FROM COVID-19 TO PSYCHOLOGICAL DISTRESS: A SYSTEMATIC REVIEW ON QUARANTINE

Background. The novel coronavirus (SARS-COV-2) and related syndrome (COVID-19) has required a worldwide measure of quarantine with severe consequences for millions of people. Methods. Since psychopathological consequences related to social restrictions have been reported, a systematic review according to Cochrane Collaboration guidelines and the PRISMA Statement was performed to quantify the effects of quarantine on mental health of adults. Major databases Pubmed, Scopus, Embase, PsycInfo, and Web of Sciencewere researched for observational studies with data on mental health indexes related to quarantine or isolation for epidemic infections. Results. Twenty-one independent studies were included for 82,312 subjects. Conclusions. The results showed that at least 20% of people exposed to these conditions reported a psychological distress, with a prevalence of PTSD, depression and, less often, generalized anxiety. Important methodological bias weakens the conclusion of most studies, opening to the need of further research on mental health after quarantine and related risk/buffering factors. Key-words: Covid-19, psychological distress, anxiety, depression, PTSD Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 7 December 2020 doi:10.20944/preprints202012.0135.v1


INTRODUCTION
On March 12, 2020, the World Health Organization (WHO) declared the 2019 novel coronavirus (SARS-COV-2) and related syndrome (COVID-19) outbreak a pandemic because almost 125,000 cases were reported to the WHO, from 118 countries and territories [1]. The adoption of restrictive measures in the perspective of public health is not new, with Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), Ebola, H1N1 influenza, and Equine Influenza that required quarantine in the past. However, this is the first outbreak of the modern age requiring a worldwide measure of quarantine to prevent the negative burden of the outbreak on people. It was progressively adopted measures of movement restrictions, closure of unnecessary activities and social isolation (quarantine) all over countries, with severe consequences in real life for millions of people.
If the isolation of confirmed and suspected cases is a crucial part of these control efforts [2], the effect of quarantine on mental health is unclear. The warning on the psychopathological consequences of outbreak and related-quarantine during the recent COVID-19 has been delivered by several letters [2][3][4][5][6] and a qualitative review on previous outbreaks [7]. If the psychological burden of quarantine in terms of feelings of sadness, worries, loneliness or hypervigilance is part of the normal reactions of human beings to uncertain and hazardous situations, the shift towards overt psychopathologic disorders needs attention and studies.
The comprehension of the consequences in term of mental health may help to guide future political choices, in order to balance the pros of limiting the pandemic and the cons of the burden on economic and psychological health. According to this aim, we present a quantitative review of studies on the current (COVID- 19) and previous outbreaks to analyse the consequences of quarantine in terms of mental health.

Materials and Methods
The objective of this systematic review is to analyse all observational studies realised on the burden of quarantine on mental health. The case-control study design, adequacy of sample size, comparison and outcome measures have been all carefully analysed to guarantee the right inclusion of selected studies.

Search strategy
Electronic searches were conducted on the major databases in the field of health and social sciences -Pubmed, Scopus, Embase, PsycInfo, and Web of Science -in order to include the broadest range of relevant literature. The search was performed using Mesh terms/Keywords (depending on the database) with the same search strategy: "Quarantine" AND "Pandemic" OR "Outbreak" OR "COVID-19" OR "Psychological distress" OR "Anxiety" OR "Depression" OR "Emotional distress/trigger" OR "Psychiatric disorder" OR "Post-Traumatic Stress Disorder (PTSD)" OR "Adjustment disorder". The selection of the search terms is based on literature on mental health [8]. The search was limited to English-written publications, and to the period from 2000 to July 2020. The starting year was 2000 because we considered the last twenty years as adequate to cover a significant period where measure of quarantine were adopted consistently (we had outbreaks of Mers, Sars, Equine influenza, Ebola). The ending point of online search was July 2020 in order to include the growing evidence concerning mental health consequences of the current quarantine related to COVID-19 pandemic. It was also performed an additional analysis of the reference list in each selected paper. The study was excluded if the full text was not retrievable.
This systematic review was based on the following inclusion criteria in order to consider studies of comparable quality, as well as to sustain the reliability and validity of results: a) studies should report data on mental health indexes linked to epidemic infections, which required containment interventions based on quarantine; b) studies should administer valid and reliable instruments, reporting the cut-off value of clinical relevance, to assess mental health impacts of quarantine; c) studies should be written in English.
Case reports, letters to the editor, meeting abstracts, book chapters were excluded in order to focus the attention on data collected during and after outbreaks and related containment interventions. Reviews were considered as additional sources of information for including empirical studies within the current systematic review. Furthermore, studies carried out on health care workers were excluded because this review aimed to evaluate mental health consequences of quarantine on general population, even though the topic has been object of a study by some Authors of the same group [9]. Ultimately, qualitative studies were excluded because the objective of this review was to attempt to quantify the impact of social isolation due to pandemic infection.

Data extraction
Study selection was performed by two independent reviewers with research expertise in clinical psychology (FG and RF) who assessed the relevance of the study for the objectives of this review. This first round of selection was based on the title, abstract, and keywords of each study. If the reviewers did not reach a consensus or the abstract did not contain sufficient information, the full text was reviewed.
In the second phase (screening), full-text reports have been evaluated to detect whether the studies met the inclusion criteria ( Figure 1). In the phase of eligibility, all full texts were retrieved, and a final check was made to exclude papers not responding to inclusion/exclusion criteria, and reaching the final consensus to decide the final number of studies to be selected.
A standardised data extraction form was prepared; data was independently extracted by two of the authors (FG and MG) and inserted in an initial database (N = 2.722; Cohen's k =.85) [10]. From this initial database, FG and MG identified 417 studies (Cohen's k =.91) that reported at least one of keywords used for the current systematic review within the title and the abstract of each manuscript. Subsequently, FG and MG excluded papers (N = 358; Cohen's k = .95) that did not highlight a combination of keywords of this review linked "Quarantine" or "Pandemic" or "Outbreak" or "COVID-19" AND "Psychological distress" or "Anxiety" or "Depression" or "Emotional distress/trigger" or "Psychiatric disorder" or "Post-Traumatic Stress Disorder (PTSD)" or "Adjustment disorder". Fifty-nine studies were screened using inclusion and exclusion criteria previously discussed. FG and MG did not reach a consensus for the inclusion of 3 studies, especially considering the possibility to compute the percentage of sample reporting clinically significant levels of psychological distress. Therefore, a third reviewer (MC) resolved these discrepancies [11], carefully assessing method and result sections of each study in order to check whether it was reported the cut-off value of instruments used to evaluate psychological distress and the portion of sample that surpassed this value.

Statistical methods
A systematic analysis was conducted according to the Cochrane Collaboration guidelines [11] and the PRISMA Statement [12]. Considering available data, it was not possible to conduct appropriate statistical analyses linked to a meta-analytic approach [13]. However, the current review provided a quantitative approach for aggregating results of studies, which considered as the main outcome the percentage of sample reporting clinically significant levels of psychological distress (for a description of cut-off scores see table 1). This index was primarily reported in the Results section of each study. With respect to overall psychological distress and each specific class of symptoms (i.e., PTSD; depression; anxiety), the analyses computed mean, standard deviation (SD), standard error (SE) and 95% confidence interval (CI) of the percentage of sample with clinically relevant scores. These indexes were estimated whenever at least three independent studies yielded data.
Furthermore, in order to control possible confounding effects of sample size, year of publications on outcomes, Spearman's correlations (ρ) between them were performed.
Furthermore, ρ was estimated between the length of quarantine period and outcomes, in order to provisionally test whether the effects of isolation on mental health depend on the period of exposure to this conditions, or alternatively, epidemic infections and related quarantine might considered themselves triggers for psychological suffering. The analyses also compared the percentage of clinically significant distress among specific symptoms using procedures based on the Z-test [13]. Bonferroni correction was applied when multiple comparisons were conducted. Moreover, Z-test procedures were used to evaluate whether other variables might affect the percentage of clinically significant psychological distress (i.e., direct vs indirect exposure to isolation; retrospective assessment vs evaluations at the moment of epidemic infection and quarantine containment; Western culture vs Eastern culture).

Risk of bias
The current systematic review assessed quality of studies included using the rating scale developed by National Institutes of Health for observational cohort and cross-sectional research designs [14]. This scale is composed of 14 items rated on 3 levels (i.e. Yes No; NA) on total score was computed in order to show how methodological strengths and biases were distributed across studies

FINDINGS
Twenty-one independent studies   (Table 1) were included for a total of 82,312 subjects.     Table 1 provides a detailed description of the characteristics of each study . Only two studies [28,35] analysed the existence of protective factors for a negative outcome: the Attachment Style Questionnaire showed that "Confidence" (OR: 0.92; p = 0.039) and "Discomfort with closeness" (OR: 0.94; p = 0.023) subscales were protective for higher psychological burden; horizontal collectivism (to see themselves as being similar to others and emphasizes common goals with others, interdependence, and sociability) is another factor linked to likely positive outcome (p < 0.001). The role of gender was analysed in few studies with female more at risk [26,27,31] than male, with one exception [34].
Risk of bias assessment (Table 2) showed a total score of overall strengths of studies included equal to 107 (36.3%). The facet reflecting overall biases highlighted a score of 111 (37.7%).
Therefore, methodological strengths and biases were equally distributed across studies included in the current system review. The most recurrent weakness of studies referred to the absence of multiple longitudinal assessments (21 studies) and the lack of adequate control of possible confounding factors on outcomes (20 studies).

DISCUSSION
The current systematic review sought to investigate the impact of epidemic infections and related quarantine containment interventions on mental health and psychological distress [36]. Specifically, this study attempted to lay the foundations for an adequate response of mental health services. With this in mind, the current review aggregated results from prior studies that investigated such topic during similar epidemic infections, albeit significantly less widespread, together with provisional data collected during current COVID-19 outbreak.
Overall, empirical findings suggested that at least one out of every five people reported a clinically significant psychological distress, independently of the length of isolation and culture. This finding is fully in line with other empirical studies which demonstrated that the isolation related to medical conditions significantly predicted the onset of psychological distress [37]. In addition to the adverse effects of isolation, the psychological distress linked to epidemic infections is largely in line with the well-recognized dysfunctional cognitive and emotional mechanisms underlying the fear of contamination [38]. With respect to the onset of specific symptoms, the analysis showed that the most recurrent clinical conditions associated to epidemic infections referred to PTSD and depression. Specifically, up to 20% of individuals who either directly or indirectly experienced an epidemic infection reported the onset of clinically significant symptoms of such conditions. Since January 2020 (date of declaration of Covid-19 in China), a sentiment analysis of Chinese social media showed an increase in negative emotions (anxiety and depression) and a decrease in life satisfaction [39].
Considering PTSD symptoms, this evidence might be related to fact that an epidemic infection represents a direct or indirect exposure to a threatened (potential) death, which is considered the core diagnostic criterion for PTSD [8]. On the contrary, the high occurrence rates of clinically significant levels of depression might linked to the well-established effects of social isolation and relational deprivation on emotional and cognitive functioning [40,41].
The high occurrence of generalized anxiety symptoms, albeit less pronounced than the other conditions, might be associated to a heightened vigilance [42] and worry [43] towards threats related to diffusion trends of epidemic infections and their consequences on every-day life [44]. According to this evidence, it is plausible to expect that at the end of the current COVID-19 pandemic, one out of every five people might develop a clinically significant psychological distress. Particularly, the recurrent conditions might be PTSD, depression and (less) generalized anxiety.
Another side of interest is linked to the detection of risk or buffering factors for developing psychopathology. Focusing current research on the investigation of risk/buffering factors for consequences on mental health should be pivotal in order to address better psychological interventions. From the current review, some evidence arise towards a protective role for factors as secure or avoidant attachment style [28] and social openness (sharing common goals with others, interdependence, and sociability) [35]. On the other hand, female gender, negative affect, and detachment [27], dysfunctional personality traits or temperament (Negative affectivity, Detachment and Disinhibition) [28,32], severe property damage and low self-perceived health condition [24], younger age with/without chronic disease [17,30] or feeling extreme fear [33] seem to be predictive of the worst outcome in terms of mental health. Current findings are consistent with the literature on traits characteristics and mental health outcomes, which found that personality traits such as neuroticism, female gender, younger age and chronic disease are positively associated with poorer mental health outcomes [45][46][47]. Moreover, state variables such as fear of infection during pandemic are associated with elevated levels of psychological distress [7].
Looking at such symptomatology and the context of its development, mental health professionals should provide tailored assessment and interventions for distressing and posttraumatic reactions.
In the context of Covid-19, psychological assessment and monitoring should include queries about Covid-19-related stressors (such as exposures to infected sources, infected family members, loss of loved ones, and physical distancing), secondary psychological consequences (economic loss, depression, anxiety, psychosomatic preoccupations, sleep disorders, increased substance use, familial conflicts and/or domestic violence), and indicators of previous vulnerability conditions (such as preexisting physical or psychological conditions). Psychoeducation or cognitive behavioral techniques may be beneficial for some patients; others will be benefit of formal mental health evaluation and care [48].
Despite this systemic review showed a clear scenario concerning psychological effects of epidemic infections and related quarantine containment interventions, it must be discussed some limitations. First, all studies were based on the administration of self-report measures that might produce a portion of false-positive cases. Therefore, the current findings should be confirmed using adequate structured clinical interviews (e.g. Structured clinical interview for DSM-5 disorders: Clinician version) [17]. Second, all studies included were crosssectional naturalistic research designs. This did not allow to definitely concluding that the event of epidemic infection and related quarantine interventions are the primary causes of the onset of psychological distress. Hence, empirical research should identify concurrent risk factors that facilitate the development and maintenance of these clinical conditions. The studies cover a range of different viruses/conditions and a range of participants, including those who had the condition, those who did not have the condition but family members who did and those who did not have the condition but were quarantined. It is possible that different types of exposures will produce very different types of psychological reactions and produce different rates of distress/psychopathology. Other factors (e.g., socioeconomic status, access to medical care, chronic disorders etc.) would also affect psychological distress and lead to different rates of psychological distress. Ultimately, the absence of multiple longitudinal assessments did not allow precisely evaluating the course of psychological distress after epidemic infections and quarantining containment procedures. Furthermore, the lack of evaluation of incidence rates of each psychological condition before the onset of epidemic infections limited to draw definitive conclusions concerning the extent of impact of such phenomena on development of psychological distress. At present, there are too few studies to examine these different critical issues and produce robust and replicable estimates of psychological distress. Of course, this historical period represents a matchless opportunity to study the clinical psychological burden of quarantine both for the long period length and for the worldwide diffusion of the social isolation. Last but not least, the wide use of survey with participation on voluntary basis add an important risk of bias. We need to study the psychological consequences of quarantine addressing the way people cope with social isolation, the predictors of maladaptive functioning, the role of pre-Covid-19 personality and mental health issues. People after hospital admission for Covid-19 should have a special attention in order to test the burden in terms of PTSD, anxiety and/or depression.
Despite these limitations, this is the first quantitative systematic review that provisionally estimates the extent of psychological distress associated to past and current epidemic infections and related quarantine interventions. Results suggest that almost one out of every five people is at risk of development of clinically significant psychological distress during and after epidemic infections. Accordingly, mental health professionals should get ready to address a possible pandemic psychological suffering linked to the current COVID-19 pandemic infection.