post hospital discharge.[21]

Psychiatric Sequalae of COVID-19

In addition to general mental health difficulties,[22,23] there are elevated rates of depression, anxiety, Post Traumatic Stress (PTS), fatigue, and sleep difficulties among COVID-19 survivors.


In 19 of 33 studies assessing depression,[2,11–14,16,17,20,24,28–34] symptom rates ranged from 10.0 to 68.5%. Previously hospitalized patients experienced high rates of depression both in the near- and long-term following hospital discharge. In the month following hospitalization, many patients endorsed subclinical levels of depression,[12,14,26] and 10.0–19.0% of patients reported moderate to severe depression.[28,30] Two to three months following discharge, rates of moderate to severe depression endured and ranged from 10.0 to 42.0%.[2,11,16,24,25,28,29,32,33] Survivors with higher depression severity endorsed greater perceived stigma related to COVID-19,[28,30] had a prior psychiatric history,[29,33] and underwent quarantine posthospitalization.[25]

In contrast, fewer studies focus on nonhospitalized COVID-19 survivors. Prevalence of depression in this group ranged from 15.0 to 68.5%.[29,31,34] Among mixed samples of previously hospitalized and never-hospitalized patients, prevalence rates ranged from 12.0 to 48.0%.[17,27] The wide range of prevalence rates are reflective of differences in assessment methods (e.g., screening questionnaires, clinical interview, self-report online surveys), used to capture symptoms of depression, differences in follow-up time frames, and global diversity of samples. Risk factors for depression in those with milder illness included female gender,[29] older age, and decreased sense of smell.[31]


Of 33 studies, 25 included anxiety assessments. Estimates of clinical anxiety among patients with COVID-19 were broad and ranged from 5.0 to 55.2%.[11,13,14,16–21,24–26,28–40] Among hospitalized survivors, rates of anxiety ranged from 5.0 to 47.8% postdischarge, while some reported only subclinical symptoms of anxiety.[26] In the near term (<2months) following hospital discharge, anxiety rates were somewhat lower than in nonhospitalized survivors. In a sample of 402 COVID-19 survivors, 32.3% of previously hospitalized patients endorsed moderate to severe anxiety, whereas 44.2% of never-hospitalized patients endorsed similar levels one month after initially presenting to an emergency room in Italy.[29] Others confirm greater rates of anxiety among never-hospitalized patients in the near term after infection.[35] Notably, those who were never hospitalized tend to be younger patients who have to return to family and work responsibilities shortly after recovery and these demands may exacerbate anxiety within this group. However, further, follow-up including prospective studies can confirm this finding and perhaps elucidate the etiology of higher rates of anxiety in nonhospitalized survivors.

Two to four months posthospitalization, survivors reported ongoing anxiety, with rates ranging from 14.0 to 47.8%.[11,16,32] The longest follow-up study to date (6 months postdischarge) indicated that 23.0% of previously hospitalized patients experienced anxiety or depression.[36] Never-hospitalized patients experienced moderate to severe anxiety, at rates of 14.0–55.2%, up to four months from symptom onset.[31,34,37] Risk factors for anxiety included illness severity,[36] medical comorbidities,[19] reduced quality of life and persistent dyspnea,[11] younger age,[14] having close relatives with COVID-19,[25] prior psychiatric history,[33] and decreased sense of smell.[31]

Acute and Posttraumatic Stress

Eleven studies reported on acute stress reaction or PTS symptoms. One study found that, among adults in quarantine facilities in China, the prevalence rate of acute stress symptoms was 31.0%.[25] PTS prevalence among patients not held in a quarantine facility ranged from 7.0 to 36.4%.[17,20,24,28–30,33–35,41] On average, 10.0–28.0% survivors endorsed symptoms consistent with acute stress reaction.[28–30,35] Risk factors for greater severity of stress response included a history of psychiatric disorders, female gender, and COVID-19 infection of a close family member, whereas retirement status and older age were related to lower psychological distress.[25]

Among studies that evaluated Post Traumatic Stress Disorder (PTSD), prevalence rates of 10.0% were reported 6 weeks postdischarge,[20] whereas others reported rates of 36.4% 2 months posthospitalization.[24] Three to four months posthospitalization, 25.6% of survivors endorsed symptoms consistent with mild PTSD, 11.3% endorsed moderate symptoms, and 5.9% endorsed severe symptoms.[41] Among never-hospitalized patients with mild illness, 7.0% met the criteria for clinically significant PTSD while 10.0% endorsed acute stress symptoms.[17]


Rates of fatigue- as measured both by formal assessment (i.e., Fatigue Assessment Scale,[12] Chalder Fatigue Scale or CFQ-11,[42] Fatigue Severity Scale,[11] SF-36 energy/fatigue subscale[17] and Borg Rating Scale of Extreme Exhaustion,[26] and by the patient report of symptoms[2,14,17,18,28,32,36] ranged from 12.7 to 88.6% across 11 studies. In one study, 10–35 days posthospitalization, 88.6% of patients endorsed fatigue,[14] however, two other studies report much lower rates (12.7–16.7%) 1 month after discharge.[12,28] Six weeks after symptom abatement or hospital discharge, 52.3% of COVID-19 survivors experienced fatigue, and 31.0% of those patients had not returned to work despite being medically cleared of COVID-19 related illness.[42]

Two to three months after hospital discharge, 40.0–69.0% of COVID-19 survivors endorsed ongoing fatigue that interfered with activities of daily living and quality of life.[2,11,17,18,26] Sixty-three percentage of COVID-19 survivors endorsed ongoing fatigue or muscle weakness at six months.[36] Risk factors for persistent fatigue included female sex and prior history of depression or anxiety.[32,42] There was generally no association between fatigue and inflammatory markers or COVID-19 disease severity;[32,42] however, one study reported that patients with moderate or severe illness endorsed worse fatigue than did those with mild illness.[17]

Sleep Difficulties

Estimates of sleep disturbance ranged from 26.0 to 52.2% across five studies.[18,19,27,32,36] Those with multiple medical comorbidities were more likely to experience sleep disturbance (41.3%) than those without (32.0%) four weeks after hospital discharge.[19] Sleep disturbance was higher among women, and increased depression risk.[32] Further, sleep disturbance appeared to persist in 26.0% of survivors, 6 months postdischarge.[36]