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


In a systematic review of 33 studies evaluating the neuropsychological and psychiatric sequelae of community-dwelling patients recovering or recovered from COVID-19, we found high rates of depression, anxiety, fatigue, and sleep disruption, and somewhat lower, but still significant, rates of PTS. Similar rates of depression and anxiety appear among patients who were previously hospitalized or never hospitalized; some studies even suggest these symptoms may be higher in never hospitalized survivors possibly due to the younger age range of these cohorts which developmentally may coincide with competing work/life responsibilities which older adults may not face. In contrast, rates of PTS appear higher among hospitalized patients. Fatigue is the most prevalent and persistent symptom at longer-term follow-up time points and may contribute to difficulties returning to preillness roles. Though longitudinal studies are scarce, cross-sectional studies at different time points postinfection suggest that psychiatric symptoms may be enduring. Consistent risk factors for psychiatric symptoms include history of psychiatric disorder and female gender. Additional risk factors are infection of a family member, isolation, perceived stigma, and medical comorbidity. Findings on age as a risk factor are inconsistent.

Overall, few studies have formally assessed neuropsychological sequelae of COVID-19, and the substantial heterogeneity of study samples and methods undermine comprehensive characterization of cognitive functioning within specific domains. Studies inconsistently excluded individuals with prior cognitive impairment. Notwithstanding, most studies included here indicate some degree of cognitive impairment among patients with previous diagnosis of COVID-19. Though rates vary, a substantial portion of survivors exhibit poor cognitive performance in the domains of attention, executive function, and memory. Our findings have several important implications for further research, clinical management, and treatment of COVID-19 survivors.

Implications for Further Research

Limited assessment of psychiatric symptoms to date does not allow for granular examination of psychiatric symptom range and acuity. Most studies to date use screening instruments to categorize and determine the severity of psychiatric disorders. Examination of patterns of symptoms or transdiagnostic processes (e.g., increased negative affect, decreased reward, rumination) may elucidate common underlying features of psychiatric sequelae post-COVID-19 to clarify mechanisms of psychiatric symptoms and inform treatment targets.

There is a need for prospective research studies that recruit large patient populations and comparison samples, comprehensively define medical and treatment course, and utilize gold-standard measures to characterize cognitive and psychiatric functioning across specific domains over time. Sample characteristics in the extant literature vary widely and often fail to characterize participants' medical comorbidities, premorbid cognitive functioning, and prior psychiatric and treatment history. Few studies examine the association between known COVID-19 risk factors (e.g., hypertension, diabetes, cardiovascular disease) and cognition or psychiatric symptoms, and studies do not consistently control for the impact of treatments.

There are few studies including nonhospitalized COVID-19 survivors. Elevated rates of psychiatric symptoms among patients who did not warrant hospitalization, as compared to those who did, suggest that, for some patients, environmental and psychological factors may contribute more to psychiatric sequalae than do disease characteristics or medical treatments. Identifying factors that contribute to psychiatric sequalae among never-hospitalized COVID-19 survivors is needed. Relatedly, prospective studies on populations that are quarantined per government directive may help to clarify the role of mood dysfunction stemming from COVID-related illness as compared to protracted isolation and perceived stigma.

This review did not focus on acute COVID-19 infection and treatment, and studies included here were predominantly conducted within the first few months of symptom abatement or hospital discharge. Longitudinal assessment across the course of viral infection/progression, treatment, and recovery is needed to document the nature of COVID-related cognitive and psychiatric difficulties over time. Such work will aid in the selection of appropriate interventions across stages of recovery.

Most studies relied on retrospective self-report assessment measures, which are susceptible to reporting biases.[43] Relatedly, neuropsychological functioning was often assessed using screening measures, thereby limiting the granular measurement of cognition. Future studies should utilize gold-standard measures of specific cognitive and psychiatric domains, which will help to elucidate specific treatment targets.

This review should be considered in the context of temporal and cultural factors that may limit generalizability. Many studies included in this review were conducted at the height of the pandemic, when understanding of the virus, its treatment, and the nature of the pandemic at large was limited. Prevalence rates of neuropsychological and psychiatric difficulty during the first peak of the pandemic may differ from those observed across subsequent waves of viral infection. Further, cultural differences, including stigma, quarantine procedures, access to, and the nature of, treatment, may underlie differing prevalence rates of neuropsychological and psychiatric symptoms across countries and regions.

Finally, given that COVID-19 disproportionately affects marginalized and ethnic minority communities, there is a critical need to explore factors that may contribute to increased risk of morbidity and mortality among this population. Treatment modalities may require modification according to the ethnocultural preferences of patients, to ensure treatment compliance, optimal recovery, and better outcomes.

Clinical Assessment and Treatment

Psychiatric symptoms should be considered highly common, distressing, and debilitating sequelae of COVID-19 that can be endure, contribute to poor adherence to medical treatments, and require assessment and treatment. Survivors of COVID-19 should routinely be screened for psychiatric symptoms, and providers should not assume that those with milder forms of COVID-19 or those who were never hospitalized will not manifest psychiatric symptoms or cognitive deficits. Cognitive screening should be performed routinely in COVID-19, with referral for more comprehensive neuropsychological assessment as indicated.

Among studies that use objective measures of cognition, memory was occasionally impaired whereas attention and executive functions appear to be commonly impaired. Cognitive remediation that introduces and practices strategies designed to support attention and executive functions may be helpful. Given the prevalence of COVID-19 infection and the varied rates of impairment, scalable interventions (e.g., digital therapeutics) that can be widely disseminated will be paramount in this population.[44]

Cognitive-behavioral (CBT) and mindfulness-based approaches targeting depression, anxiety, and sleep difficulties are likely to be beneficial for survivors. Cognitive restructuring and mindfulness focused on self-compassion can target perceived discrimination while modified forms of behavioral activation can ameliorate depression symptoms. CBT for anxiety may be especially useful for individuals with ongoing shortness of breath postdischarge from the hospital. Activity pacing and graded increase in activities, together with medical management, may help those with fatigue symptoms. Sleep hygiene and CBT for insomnia are recommended to address ongoing sleep difficulties. Cognitive processing therapy or prolonged exposure therapy may be beneficial for ICU survivors who experience PTS symptoms. Given the rates of psychiatric symptoms reported to date, mechanisms for broad dissemination of interventions should be considered.[45]


Limitations of this review include a limited time frame (December 2019 to February 2021). Given the surge of research on COVID-19, timeframe restrictions on literature searches notably limit the inclusion of emerging data on the topic. Further, this review excluded studies with samples of hospitalized patients to minimize the review of neuropsychological and psychiatric sequelae stemming from factors related to inpatient hospitalization. In doing so, however, this review could not document cognitive and psychiatric deficits among acutely, and often critically, ill patients. Although outside the scope of the current paper, greater understanding of the nature of neuropsychological and psychiatric functioning across hospitalization course is needed. Indeed, delirium is common in patients treated in the ICU, which can cause severe and persistent cognitive dysfunction,[46–48] and depression, anxiety, and PTSD are frequently experienced by survivors of critical illness.[49,50]