key: cord-1018925-019rcbpg
authors: Vindegaard, Nina; Eriksen Benros, Michael
title: COVID-19 pandemic and mental health consequences: systematic review of the current evidence
date: 2020-05-30
journal: Brain Behav Immun
DOI: 10.1016/j.bbi.2020.05.048
sha: 32b39825ba3d25c85c5cb7f3654a9e5a6e052c7f
doc_id: 1018925
cord_uid: 019rcbpg

BACKGROUND: During the COVID-19 pandemic general medical complications have received the most attention, whereas only few studies address the potential direct effect on mental health of SARS-CoV-2 and the neurotropic potential. Furthermore, the indirect effects of the pandemic on general mental health are of increasing concern, particularly since the SARS-CoV-1 epidemic (2002-2003) was associated with psychiatric complications. METHODS: We systematically searched the database Pubmed including studies measuring psychiatric symptoms or morbidities associated with COVID-19 among infected patients and among none infected groups the latter divided in psychiatric patients, health care workers and non-health care workers. RESULTS: A total of 43 studies were included. Out of these, only two studies evaluated patients with confirmed COVID-19 infection, whereas 41 evaluated the indirect effect of the pandemic (2 on patients with preexisting psychiatric disorders, 20 on medical health care workers, and 19 on the general public). 18 of the studies were case-control studies/compared to norm, while 25 of the studies had no control groups. The two studies investigating COVID-19 patients found a high level of post-traumatic stress symptoms (PTSS) (96.2%) and significantly higher level of depressive symptoms (p=0.016). Patients with preexisting psychiatric disorders reported worsening of psychiatric symptoms. Studies investigating health care workers found increased depression/depressive symptoms, anxiety, psychological distress and poor sleep quality. Studies of the general public revealed lower psychological well-being and higher scores of anxiety and depression compared to before COVID-19, while no difference when comparing these symptoms in the initial phase of the outbreak to four weeks later. A variety of factors were associated with higher risk of psychiatric symptoms and/or low psychological well-being including female gender, poor-self-related health and relatives with COVID-19. CONCLUSION: Research evaluating the direct neuropsychiatric consequences and the indirect effects on mental health is highly needed to improve treatment, mental health care planning and for preventive measures during potential subsequent pandemics.

The world is currently facing the COVID-19 pandemic with a novel corona virus, SARS-CoV-2, initially observed in Wuhan, Hubei, China in the end of 2019. 1 The reported symptoms of COVID-19 are primarily respiratory with acute respiratory distress syndrome ultimately leading to dead in the most severe cases. 2 However, COVID-19 have also been shown to affect other organs, including the brain, and recently reports on neurological symptoms due to COVID-19 infection are emerging. [3] [4] [5] [6] [7] There are indications of neurotropic properties of SARS-CoV-2; however, yet little appears to be known about the exact mechanisms on how it affects brain functioning. 8 COVID-19 is a betacoronavirus 9 and knowledge from other outbreaks with viruses from the corona family, like SARS-CoV-1, 10 can now be useful, despite differences between the viruses. Psychiatric symptoms including posttraumatic stress symptoms (PTSS)/posttraumatic stress disorder (PTSD), anxiety and depression among patients with SARS-CoV-1 have been reported during the SARS epidemic 11, 12 and after 1 month, 13, 14 1 year 15 and 30 months and longer. 16, 17 Also psychiatric symptoms of PTSD, depression and anxiety have been described among health care workers during 18 and 2 months 19 , 2 20 and 3 years 21 after the SARS epidemic as well as among the general public during 22 and after the epidemic. 23, 24 We aimed to systematically review the literature in order to provide an overview of the psychiatric complications to COVID-19 infection (direct effect) and how COVID-19 are currently affecting mental health among psychiatric patients and general public (indirect effect) alongside with factors altering the risk of psychiatric symptoms in both groups.

The following studies were included:

1. Studies reporting psychiatric symptoms/morbidity of patients with current or prior SARS-CoV-2 infection.

2. Studies reporting psychiatric symptoms/morbidity of psychiatric patients during the COVID-19 pandemic 3. Studies measuring psychiatric symptoms/morbidity/mental health during the COVID-19 in uninfected/not known to be infected participants, divided in health care workers and nonhealth care workers Papers with psychiatric symptoms/morbidity in the elderly (including dementia), children/adolescents (including Attention Deficit Hyperactivity Disorder and autism), substance abuse and somatic disease as primary outcome were not included.

Studies were identified by searching the database PubMed. Only papers published in English were included. The publication period was unlimited. The search was performed at the May 10, 2020.

(Psychiatry OR "mental health disorders" OR "mental health") AND (COVID-19 OR SARS-CoV-2)

One investigator (NV) screened titles and abstracts to exclude obviously irrelevant articles and further examined the remaining full text reports to determine compliance with inclusion criteria. One investigator (NV) screened relevant reviews for additional trials and NV examined full text reports of these additional records. The study selection process is illustrated in Supplementary Figure 1 .

The data extraction was carried out by one investigator (NV) but repeated.

We sought for the following information in the full-text records: journal information (authors and year of publication), study design and instruments, number of participants, demographics (sex, age, employment (health-care/non-health care)), psychiatric symptoms/morbidity and infectious status (currently infected, previously infected, no history of infection).

The initial search resulted in 460 hits and additional 4 papers were identified from the references in reviews from the search. Of these 101 were included for full text review leading to inclusion of 43 papers (Table 1 and 2). Out of these, two papers evaluated patients with confirmed COVID-19 infection, and 41 the indirect effect of the pandemic (2 on patients with preexisting psychiatric disorders, 20 on medical health care workers and 19 on the general public). 18 of the studies were case-control studies or compared to norms, while 25 of the studies had no control groups.

Only two papers 25,26 reported on psychiatric symptoms among patients with COVID-19. The first study showed that PTSS were present among 96.2% out of 714 hospitalized but stabile patients. The second study showed that the prevalence of depression (29.2%) was elevated (p=0.016) among 57 patients newly recovered from COVID-19 compared to participants in quarantine (9.8%), while no difference in anxiety level was found (P=0.154).

One study evaluated symptoms of patients with eating disorders during the pandemic and found 37.5% to report worsening in their eating disorder symptomatology and 56.2% to report additional anxiety symptoms, 27 while another study reported that 20.9% of patients with preexisting psychiatric disorders reported worsening of their symptoms, but did not report the preexisting diagnoses. 28 

Among health care workers depression/depressive symptoms (five papers) and anxiety (seven papers) were increased (compared to norms, 29, 30 administrative staff, 31,32 non-frontline workers 33 or the pandemic was under control, 34 or to experienced staff 35 ), while two papers found no difference (compared to the general public 36 and non-frontline workers 37 ). Poor sleep quality was found among health care workers compared to norms. 38 No difference in PTSS was observed, 39 and Vicarious traumatization scale scores were actually less elevated (P < 0.001) when comparing to the general public. 40 Higher levels of obsessive-compulsive disorder symptoms were reported in medical health workers compared to non-medical staff. 32 

Regarding the general public one paper revealed lower psychological well-being (WHO-5) compared to before COVID-19, 41 and one study revealed increased use of words as emotional indicators of anxiety and depression (on Weibo), when compared to prior to the outbreak. 42 Furthermore a study of parents of children hospitalized during the epidemic period had significant higher scores of anxiety, depression and dream anxiety compared to parents of children hospitalized in the non-epidemic period (all p <0.001). 43 However, a study found no significant difference in anxiety, depression or stress symptoms when comparing scores measured in a period with increase in number of confirmed cases to a period with increase in number of recovered cases (P>0.05); however, only 333 of the 1,210 cases were followed up. 44 One study found no significant difference in any items between workers/technical staff (n=551) and management/executive staff (n=122) (all P >0.05), 45 and one study found no difference between being in quarantine (n = 1443) or not (n = 836). 46 

The following factors were reported to be associated with risk of psychiatric symptoms among health care workers and the general public:

The following sociodemographic factors were associated with depression and/or anxiety: living alone, 47 lower educational level, 48,49 but also higher, 50 student status, 51 not having a child, 49 or having ≥2 children, 52 living in urban areas (Hubei), 48, 53 but also in rural areas, 32,47 female gender 32, 33, 49, 51, 53 was reported frequently, but was not consistent, 29,48 while reports on age as a risk factor were inconsistent. 48,49,54

Current medical disease (including psychiatric disorders and substance abuse), 32,44,53 and a past medical history (including psychiatric history and substance abuse) 44, 49, 52, 53 were associated with/increased the risk of depression and/or anxiety.

Poor-self rated health, 44, 48, 51 poor sleep quality, 50 higher perceived stress load, 30,50 previous distressful lifeevents, 49 lack of psychological preparedness, 50 perceived self-efficacy to help the patients, 50 lacking knowledge of the pandemic, 50,51 not taking precautionary measures, 51 and impacts on daily life. 46 Furthermore relatives/friends/acquaintance suspected of/acquired COVID-19, 47, 49, 50, 52, 53, 55 less family support, 50 low social capital (during isolation), 56 unsteady family income, 47 and higher social media exposure 48 were associated with/increased the risk of depression and/or anxiety.

Working in frontline compared to second line, 31, 33 secondary hospital compared to tertiary, 33 title intermediate compared to junior, 33 and >10 years of working 33 were associated with/increased the risk of depression and/or anxiety.

The risk of PTSS were positively associated with female gender, 39,57 living in Hubei province, 39, 57 lower education 57 and subjective sleep quality, 39,57 but not with age. 39 A variety of factors was associated with higher psychological distress/affected general mental health 33 

A total of 43 studies were included. Only two studies had investigated mental health issues in COVID-19 patients finding a high level of PTSS (96.2%) and significantly higher level of depressive symptoms (29.2%). Two studies reported symptoms on psychiatric patients, which appeared to have worsening in psychiatric symptomatology. Among health care workers depression/depressive symptoms, anxiety, psychological distress and poor sleep quality were increased. Regarding the general public one paper revealed lower psychological well-being (WHO-5) compared to before COVID-19, while a longitudinal study found no difference in anxiety, depression or stress symptoms early in the pandemic compared to after four weeks. A variety of factors were associated with higher risk of psychiatric symptoms and/or low psychological well-being of the general public including female gender, front-line health care workers, and poor self-rated health.

It is well known that surviving critical illness can induce PTSS 66 and in line with this, levels of PTSS were found to be very high (96.2%) among patients during hospital admission with COVID-19 infection, 25 which is far higher than found in the general public (7%). 57 The risk of depression was also found to be higher among patients with COVID-19. 26 It is generally established that infections are associated with a higher risk of mood disorders, 67 and there seems to be a higher risk after severe infections. 68 This is in line with the findings from the SARS-CoV-1 epidemic revealing depressive symptoms among patients during the infection. 11, 12 This higher risk could be due to the corona-virus affecting the brain directly or indirectly by inducing a massive cytokine response affecting the brain. 8 Of notice is that among patients with prior SARS-CoV-1 infection a higher rate of depression/depressive symptoms was observed after 1 month 13, 14 and 1 year. 15 The SARS-CoV-1 spread to more than 26 countries affecting more than 8000 people 69 and 774 died from the infection, 16 while COVID-19 has already spread to 185 countries affecting more than 4.238.703 people 70 and we must expect a huge after-wave of patients surviving COVID-19 suffering from depression.

Regarding anxiety the evidence is still scarce, and this should be investigated further since anxiety symptoms were reported during 11 and following 13,14 SARS-CoV-1. Furthermore SARS-CoV-1 has been shown to induce affective psychosis at least during the acute phase of the illness, 71 but we found no papers addressing this matter yet for SARS-CoV-2. Severe infections and inflammatory processes can cause delirium with a broad variety of psychiatric symptoms and encephalopathy, which has been reported among SARS-CoV-2 positive patients, but the evidence is still scarce and the neurotropic potential of SARS-CoV-2 needs to be elucidated. 72 

Worsening of the psychiatric symptoms among some patients with pre-existing psychiatric disorders, was reported, 27, 28 and two case studies report on the COVID-19 pandemic being a part of the psychotic content of two non-infected patients admitted to the psychiatric word. 73, 74 However, our systematic review reveals that knowledge on the COVID-19 impact on patients with preexisting psychiatric disorders is very scarce, and the knowledge of impact from earlier pandemics/epidemics on this group is also very limited.

From previous studies of the SARS CoV-1 epidemic it is known that health care workers are at risk of anxiety and depressive symptoms, which the current studies indicate also is the case of COVID- 19 . Health care workers should be regarded as a highly exposed group with a higher risk of psychiatric symptoms during the COVID-19 pandemic, and risk factors are female gender and frontline workers among others.

Currently data is scarce, but indicates that mental health is affected in the general public, when compared to before the outbreak; 41 however, the only longitudinal study (following 333 participants up) found no difference in depression, anxiety and stress in the period with many new cases compared to the period with many recovering. 44 This is interesting, since it is known from the prior SARS-CoV-1 epidemic that those in the general public, who were impacted of the epidemic (e.g. by quarantine) had psychiatric symptoms months after control of the epidemic, 24 and this could indicate that long lasting symptoms after SARS-CoV-2 also must be expected.

Many risk factors (especially of depressive and anxiety symptoms) has been reported, but most of them are already well-known risk factors for mental health conditions (e.g. female gender, 75 current or past medical history, 76 and poor-self-related health 77 ). However the pandemic is adding an aspect of quarantine and isolation that is also an established risk factor with psychological impact, 78 like worrying about family, friends and acquaintances being infected is also a newly added dimension.

Due to the altered living conditions many of the identified risk factors will increase most likely leading to an increase in patients.

There are indications in the literature of a neurotropic effect of SARS-CoV-2. Evidence of a variety of neurological symptoms among patients suffering from COVID-19 is evolving, 79 and delirium is a frequently reported symptom of SARS-CoV-2 and could be caused by a direct CNS invasion. 72 Interestingly two case studies reports SARS-CoV-2 meningitis/encephalitis; 80,81 however, only one of them had a confirmed positive SARS-CoV-2 RT-PCR test on CSF. 80 ACE2 is a functional receptor for SARS-CoV-2 82 and it is known that ACE2 is expressed in neurons, 8 which is interesting in the light of the many reports of anosmia as an early symptom of COVID-19, 83 since SARS-CoV-1 has been suggested to enter the brain trough the olfactory bulb. 84 Taken together this indicates that SARS-CoV-2 could be neurotrophic entering the brain through the olfactory bulb, leading to an increase in neuropsychiatric symptoms among the patients surviving COVID-19.

When discussing the potential effects of SARS-CoV-2 on the brain it is worth noting the reports on altered peripheral immunological alterations among COVID-19 patients. 8 Significantly higher levels of neutrophils, but significantly lower levels of lymphocytes have been reported among severe cases compared to nonsevere, 79 and patients with SARS-CoV-2 have been reported to have high amounts of the pro-inflammatory cytokines (IL-1beta, IFN-gamma, IP10 and MCP-1) suggesting a Th1 response. 1 A pro-inflammatory response has been reported among patients with MDD in both plasma 85 and CSF, 86 and the associations between neuropsychiatric symptoms and proinflammatory response needs to be elucidated further.

The strength of this review is that it was systematically conducted. The study is limited by several factors. Firstly, the majority of the studies were conducted in Asia (only four studies from Europe and none from other continents), limiting the current generalization of the results. Secondly, most of the studies were cross-sectional (35/43) and with a variety of reported outcomes, measuring of outcomes and statistical analysis was revealed. Thirdly, the literature on psychiatric symptoms among patients with SARS-CoV-2 infection and among psychiatric patients were very limited.

Although the current evidence is scarce concerning direct effects of COVID-19 on mental health, there are indications of increased levels of PTSS and depression following the COVID-19 infection.

Regarding the indirect effects of COVID-19 on general mental health there seems to be evidence of an increase in depressive and anxiety symptoms along with negative impact on general mental health, particularly among health care workers. Research evaluating the direct neuropsychiatric consequences and the indirect effects on mental health is highly needed to improve treatment, mental health care planning and for preventive measures during potential subsequent pandemics.

The present study was funded by an unrestricted grant from The Lundbeck Foundation (grant number R268-2016-3925). 

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Abbreviations: PCL-C: self-reported PTSD Checklist (5 or 17 items), GHQ-9/12: 9/12-item General Health Questionnaire, GAD-7: 7-item Ge Depression Scale, SAS: Self-rating Anxiety Scale, CES-D: Center for Epidemiology Scale for Depression, PSQI: Pittsburgh Sleep Quality Inde Impact of Event Scale-Revised, VTS: Vicarious Traumatization Scale, NRS: numeric rating scale on fear, HAMA: Hamilton Anxiety Scale, HA Self-Efficacy Scale, SARS: Stanford Acute Stress Reaction, SSRS: Social Support Rate Scale, SF-36: 36-Item Short Form Survey, SCL-90-R: Health Questionnaire-2/4/9 items.