key: cord-0760262-01tdp8bk authors: Vanderlind, William Michael; Rabinovitz, Beth B.; Miao, Iris Yi; Oberlin, Lauren E.; Bueno-Castellano, Christina; Fridman, Chaya; Jaywant, Abhishek; Kanellopoulos, Dora title: A systematic review of neuropsychological and psychiatric sequalae of COVID-19: implications for treatment date: 2021-05-19 journal: Curr Opin Psychiatry DOI: 10.1097/yco.0000000000000713 sha: e27f28959b82d0676ba9d331648e04adf461a62f doc_id: 760262 cord_uid: 01tdp8bk 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. The novel coronavirus (SARS-CoV-2) that causes coronavirus disease (COVID-19) impacts multiple organ systems [1] . Mortality rates are staggering, and morbidity trends have been the focus of numerous investigations. Persisting symptoms following infection are increasingly reported, including psychiatric symptoms and cognitive concerns [2, 3] , which are likely salient contributors to morbidity and disability. Although the etiology is still largely unknown, cognitive deficits may arise from stroke, meningitis, hypoxia, and inflammatory injury [4] [5] [6] [7] [8] or from the invasive interventions required to treat Objective neuropsychological assessment Abnormal cognitive performance was documented in approximately 15.0-40.0% of participants 10-105 days following hospital discharge [11 & ,12 & , 13 && ,14 && , [15] [16] [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 Neuropsychological weaknesses are not uncommon among COVID-19 survivors, particularly in the domains of attention and executive functioning. COVID-19 is associated with high rates of psychiatric symptoms, including anxiety, depression, fatigue, sleep disruption, and posttraumatic stress, and consistent risk factors for psychiatric symptoms include the history of a psychiatric disorder and female gender. Rates of anxiety and depression are similar, if not higher, among patients who were never hospitalized compared to those who required inpatient hospitalization, whereas rates of posttraumatic stress appear higher among previously hospitalized patients. Literature on neuropsychological functioning in COVID-19 is scarce, and the heterogeneity of patient samples, methods, and timeframe of assessment limit the characterization of neuropsychological and psychiatric sequelae among COVID-19 survivors. There is a pressing 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. 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. [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] . 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 followup 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] . 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% [17,20,24,28,29 & , 30,33-35,41] . On average, 10.0-28.0% survivors endorsed symptoms consistent with acute stress reaction [28,29 & ,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 [ ]. 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] . Sixtythree 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] . 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 && ]. 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. 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 COVIDrelated 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. 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 mindfulnessbased 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] [47] [48] , and depression, anxiety, and PTSD are frequently experienced by survivors of critical illness [49, 50] . This systematic review highlights cognitive deficits and psychiatric symptoms associated with COVID-19. Cognitive and psychiatric dysfunction has the potential to negatively impact survivors' social and occupational functioning during and after recovery. Primary findings from this paper shed light on important treatment targets for this population. Future research is essential to further delineate a granular characterization of cognitive and psychiatric functioning among COVID-19 survivors over time, which will enhance treatment specificity and efficacy across various stages of recovery. 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There are no conflicts of interest.