Skip to main content

REVIEW article

Front. Public Health, 08 August 2022
Sec. Public Mental Health

Acute and chronic neuropsychiatric symptoms in novel coronavirus disease 2019 (COVID-19) patients: A qualitative review

  • 1Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, United States
  • 2Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, United States
  • 3George E. Wahlen Department of Veterans Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical Center (MIRECC), Salt Lake City, UT, United States

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a global pandemic by the World Health Organization (WHO) on March 11th, 2020. It has had unprecedented adverse effects on healthcare systems, economies, and societies globally. SARS-CoV-2 is not only a threat to physical health but has also been shown to have a severe impact on neuropsychiatric health. Many studies and case reports across countries have demonstrated insomnia, depressed mood, anxiety, post-traumatic stress disorder (PTSD), and cognitive change in COVID-19 patients during the acute phase of the infection, as well as in apparently recovered COVID-19 patients. The goal of this narrative review is to synthesize and summarize the emerging literature detailing the neuropsychiatric manifestations of COVID-19 with special emphasis on the long-term implications of COVID-19.

Introduction

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide and the number of confirmed cases continues to rise daily posing a public health emergency. As of September 2021, a year and a half after the onset of the pandemic, there have been over 228 million confirmed cases and 4.6 million deaths globally (1). The COVID-19 syndrome primarily targets the respiratory system, resulting in symptoms such as fever, headache, dry cough, dyspnea, and dizziness (2, 3). These symptoms vary drastically from person to person, ranging from mild hypoxia to acute respiratory distress syndrome (ARDS) and sometimes death (4). SARS-CoV-2 enters human host cells primarily by binding to the cellular receptor angiotensin-converting enzyme 2 (ACE2) and by the action of the transmembrane serine protease 2 (TMPRSS2) for S protein priming (5). As treatment and mitigation efforts have progressed, there is increasing evidence that COVID-19 may have long-term system-wide health effects not limited to the respiratory system but extending to multiple organ systems including cardiac, gastrointestinal, renal, hematological, and central nervous systems, all of which express ACE-2 receptors (68). As an increasing number of patients have been diagnosed with COVID-19 more and more studies have shown central nervous system (CNS) involvement in COVID-19, with several studies and case reports/series demonstrating changes in mood and presence of psychological symptoms in COVID-19 patients (9). Overall, these studies suggest that neuropsychiatric symptoms may be observed in COVID-19 patients long after the infection is no longer detectable raising concerns about the long-term neuropsychiatric consequences in remitted COVID-19 patients.

There is a documented, but under-researched history of respiratory viral diseases associated with both acute and long-lasting psychopathological consequences (10). Coronavirus exposure has also been implicated in neuropsychiatric diseases during and after the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) outbreaks (11). Coronaviruses including the SARS and MERS viruses have been shown to be potentially neurotropic, neurovirulent, and neuroinvasive (12). SARS patients who recovered reported psychiatric symptoms, including post-traumatic stress disorder (PTSD), depression, panic disorder, and obsessive-compulsive disorder (OCD) at 1–50 months follow up (1315). Confusion and delirium were the most commonly reported symptoms during the acute stage of SARS and MERS (11). Moreover, seropositivity for coronaviruses was shown to be associated with suicide and psychosis persisting 1 year after SARS (16). Additionally, both SARS and MERS coronaviruses have demonstrated neuroinvasive potential (17, 18), with supporting evidence coming from animal studies demonstrating that SARS-CoV is capable of entering the brain upon intranasal infection of mice expressing human ACE2 (19). Thus, there is evidence suggesting that neurotropic respiratory viruses can result in chronic brain pathology that manifest as cognitive decline, mood disorders, and psychotic illness, highlighting the crucial importance of carefully tracking the neuropsychiatric sequelae of COVID-19.

The psychological impact of COVID-19 is increasingly being recognized among vulnerable groups, including health care workers, individuals in quarantine, patients with chronic medical diseases and psychiatric disorders, as well as the public in general (20). To date, there has been significant evidence demonstrating the detrimental effects of extended isolation and pandemic-related stress on mental health (21, 22). Quarantine has caused increased stress and trauma across many groups including the elderly, victims of intimate partner violence, and multi-unit households, and also affect the mental health of the general public. We focus the current review on the psychiatric sequelae of SARS-CoV-2 in COVID-19 patients (active or recovered) since it has been shown that COVID-19 patients may be especially vulnerable to depression and anxiety, second only to individuals with chronic disease with regard to point prevalence of depression and anxiety (23). The scope of the review does not include how stress related to the pandemic and social isolation due to lockdown measures adversely affects the mental health of populations that have not been infected with SARS-CoV-2.

There is increasing evidence for the psychiatric sequelae of SARS-CoV-2, though to date most research on this topic is limited to case reports/series, self-report questionnaire surveys, and mental disorder surveys (see Limitations section). Studies have reported symptoms such as anxiety, depression, and mania in COVID-19 patients. In addition, altered cognitive abilities are commonly reported. Importantly, some people who had a COVID-19 infection, even those described as “mild,” continue to suffer from persisting or cyclical respiratory and cardiovascular symptoms, as well as cognitive complaints and fatigue after the acute phase of the illness (24). This post-COVID condition is not clearly defined. It is sometimes called “post-COVID syndrome,” “long COVID,” or “post-acute COVID-19 syndrome” (25). A recent whole-brain voxel-based positron emission tomography (PET) study demonstrated brain hypometabolism in long COVID patients with biologically confirmed SARS-CoV-2 infection and functional complaints of a possible central origin, 26–155 days after the initial symptoms of infection, in comparison to healthy subjects, matched for age and sex, without antecedents of SARS-CoV-2 infection (26). There is a critical need to better characterize the individual experience as well as the biological correlates of long-COVID in order to facilitate clinicians' understanding of what is needed to help COVID patients in their recovery.

The goal of this narrative literature review is to synthesize the emerging literature detailing both the acute and chronic neuropsychiatric manifestations of COVID-19. The PubMed, PubMed Central, Google Scholar, and bioRxiv databases were searched from March 2020 to September 2021 for pertinent articles using a non-systematic approach. Common search terms included: “Psychiatry and COVID-19,” “Neurobiological Implication of SARS-CoV-2,” “Biological Mental Health and COVID-19,” and “Neuropsychiatric fallout of COVID-19.” We included articles that were in English and where study participants had a current or past diagnosis of COVID-19. Furthermore, we discuss potential neurobiological mechanisms through which the novel coronavirus may impact the CNS and result in neuropsychiatric complications. Finally, we suggest several areas of investigation that may lead to a better understanding of the impacts of COVID-19 on mental health.

Neuropsychiatric symptoms and COVID-19

Acute neuropsychiatric symptoms of COVID-19

Manifestations such as insomnia, psychosis, cognitive impairment, and mood disorders during the acute stage of COVID-19 infection have been described in numerous reports (Table 1). In one study, 50 (35%) of 144 patients had symptoms of anxiety and 41 (28%) had symptoms of depression, although these assessments were not diagnostic (35). In another study comparing 26 patients with SARS-CoV-2 infection with patients with other forms of pneumonia and age- and sex-matched healthy controls, the authors reported that scores on both the Hamilton Depression Scale and the Hamilton Anxiety Scale were higher for the SARS-CoV-2 group than for either of the other groups. However, these scores improved significantly after the first week of their hospital stay (53). A recently published study of 58 patients with COVID-19 who had been admitted to two ICUs in France described agitation in 40 (69%) patients and confusion in 26 (65%) of 40 patients who were assessed using the Confusion Assessment Method for the ICU. At discharge, 15 (33%) of 45 patients who were assessed had a dysexecutive syndrome with symptoms such as inattention, disorientation, or poorly organized movements in response to command (36). In the same vein, a study of hospitalized COVID-19 patients in Turkey showed that 34.9% of participants had significant levels of anxiety and 42.0% had depression at or above threshold (48). A study comparing the mental status and inflammatory markers of 103 patients hospitalized with mild COVID-19 symptoms and 103 matched COVID-19 negative controls showed COVID-19 patients demonstrated higher levels of depression, anxiety, and post-traumatic stress symptoms as assessed in online surveys (54). Levels of C-reactive protein (CRP), a peripheral inflammatory indicator, correlated positively with the PHQ-9 total score of patients who presented symptoms of depression, suggesting a potential inflammatory pathway underlying these symptoms (54).

TABLE 1
www.frontiersin.org

Table 1. Studies investigating acute neuropsychiatric sequalae.

One of the largest studies reported examined data from medical records of 40,469 COVID-19 positive cases, mostly from the United States of America (76%), and found that 22.5% had neurological and/or psychiatric manifestations, with anxiety and related disorders being the most prevalent (4.6%) (42). A surveillance study completed in the United Kingdom (UK) showed that 39 cases in a cohort of 125 COVID-19 hospitalized patients presenting with neurological manifestations (Coronerve National Registry Study) also displayed altered mental status. This subgroup of patients was found to have encephalopathy (n = 16) and neuropsychiatric syndromes (n = 23). One symptom that is generally limited to the acute phase of symptomology is psychosis with new-onset psychosis being reported in several studies. One study found that among neuropsychiatric syndromes, new-onset psychosis was the most common (n = 10) followed by other related psychiatric disorders (n = 7) (50). In addition, in a Spanish cohort of hospitalized COVID-19 patients (n = 841), about 20% of the sample were reported to develop neuropsychiatric symptoms including insomnia (13%), anxiety (8%), depression (5%), and psychosis (1.3%) (47).

There have also been case reports and case series indicating the presence of manic and psychotic symptoms in COVID-19 patients with no prior psychiatric diagnosis (29, 39). For example, a Spanish case series highlighted new-onset psychosis in several infected COVID-19 patients (52) and an American case-series described three patients who developed psychoses during infection, albeit some had a prior psychiatric history (34). Parra and colleagues reported several SARS-CoV-2 infected patients that experienced new-onset psychosis during the infection, with delusion, auditory and visual hallucinations, and orientation/attention disturbances being the most common (43). Other large case series have reported high rates of first-episode psychoses in otherwise asymptomatic patients with confirmed SARS-CoV-2 infection. For instance, Iqbal et al. reported nine cases of psychoses contemporaneous to diagnosis with COVID-19 (55). Very few studies have assessed psychiatric symptoms of COVID-19 patients by using psychiatric interviews. One such study of hospitalized COVID-19 patients in China identified 11 symptoms in this patient population, including insomnia, aggressive behaviors, delusions, and hallucinations (56). However, given the small sample size (n = 25), and the fact that participants were patients who received psychiatric inpatient care for comorbid first-onset mental disorders, these findings may have limited generalizability.

Delirium is the most common acute neuropsychiatric syndrome (41) and may be the most prominent presenting feature of COVID-19 in older adults and those with dementia (45). Delirium is associated with poorer outcomes (41) and is especially prevalent among patients requiring intensive care (36). Taken together, it is clear that patients with active COVID-19 infection can exhibit a range of neuropsychiatric symptoms with similar findings independent of geographical boundaries. However, the underlying pathological mechanisms have not been fully established, and a considerable number of reports in the literature remain conceptual, as studies investigating the neuropsychological effects of SARS-CoV-2 are few and limited in scale.

Chronic neuropsychiatric symptoms of COVID-19

An emerging research base is highlighting the potential long-term neuropsychological consequences of COVID-19 infection (Table 1). In a sample of recovered COVID-19 patients at 1-month follow-up after hospital treatment in Milan, a significant proportion of patients self-rated in the psychopathological range: 28% for PTSD, 31% for depression, 42% for anxiety, 20% for obsessive compulsive symptoms, and 40% for insomnia (9). Importantly, baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation, is positively associated with scores of depression and anxiety at follow-up (9). Results from this study should be considered preliminary, as these data are based on self-reported questionnaires and not on clinically assessed standardized evaluation or DSM-5 diagnoses.

In another survey-based study of COVID-19 patients (n = 675) who were discharged from the hospital in Wuhan, China, moderate to severe anxiety was reported by 10.4%, and moderate to severe depression was found among 19% of the sample (71). In addition, 12.4% surpassed the cutoff for provisional PTSD diagnosis, which is in contrast with the finding that 96% of patients currently hospitalized for COVID-19 showed clinically significant symptoms of PTSD due to COVID-19 (30). The presence of PTSD symptoms due to COVID-19 may be substantially higher in hospitalized patients due to acute illness and may resolve considerably after discharge. Furthermore, the study by Liu et al. noted that perceived discrimination (disconnect/rejection from family and community) was strongly associated with anxiety, depression, and PTSD (71).

Consistent with the studies above, Tomasoni et al. detected a substantial proportion of clinically and virologically recovered COVID-19 patients still suffering from anxiety (29%) and depression (11%) symptoms (68). Moreover, subjects with pathological HADS-A/D scores complained of the persistence of cognitive deficits more frequently than patients with scores in the normal range. In addition, Poyraz et al. investigated psychiatric symptomatology and protracted symptoms in patients who had recovered from the acute COVID-19 infection and found that after a mean of almost 50 days following the diagnosis, 34.5% of the sample reported clinically significant PTSD, anxiety, and/or depression, with PTSD being the most common condition reported (25.4%) (64). Predictors of PTSD symptom severity were the female sex, past traumatic events, protracted symptoms, stigmatization, and a negative view on the COVID-19 pandemic (64). A study of Italians over the age of 60 who had fully recovered from COVID-19 showed the sample experienced considerably more psychological distress than the Italian and worldwide general population, as measured by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego (61). The authors also found women to be more vulnerable to psychological distress than their male counterparts post COVID-19 infection. Patients who recovered from COVID-19 and who reported psychological distress presented with more occurrences of cyclothymic and depressive affective temperaments and scored higher on the dimensions of lack of impulse control and lack of clarity using the Difficulties in Emotion Regulation Scale (61). In a holistic study of discharged COVID-19 patients that assessed the medium-term effects of SARS-CoV-2 infection on mental and cognitive health, the authors reported that recovered patients had a higher burden of self-reported mood and dysexecutive cognitive symptoms (65). Furthermore, a large retrospective study examining COVID-19 patients in the United States of America found a bidirectional relationship between COVID-19 and mental illness, where COVID-19 diagnosis was associated with an increased incidence of psychiatric diagnosis in patients with no previous reports of mental illness (49). At 90 days, the estimated probability of having been newly diagnosed with a psychiatric illness after COVID-19 diagnosis was 5.8%. Further, a psychiatric diagnosis in the previous year was associated with a higher incidence of COVID-19 diagnosis (49). In agreement, a large case-control study based on electronic health records of patients in the US found that the odds of being diagnosed with COVID-19 were higher for patients with attention deficit hyperactivity disorder, bipolar disorder, depression, and schizophrenia (51). The authors hypothesized that this finding could be attributed to the potential lack of compliance with preventive behaviors and problems with the appraisal of health information in patients with mental health disorders. Furthermore, the authors posited that life circumstances (living in crowded hospitals or residencies) and socioeconomic disadvantage (homelessness) in patients with mental illnesses could also be contributing factors to this finding.

Relative to mood symptoms, the long-term effect of COVID-19 on cognitive function has been understudied. An investigation of recovered COVID-19 patients (10–35 days after hospital discharge), presenting with headache, anosmia, dysgeusia, diarrhea, and those who required oxygen therapy had lower scores in memory, attention, and executive function subtests as compared to asymptomatic patients (27). A T score lower than 30 was observed in memory domains, attention and semantic fluency [2 (5.7%)] in working memory, mental flexibility [3 (8.6%)] and, phonetic fluency [4 (11.4%)] (27). In addition, higher scores in anxiety and depression were found in patients with cognitive complaints (27). Further, in a sample of 71 COVID-19 hospitalized patients, those who were diagnosed with delirium during their hospitalization (42%) had lower cognitive scores on a telephone screening interview 4 weeks after discharge, although the between-group comparison did not reach statistical significance (p = 0.06) (41). Recovered COVID-19 patients have also exhibited reduced cognitive processing in the sustained attention domain as revealed by the continuous performance test (CPT) (70). A potential correlation between serum CRP level and reaction time in CPT was also reported, though further research is needed on the relationship between inflammatory factors and cognition (70). A recent UK study demonstrated substantial neurocognitive diminishment in mostly young adults who recovered from acute uncomplicated COVID-19 (median time after infection = 85 days) when compared to age-matched controls (69). Of note was the fact that the deficits in episodic memory, difficulties in concentration, and attention were not associated with fatigue, depression, hospitalization, treatment, viremia, or acute inflammation (69). Further, neuropsychological investigations from a German case series provide evidence of marked impairment of cognition independent of delirium and outlasting the duration of acute infection with SARS-CoV-2 (59). Finally, in the longest follow-up study of COVID-19 patients thus far, Logue et al. showed that 13.6% of participants reported persistent fatigue and loss of smell or taste, and about 2.3% of the participants reported brain fog or cognitive problems for as long as 9 months after illness (72). These results suggest that recovered COVID-19 patients may present with reduced cognitive function which may have important implications for returning to the demands of school and work Table 2.

TABLE 2
www.frontiersin.org

Table 2. Studies investigating chronic neuropsychiatric sequalae.

Impact of ICU admissions in COVID-19 on mental health

As of late December 2020, roughly 326.7 COVID-19 cases out of 100,000 resulted in hospitalization in the United States of America (CDC, 2020). The relationship between hospitalization, particularly the need for ICU care and COVID-19 may signal greater compromise in patient mental and cognitive health. For instance, a study on patients admitted to the ICU (n = 116) showed that 41.4% of patients reported at least one long-term mental health consequence within 6 months of discharge (73). Out of the patients experiencing mental health consequences, anxiety and depression (or the combination of the two) were the most prominent syndromes, at 28.4 and 20.7% of patients, respectively (73). In a separate study that included ICU patients receiving mechanical ventilation, symptoms of anxiety and depression were evident at 3 months follow-up in ~30 and ~21%, respectively, as well as PTSD in 29.9–34.3% of patients (74). Patients in the ICU with ARDS and severe illness (91% on ventilation) had average global cognition scores 1.5 standard deviations (SD) below the age-adjusted mean population and appeared similar to patients with mild cognitive impairment (75). These findings suggest that if patients admitted to the ICU with COVID-19 follow these initially observed trends, they may experience the virus's effects for extended periods. Thus, examination of the relationship between ICU admission and illness severity in COVID-19 patients will be an important area of research to determine what factors may contribute to the long-term effects on cognitive and mental health.

Potential neurobiological mechanisms

The burgeoning body of literature on COVID-19 infection suggests it is associated with acute and chronic neuropsychiatric sequelae; however, the mechanisms underlying this association are not completely understood but appear to be multifactorial. There are several proposed biological mechanisms including direct neuroinvasion, cytokine network dysregulation, post-infectious neuronal autoimmunity and acute neurovascular events as well as psychological and environmental mechanisms such as social isolation that may play a role in the emergence of these syndromes (76, 77). There are complex challenges in assessing the true role of SARS-CoV-2 in neuropsychiatric disease, the most pertinent of which is separating the specific impact of the virus from both the broader disease response and the social, cultural and psychological circumstances in which an infection has occurred (77).

Concerning direct neuroinvasion, human autopsy studies have identified viral RNA transcripts in brain tissues (7880) and viral proteins in the endothelial cells within the olfactory bulb (81) in people who succumbed to COVID-19. There have been several reported cases of SARS-CoV-2 presence in the cerebral spinal fluid (CSF). For instance, in one case, the presence of the viral genome of SARS-CoV-2 was detected using deep sequencing in the CSF of a patient presenting with CNS demyelinating disease (82). In another case, a COVID-19 patient with meningitis had SARS-CoV-2 presence in the CSF confirmed using polymerase chain reaction (PCR) (83). Additionally, a recent study using human induced pluripotent stem cell (hiPSC) lines derived from healthy individuals to generate forebrain-specific human neural progenitor cells (hNPCs), indicated that SARS-CoV-2 can infect cells of neural origin, and suggested that infected cells can promote the death of nearby cells (84). One of the most frequently proposed routes of neuroinvasion is through the olfactory bulb. In a study of 32 COVID-19 patient autopsies, SARS-CoV-2 RNA was found in the olfactory mucosa of 13 patients, and 3 patients displayed detectable levels of SARS-CoV-2 RNA in the olfactory bulb (85). In the same study, axonal damage was noted in the olfactory area, as well as SARS-CoV-2 RNA in connected areas such as the cornea, uvula, trigeminal ganglion, and medulla oblongata, suggesting, that axonal transport originating in the olfactory bulb could be a route of neuroinvasion of SARS-CoV-2 (85). Overall, this study provided evidence that SARS-CoV-2 may enter the CNS via trespassing the neuro-mucosal interface in the olfactory mucosa by exploiting the close vicinity of olfactory mucosal and nervous tissue, including delicate olfactory and sensitive nerve endings.

Inflammation caused by neuroinvasion and peripheral immune response to SARS-CoV-2 has the potential to induce brain changes that can be associated with increased risk for psychiatric consequences. Previous studies have shown that peripheral immune response and inflammation can cause and exacerbate acute and chronic neuroinflammatory responses (8691). SARS-CoV-2 infection is also reported to trigger a cytokine storm whose effects on the CNS may have unpredictable consequences in both the short and the long-term. Related to the cytokine storm is the suggested reactivation of viruses such as Epstein-Barr virus, herpes simplex virus 1, and varicella-zoster virus; the reactivation of dormant viruses may prolong inflammation and, as such, prolong symptomology (92, 93). Numerous neurological and psychiatric diseases are known to have a neuroinflammatory component involving the same factors that are stimulated during the final stage of COVID-19. Of particular interest is the impact that these molecular mechanisms may have on the development and progression of neurodegenerative diseases as well as on psychiatric disorders, especially affective disorders, whose pathogenesis were found to involve neuroinflammatory mechanisms (94). Although the evidence supporting a causal role for COVID-19 associated neuroinflammation as it relates to psychiatric disease is limited, it is plausible that COVID-19 patients with a neuroinflammatory signature may be vulnerable to the development of mood and other disorders. In support of this perspective, baseline SII, an objective marker of the balance between host systemic inflammation and the immune response status was positively associated with measures of anxiety and depression at follow-up in COVID-19 patients (9). Furthermore, plasma CRP levels (marker of systemic inflammation) have been shown to correlate with deficits on the continuous performance test in recovered COVID-19 patients, suggesting that inflammation may play a role in cognitive complaints in remitted patients (70). Further studies also support the role of inflammation in the development of post COVID-19 syndrome. A study of 121 mild COVID-19 cases found that extended symptomology was associated with higher inflammatory markers [elevated neutrophil, NLR, fibrinogen, and CRP levels (95)]. A study by Yang et al. examined the transcriptomes of eight deceased COVID-19 patients compared to fourteen controls. Despite no molecular evidence of COVID-19 in the brain, they found greater disruptions in all types of cells examined (neurons, glia, immune cells) compared to those that died of alternate causes. Additionally, the sequalae of the COVID-19 patients' brains included inflammation, neurodegeneration, and disrupted signaling, similar to those of other brain-based disorders including schizophrenia, depression, and disrupted cognition (96). These suggest the underlying cellular mechanisms for acute and chronic symptomology such as headaches, mood disorders, brain fog, and cognitive disruptions may be a disruption or dysregulation of neuro-cellular function. Although the degree of neuroinvasiveness and neurological effects of SARS-CoV-2 is still under investigation, it is clear that it generates significant immunological responses in the CNS, which may relate to the development of neuropsychiatric symptomology Figure 1.

FIGURE 1
www.frontiersin.org

Figure 1. Potential etiology of COVID-19 neuropsychiatric symptoms. Following infection with SAR-CoV-2 there are several mechanisms that can potentially lead to a viral neurological invasion. The subsequent neurological invasion increases the already present cytokine storm leading to a feedback loop of biological consequences including neuronal/glial death, immune dysregulation, and virus reactivation; consequences that may potentially worsen symptomology of infection. The fallout of neurological invasion may account, at least in part, for chronic symptomology. Additionally, the risk and severity of the discussed fallout may be amplified by sociodemographic stress.

Limitations

There are limitations of this review that need to be acknowledged. Firstly, this is not a systematic review but rather a narrative review, which makes it subject to selection bias regarding the articles included while searching in databases without a structured format. The articles included in the review may also have a few limitations given that research on this topic is currently in nascent stages. As of October of 2021, the World Health Organization established a definition of post-COVID-19 condition (long COVID) through Delphi consensus and requires symptoms not explainable by other means 3 months after infection and persisting for 2 months (1). Many of the papers in our review characterize chronic COVID-19 symptomology differently as the consensus was not yet established at the time of publication. As such, papers featuring chronic symptomology are noted based on the characterizations of the paper's authors and references to “recovery” within the paper. Further, most studies are cross-sectional and hence causality cannot be established. In the same vein, pre-pandemic measures of mood and cognition are not available in most of the studies making it difficult to disentangle the effects of SARS-CoV-2 infection on these measures from pre-existing problems with mood and cognitive ability. In addition, limitations related to measurements and methodological approaches should be considered when interpreting the results. Most of the studies used online surveys and self-reports to assess mood and cognitive ability, which may have limited sensitivity and specificity when compared to structured clinical interviews (97). Finally, it is difficult to disentangle the effects of COVID-19 infection vs. pandemic-related stress since both may contribute to long-term sequelae via neuroimmune mechanisms.

Future directions

It is reported that pandemic-related sociodemographic factors including isolation, economic uncertainty, and hospitalization have an impact on mental health. Further, it is increasingly evident that the physiological effects of SARS-CoV-2 on the brain and in the periphery of the body have potentially deleterious effects impacting neuropsychological health. Moving forward there is a need for reporting of methods used in determination of COVID-19 populations and increased longitudinal research in recovered COVID-19 patients to investigate the effects of the virus on psychiatric and cognitive health. Prospective studies should utilize comprehensive cognitive and neuropsychiatric assessments along with brain imaging to better understand the long-term CNS effects of COVID-19. Second, a better characterization and understanding of the term “brain-fog” that many “long COVID-19” patients report is needed as the symptoms of the fog relate to many mood symptoms and cognitive deficits that could be detrimental in the long-term. It is necessary to identify any long-term sequelae and provide mental health support and cognitive rehabilitation to minimize the potential negative effects on psychosocial functioning and quality of life of recovered COVID-19 patients. Third, given the increased risk of negative health outcomes in older individuals, future studies should examine and determine whether COVID-19 may trigger or aggravate neurodegenerative processes in this vulnerable group, as an early diagnosis and intervention are the most important strategies to slow the progression of neurodegenerative disorders. One promising area is in the delineation of changes in neuroinflammatory markers to ascertain the role of neuroinflammation in driving the neuropsychiatric symptoms in active and recovered COVID-19 patients (98).

Finally, mechanistic studies that better inform our understanding of the neurobiological features underlying the neuropsychiatric sequelae of COVID-19 infection will help focus the development of therapeutic targets that may help reduce the long-term burden of COVID-19 in recovered patients.

Conclusions

To date there has been little attention to what may delineate the chronic and acute symptomologies of COVID-19. This review offers a novel investigation into how the neurological effects of SARS-CoV-2 may mediate some of the differences between chronic and acute symptomology. This review suggests that COVID-19 likely has important neuropsychiatric effects in in both the short and longer term. Patients in the acute phase of the illness commonly showed impairment in mood, mania, PTSD-like symptoms, sleep disturbances, and delirium. These symptoms were also prevalent in recovered COVID-19 patients. While sociodemographic and environmental factors such as pandemic-related stress and social isolation undoubtedly play a role in the development of these COVID-19 associated neuropsychiatric syndromes, a number of hypotheses have been proposed highlighting potential neurobiological mechanisms as causal factors for the observed neuropsychiatric symptoms, with inflammatory pathways being the most prominent. The scale of the pandemic will require that brain health be an integral focus of research and clinical service planning in the future.

Author contributions

CJS developed the concept for the review, conducted the literature search, and drafted the manuscript. CS supported the literature search and supplemented and edited the manuscript. DY-T provided oversight for the manuscript and collaborated on the conceptualization of the project and interpretation of the findings. PR supported and advised on the conceptualization of the project and literature search. All authors reviewed and edited the manuscript.

Funding

This manuscript is supported by funding from the Utah Science Technology and Research Initiative (USTAR) to DY-T and is also supported by the Medical Research Service of the Veteran Affairs Salt Lake City Health Care System, the Department of Veteran Affairs Rocky Mountain Network Mental Illness Research, Education, and Clinical Center (MIRECC). The views in this paper are those of the authors and do not necessarily represent the official policy or position of the Department of Veteran Affairs or the United States Government.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. World Health Organization. (2021). Available online at: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19-−21-september-2021 (accessed May 1, 2022).

Google Scholar

2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel Coronavirus in Wuhan, China. Lancet. (2020) 395:497–506. doi: 10.1016/S0140-6736(20)30183-5

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. (2020) 34:101623. doi: 10.1016/j.tmaid.2020.101623

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Burke RM, Killerby ME, Newton S, Ashworth CE, Berns AL, Brennan S, et al. Symptom profiles of a convenience sample of patients with COVID-19 - United States, January–April 2020. MMWR Morb Mortal Wkly Rep. (2020) 69:904–8. doi: 10.15585/mmwr.mm6928a2

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. (2020) 181:271–80.e8. doi: 10.1016/j.cell.2020.02.052

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Aghagoli G, Gallo Marin B, Katchur NJ, Chaves-Sell F, Asaad WF, Murphy SA. Neurological involvement in COVID-19 and potential mechanisms: a review. Neurocrit Care. (2021) 34:1062–71. doi: 10.1007/s12028-020-01049-4

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Fajar JK, Ilmawan M, Mamada S, Mutiawati E, Husnah M, Yusuf H, et al. Global prevalence of persistent neuromuscular symptoms and the possible pathomechanisms in COVID-19 recovered individuals: a systematic review and meta-analysis. Narra J. (2021). doi: 10.52225/narra.v1i3.48

CrossRef Full Text | Google Scholar

8. Fahriani M, Ilmawan M, Fajar JK, Maliga HA, Frediansyah A, Masyeni S, et al. Persistence of long COVID symptoms in COVID-19 survivors worldwide and its potential pathogenesis - A systematic review and meta-analysis. Narra J. (2021) 1:1–14. doi: 10.52225/narraj.v1i2.36

CrossRef Full Text | Google Scholar

9. Mazza MG, De Lorenzo R, Conte C, Poletti S, Vai B, Bollettini I, et al. Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors. Brain Behav Immun. (2020) 89:594–600. doi: 10.1016/j.bbi.2020.07.037

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Bohmwald K, Gálvez NMS, Ríos M, Kalergis AM. Neurologic alterations due to respiratory virus infections. Front Cell Neurosci. (2018) 12:386. doi: 10.3389/fncel.2018.00386

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry. (2020) 7:611–27. doi: 10.1016/S2215-0366(20)30203-0

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Desforges M, Le Coupanec A, Dubeau P, Bourgouin A, Lajoie L, Dubé M, et al. Human Coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system? Viruses. (2019) 12:14. doi: 10.3390/v12010014

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. (2020) 87:18–22. doi: 10.1016/j.bbi.2020.03.031

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Cheng SK, Wong CW, Tsang J, Wong KC. Psychological distress and negative appraisals in survivors of severe acute respiratory syndrome (SARS). Psychol Med. (2004) 34:1187–95. doi: 10.1017/S0033291704002272

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Lam MH, Wing YK, Yu MW, Leung CM, Ma RC, Kong AP, et al. Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term follow-up. Arch Intern Med. (2009) 169:2142–7. doi: 10.1001/archinternmed.2009.384

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Okusaga O, Yolken RH, Langenberg P, Lapidus M, Arling TA, Dickerson FB, et al. Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts. J Affect Disord. (2011) 130:220–5. doi: 10.1016/j.jad.2010.09.029

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Glass WG, Subbarao K, Murphy B, Murphy PM. Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol. (2004) 173:4030–9. doi: 10.4049/jimmunol.173.6.4030

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol. (2008) 82:7264–75. doi: 10.1128/JVI.00737-08

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Doobay MF, Talman LS, Obr TD, Tian X, Davisson RL, Lazartigues E. Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol. (2007) 292:R373–81. doi: 10.1152/ajpregu.00292.2006

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Holmes EA, O'Connor RC, Perry VH, Tracey I, Wessely S, Arseneault L, et al. Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for mental health science. Lancet Psychiatry. (2020) 7:547–60. doi: 10.1016/S2215-0366(20)30168-1

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Boyraz G, Legros DN, Tigershtrom A. COVID-19 and traumatic stress: the role of perceived vulnerability, COVID-19-related worries, and social isolation. J Anxiety Disord. (2020) 76:102307. doi: 10.1016/j.janxdis.2020.102307

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Ettman CK, Gradus JL, Galea S. Invited commentary: reckoning with the relationship between stressors and suicide attempts in a time of COVID-19. Am J Epidemiol. (2020) 189:1275–7. doi: 10.1093/aje/kwaa147

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Wu T, Jia X, Shi H, Niu J, Yin X, Xie J, et al. Prevalence of mental health problems during the COVID-19 pandemic: a systematic review and meta-analysis. J Affect Disord. (2021) 281:91–8. doi: 10.1016/j.jad.2020.11.117

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Kingstone T, Taylor AK, O'Donnell CA, Atherton H, Blane DN, Chew-Graham CA. Finding the 'right' GP: a qualitative study of the experiences of people with long-COVID. BJGP Open. (2020) 4:bjgpopen20X101143. doi: 10.3399/bjgpopen20X101143

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Lambert NJSC. COVID-19 “Long Hauler” Symptoms Survey Report. Indiana University School of Medicine (2020).

PubMed Abstract | Google Scholar

26. Guedj E, Campion JY, Dudouet P, Kaphan E, Bregeon F, Tissot-Dupont H, et al. (18)F-FDG brain PET hypometabolism in patients with long COVID. Eur J Nucl Med Mol Imaging. (2021) 48:2823–33. doi: 10.1007/s00259-021-05215-4

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Almeria M, Cejudo JC, Sotoca J, Deus J, Krupinski J. Cognitive profile following COVID-19 infection: clinical predictors leading to neuropsychological impairment. Brain Behav Immun Health. (2020) 9:100163. doi: 10.1016/j.bbih.2020.100163

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Abdel Azim GS, Osman MA. Neurological manifestations in mild and moderate cases of COVID-19. Egypt J Neurol Psychiatr Neurosurg. (2021) 57:109. doi: 10.1186/s41983-021-00363-8

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Beach SR, Praschan NC, Hogan C, Dotson S, Merideth F, Kontos N, et al. Delirium in COVID-19: a case series and exploration of potential mechanisms for central nervous system involvement. Gen Hosp Psychiatry. (2020) 65:47–53. doi: 10.1016/j.genhosppsych.2020.05.008

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Bo HX, Li W, Yang Y, Wang Y, Zhang Q, Cheung T, et al. Posttraumatic stress symptoms and attitude toward crisis mental health services among clinically stable patients with COVID-19 in China. Psychol Med. (2021) 51:1052–3. doi: 10.1017/S0033291720000999

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Cai X, Hu X, Ekumi IO, Wang J, An Y, Li Z, et al. Psychological distress and its correlates among COVID-19 survivors during early convalescence across age groups. Am J Geriatr Psychiatry. (2020) 28:1030–9. doi: 10.1016/j.jagp.2020.07.003

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Chou SH, Beghi E, Helbok R, Moro E, Sampson J, Altamirano V, et al. Global incidence of neurological manifestations among patients hospitalized with COVID-19-A report for the GCS-NeuroCOVID consortium and the ENERGY consortium. JAMA Netw Open. (2021) 4:e2112131. doi: 10.1001/jamanetworkopen.2021.12131

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Dravid AN, Mane DN, Khan ZA. Neurological issues during severe COVID-19 in a tertiary level hospital in Western India. Neurosci Lett. (2021) 749:135692. doi: 10.1016/j.neulet.2021.135692

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Ferrando SJ, Klepacz L, Lynch S, Tavakkoli M, Dornbush R, Baharani R, et al. COVID-19 psychosis: a potential new neuropsychiatric condition triggered by Novel Coronavirus infection and the inflammatory response? Psychosomatics. (2020) 61:551–5. doi: 10.1016/j.psym.2020.05.012

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Kong X, Kong F, Zheng K, Tang M, Chen Y, Zhou J, et al. Effect of psychological-behavioral intervention on the depression and anxiety of COVID-19 patients. Front Psychiatry. (2020) 11:586355. doi: 10.3389/fpsyt.2020.586355

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Helms J, Kremer S, Merdji H, Schenck M, Severac F, Clere-Jehl R, et al. Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients. Crit Care. (2020) 24:491. doi: 10.1186/s13054-020-03200-1

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Khan SH, Lindroth H, Perkins AJ, Jamil Y, Wang S, Roberts S, et al. Delirium incidence, duration, and severity in critically ill patients with Coronavirus Disease 2019. Crit Care Explor. (2020) 2:e0290. doi: 10.1097/CCE.0000000000000290

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Li L, Li F, Fortunati F, Krystal JH. Association of a prior psychiatric diagnosis with mortality among hospitalized patients with Coronavirus Disease 2019 (COVID-19) infection. JAMA Netw Open. (2020). 3:e2023282. doi: 10.1001/jamanetworkopen.2020.23282

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Losee S, Hanson H. COVID-19 delirium with psychosis: A case report. S D Med. (2020) 73:346–9.

PubMed Abstract | Google Scholar

40. Lu S, Wei N, Jiang J, Wu L, Sheng J, Zhou J, et al. First report of manic-like symptoms in a COVID-19 patient with no previous history of a psychiatric disorder. J Affect Disord. (2020) 277:337–40. doi: 10.1016/j.jad.2020.08.031

PubMed Abstract | CrossRef Full Text | Google Scholar

41. McLoughlin BC, Miles A, Webb TE, Knopp P, Eyres C, Fabbri A, et al. Functional and cognitive outcomes after COVID-19 delirium. Eur Geriatr Med. (2020) 11:857–62. doi: 10.1007/s41999-020-00353-8

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Nalleballe K, Reddy Onteddu S, Sharma R, Dandu V, Brown A, Jasti M, et al. Spectrum of neuropsychiatric manifestations in COVID-19. Brain Behav Immun. (2020) 88:71–4. doi: 10.1016/j.bbi.2020.06.020

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Parra A, Juanes A, Losada CP, Álvarez-Sesmero S, Santana VD, Martí I, et al. Psychotic symptoms in COVID-19 patients. A retrospective descriptive study. Psychiatry Res. (2020) 291:113254. doi: 10.1016/j.psychres.2020.113254

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Parker C, Slan A, Shalev D, Critchfield A. Abrupt late-onset psychosis as a presentation of Coronavirus 2019 disease (COVID-19): a longitudinal case report. J Psychiatr Pract. (2021) 27:131–6. doi: 10.1097/PRA.0000000000000533

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Poloni TE, Carlos AF, Cairati M, Cutaia C, Medici V, Marelli E, et al. Prevalence and prognostic value of Delirium as the initial presentation of COVID-19 in the elderly with dementia: an Italian retrospective study. EClinicalMedicine. (2020) 26:100490. doi: 10.1016/j.eclinm.2020.100490

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Ray STJ, Abdel-Mannan O, Sa M, Fuller C, Wood GK, Pysden K, et al. Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study. Lancet Child Adolesc Health. (2021) 5:631–41. doi: 10.1016/S2352-4642(21)00193-0

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Romero-Sánchez CM, Díaz-Maroto I, Fernández-Díaz E, Sánchez-Larsen Á, Layos-Romero A, García-García J, et al. Neurologic manifestations in hospitalized patients with COVID-19: the ALBACOVID registry. Neurology. (2020) 95:e1060–70. doi: 10.1212/WNL.0000000000009937

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Sahan E, Ünal SM, Kirpinar I. Can we predict who will be more anxious and depressed in the COVID-19 ward? J Psychosom Res. (2021) 140:110302. doi: 10.1016/j.jpsychores.2020.110302

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Taquet M, Luciano S, Geddes JR, Harrison PJ. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62,354 COVID-19 cases in the USA. Lancet Psychiatry. (2020) 8:130–40. doi: 10.1101/2020.08.14.20175190

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Varatharaj A, Thomas N, Ellul MA, Davies NWS, Pollak TA, Tenorio EL, et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry. (2020) 7:875–82. doi: 10.1016/S2215-0366(20)30287-X

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Wang Q, Xu R, Volkow ND. Increased risk of COVID-19 infection and mortality in people with mental disorders: analysis from electronic health records in the United States. World Psychiatry. (2021) 20:124–30. doi: 10.1002/wps.20806

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Rentero D, Juanes A, Losada CP, Álvarez S, Parra A, Santana V, et al. New-onset psychosis in COVID-19 pandemic: a case series in Madrid. Psychiatry Res. (2020) 290:113097. doi: 10.1016/j.psychres.2020.113097

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Yang L, Wu D, Hou Y, Wang X, Dai N, Wang G, et al. Analysis of psychological state and clinical psychological intervention model of patients with COVID-19. medRxiv. 2020:2020.03.22.20040899. doi: 10.1101/2020.03.22.20040899

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Guo Q, Zheng Y, Shi J, Wang J, Li G, Li C, et al. Immediate psychological distress in quarantined patients with COVID-19 and its association with peripheral inflammation: a mixed-method study. Brain Behav Immun. (2020) 88:17–27. doi: 10.1016/j.bbi.2020.05.038

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Iqbal Y, Al Abdulla MA, Albrahim S, Latoo J, Kumar R, Haddad PM. Psychiatric presentation of patients with acute SARS-CoV-2 infection: a retrospective review of 50 consecutive patients seen by a consultation-liaison psychiatry team. BJPsych Open. (2020) 6:e109. doi: 10.1192/bjo.2020.85

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Xie Q, Fan F, Fan XP, Wang XJ, Chen MJ, Zhong BL, et al. COVID-19 patients managed in psychiatric inpatient settings due to first-episode mental disorders in Wuhan, China: clinical characteristics, treatments, outcomes, and our experiences. Transl Psychiatry. (2020) 10:337. doi: 10.1038/s41398-020-01022-x

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Buonsenso D, Munblit D, De Rose C, Sinatti D, Ricchiuto A, Carfi A, et al. Preliminary evidence on long COVID in children. Acta Paediatr. (2021) 110:2208–11. doi: 10.1111/apa.15870

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Gramaglia C, Gambaro E, Bellan M, Balbo PE, Baricich A, Sainaghi PP, et al. Mid-term psychiatric outcomes of patients recovered from COVID-19 from an Italian cohort of hospitalized patients. Front Psychiatry. (2021) 12:667385. doi: 10.3389/fpsyt.2021.667385

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Groiss SJ, Balloff C, Elben S, Brandenburger T, Müttel T, Kindgen-Milles D, et al. Prolonged neuropsychological deficits, central nervous system involvement, and brain stem affection after COVID-19-A case series. Front Neurol. (2020) 11:574004. doi: 10.3389/fneur.2020.574004

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Hampshire A, Trender W, Chamberlain SR, Jolly A, Grant JE, Patrick F, et al. Cognitive deficits in people who have recovered from COVID-19 relative to controls: an N=84,285 online study. medRxiv. (2020) 2020.10.20.20215863. doi: 10.1101/2020.10.20.20215863

CrossRef Full Text | Google Scholar

61. Janiri D, Kotzalidis GD, Giuseppin G, Molinaro M, Modica M, Montanari S, et al. Psychological distress after COVID-19 recovery: reciprocal effects with temperament and emotional dysregulation. An exploratory study of patients over 60 years of age assessed in a post-acute care service. Front Psychiatry. (2020) 11:590135. doi: 10.3389/fpsyt.2020.590135

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Matos AMB, Dahy FE, de Moura JVL, Marcusso RMN, Gomes ABF, Carvalho FMM, et al. Subacute cognitive impairment in individuals with mild and moderate COVID-19: a case series. Front Neurol. (2021) 12:678924. doi: 10.3389/fneur.2021.678924

PubMed Abstract | CrossRef Full Text | Google Scholar

63. O'Keefe JB, Minton HC, Morrow M, Johnson C, Moore MA, O'Keefe GAD, et al. Postacute sequelae of SARS-CoV-2 infection and impact on quality of life 1-6 months after illness and association with initial symptom severity. Open Forum Infect Dis. (2021) 8:ofab352. doi: 10.1093/ofid/ofab352

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Poyraz B, Poyraz CA, Olgun Y, Gürel Ö, Alkan S, Özdemir YE, et al. Psychiatric morbidity and protracted symptoms after COVID-19. Psychiatry Res. (2021) 295:113604. doi: 10.1016/j.psychres.2020.113604

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Raman B, Cassar MP, Tunnicliffe EM, Filippini N, Griffanti L, Alfaro-Almagro F, et al. Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge. EClinicalMedicine. (2021) 31:100683. doi: 10.1016/j.eclinm.2020.100683

PubMed Abstract | CrossRef Full Text | Google Scholar

66. Sigfrid L, Drake TM, Pauley E, Jesudason EC, Olliaro P, Lim WS, et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. (2021) 8:100186. doi: 10.1016/j.lanepe.2021.100186

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Stephenson T, Stephenson T, Pereira SP, Shafran R, De Stavola B, Rojas N, et al. Long COVID - the physical and mental health of children and non-hospitalised young people 3 months after SARS-CoV-2 infection; a national matched cohort study (The CLoCk) study. Lancet Child Adolesc Health. (2021) 6:1–5. doi: 10.21203/rs.3.rs-798316/v1

CrossRef Full Text | Google Scholar

68. Tomasoni D, Bai F, Castoldi R, Barbanotti D, Falcinella C, Mulè G, et al. Anxiety and depression symptoms after virological clearance of COVID-19: a cross-sectional study in Milan, Italy. J Med Virol. (2021) 93:1175–9. doi: 10.1002/jmv.26459

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Woo MS, Malsy J, Pöttgen J, Seddiq Zai S, Ufer F, Hadjilaou A, et al. Frequent neurocognitive deficits after recovery from mild COVID-19. Brain Commun. (2020) 2:fcaa205. doi: 10.1093/braincomms/fcaa205

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Zhou H, Lu S, Chen J, Wei N, Wang D, Lyu H, et al. The landscape of cognitive function in recovered COVID-19 patients. J Psychiatr Res. (2020) 129:98–102. doi: 10.1016/j.jpsychires.2020.06.022

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Liu N, Zhang F, Wei C, Jia Y, Shang Z, Sun L, et al. Prevalence and predictors of PTSS during COVID-19 outbreak in China hardest-hit areas: gender differences matter. Psychiatry Res. (2020) 287:112921. doi: 10.1016/j.psychres.2020.112921

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Logue JK, Franko NM, McCulloch DJ, McDonald D, Magedson A, Wolf CR, et al. Sequelae in adults at 6 months after COVID-19 infection. JAMA Netw Open. (2021) 4:e210830. doi: 10.1001/jamanetworkopen.2021.0830

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Demoro G, Damico V, Murano L, Bolgeo T, D'Alessandro A, Dal Molin A. Long-term consequences in survivors of critical illness. Analysis of incidence and risk factors. Ann Ist Super Sanita. (2020) 56:59–65. doi: 10.4415/ANN_20_01_09

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Garrouste-Orgeas M, Flahault C, Vinatier I, Rigaud JP, Thieulot-Rolin N, Mercier E, et al. Effect of an ICU diary on posttraumatic stress disorder symptoms among patients receiving mechanical ventilation: a randomized clinical trial. JAMA. (2019) 322:229–39. doi: 10.1001/jama.2019.9058

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, et al. Long-term cognitive impairment after critical illness. N Engl J Med. (2013) 369:1306–16. doi: 10.1056/NEJMoa1301372

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Troyer EA, Kohn JN, Hong S. Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain Behav Immun. (2020) 87:34–9. doi: 10.1016/j.bbi.2020.04.027

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Watson CJ, Thomas RH, Solomon T, Michael BD, Nicholson TR, Pollak TA. COVID-19 and psychosis risk: real or delusional concern? Neurosci Lett. (2021) 741:135491. doi: 10.1016/j.neulet.2020.135491

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. (2020) 383:590–2. doi: 10.1056/NEJMc2011400

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, et al. Neurological associations of COVID-19. Lancet Neurol. (2020) 19:767–83. doi: 10.1016/S1474-4422(20)30221-0

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Solomon IH, Normandin E, Bhattacharyya S, Mukerji SS, Keller K, Ali AS, et al. Neuropathological features of COVID-19. N Engl J Med. (2020) 383:989–92. doi: 10.1056/NEJMc2019373

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. (2020) 370:856–60. doi: 10.1126/science.abd2985

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Domingues RB, Mendes-Correa MC, de Moura Leite FBV, Sabino EC, Salarini DZ, Claro I, et al. First case of SARS-CoV-2 sequencing in cerebrospinal fluid of a patient with suspected demyelinating disease. J Neurol. (2020) 267:3154–6. doi: 10.1007/s00415-020-09996-w

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis. (2020) 94:55–8. doi: 10.1016/j.ijid.2020.03.062

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Bullen CK, Hogberg HT, Bahadirli-Talbott A, Bishai WR, Hartung T, Keuthan C, et al. Infectability of human BrainSphere neurons suggests neurotropism of SARS-CoV-2. Altex. (2020) 37:665–71. doi: 10.14573/altex.2006111s

PubMed Abstract | CrossRef Full Text | Google Scholar

85. Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci. (2020) 24:168–75. doi: 10.1101/2020.06.04.135012

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Stüve O, Zettl U. Neuroinflammation of the central and peripheral nervous system: an update. Clin Exp Immunol. (2014) 175:333–5. doi: 10.1111/cei.12260

PubMed Abstract | CrossRef Full Text | Google Scholar

87. Kempuraj D, Thangavel R, Selvakumar GP, Ahmed ME, Zaheer S, Raikwar SP, et al. Mast cell proteases activate astrocytes and Glia-neurons and release Interleukin-33 by activating p38 and ERK1/2 MAPKs and NF-κB. Mol Neurobiol. (2019) 56:1681–93. doi: 10.1007/s12035-018-1177-7

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Kempuraj D, Thangavel R, Selvakumar GP, Zaheer S, Ahmed ME, Raikwar SP, et al. Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration. Front Cell Neurosci. (2017) 11:216. doi: 10.3389/fncel.2017.00216

PubMed Abstract | CrossRef Full Text | Google Scholar

89. Kustrimovic N, Marino F, Cosentino M. Peripheral immunity, immunoaging and neuroinflammation in Parkinson's disease. Curr Med Chem. (2019) 26:3719–53. doi: 10.2174/0929867325666181009161048

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Cabrera-Pastor A, Llansola M, Montoliu C, Malaguarnera M, Balzano T, Taoro-Gonzalez L, et al. Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: underlying mechanisms and therapeutic implications. Acta Physiol. (2019) 226:e13270. doi: 10.1111/apha.13270

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Magrone T, Magrone M, Russo MA, Jirillo E. Peripheral immunosenescence and central neuroinflammation: a dangerous liaison - A dietary approach. Endocr Metab Immune Disord Drug Targets. (2020) 20:1391–411. doi: 10.2174/1871530320666200406123734

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Xu R, Zhou Y, Cai L, Wang L, Han J, Yang X, et al. Co-reactivation of the human herpesvirus alpha subfamily (herpes simplex virus-1 and varicella zoster virus) in a critically ill patient with COVID-19. Br J Dermatol. (2020) 183:1145–7. doi: 10.1111/bjd.19484

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of long COVID prevalence and its relationship to Epstein-Barr virus reactivation. Pathogens. (2021) 10:763. doi: 10.3390/pathogens10060763

PubMed Abstract | CrossRef Full Text | Google Scholar

94. Serrano-Castro PJ, Estivill-Torrús G, Cabezudo-García P, Reyes-Bueno JA, Ciano Petersen N, Aguilar-Castillo MJ, et al. Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: a delayed pandemic? Neurologia. (2020) 35:245–51. doi: 10.1016/j.nrleng.2020.04.002

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Maamar M, Artime A, Pariente E, Fierro P, Ruiz Y, Gutiérrez S, et al. Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: a cross-sectional study. Curr Med Res Opin. (2022) 38:901–9. doi: 10.1080/03007995.2022.2042991

PubMed Abstract | CrossRef Full Text | Google Scholar

96. Yang AC, Kern F, Losada PM, Agam MR, Maat CA, Schmartz GP, et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature. (2021) 595:565–71. doi: 10.1038/s41586-021-03710-0

PubMed Abstract | CrossRef Full Text | Google Scholar

97. Stuart AL, Pasco JA, Jacka FN, Brennan SL, Berk M, Williams LJ. Comparison of self-report and structured clinical interview in the identification of depression. Compr Psychiatry. (2014) 55:866–9. doi: 10.1016/j.comppsych.2013.12.019

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Rauf A, Badoni H, Abu-Izneid T, Olatunde A, Rahman MM, Painuli S, et al. Neuroinflammatory markers: key indicators in the pathology of neurodegenerative diseases. Molecules. (2022) 27:3194. doi: 10.3390/molecules27103194

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: COVID-19, neuropsychiatric, depression, anxiety, PTSD, delirium, cognition, long-COVID

Citation: Smith CJ, Renshaw P, Yurgelun-Todd D and Sheth C (2022) Acute and chronic neuropsychiatric symptoms in novel coronavirus disease 2019 (COVID-19) patients: A qualitative review. Front. Public Health 10:772335. doi: 10.3389/fpubh.2022.772335

Received: 08 September 2021; Accepted: 11 July 2022;
Published: 08 August 2022.

Edited by:

Talha Bin Emran, Begum Gulchemonara Trust University, Bangladesh

Reviewed by:

Denis Baranenko, ITMO University, Russia
Harapan Harapan, Syiah Kuala University, Indonesia
Md. Mominur Rahman, Daffodil International University, Bangladesh

Copyright © 2022 Smith, Renshaw, Yurgelun-Todd and Sheth. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Calen J. Smith, calen@ucsd.edu

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.