PROCEEDINGS OF THE LATVIAN ACADEMY OF SCIENCES. Section B, Vol. 74 (2020), No. 6 (729), pp. 347–357. DOI: 10.2478/prolas-2020-0053 Review MENTAL DISORDERS FOLLOWING COVID-19 INFECTION: A SYSTEMATIC REVIEW OF ACUTE AND LONG-TERM PSYCHIATRIC MANIFESTATIONS AND ASSOCIATED BRAIN CHANGES Paale Ruben Fischer1and Lubova Renemane2,3 1 Rîga Stradiòð University, 16 Dzirciema Str., Rîga, LV-1007, LATVIA, [email protected] 2 Faculty of Medicine, Rîga Stradiòð University, 2 Tvaika Str., Rîga, LV-1005, LATVIA, [email protected] 3 Via Una Clinic, 10 Katrînas Dambis, LV-1045, Rîga, LATVIA # Corresponding author Lubova Renemane Communicated by Guna Laganovska The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the respira- tory tract, but sometimes also other organs, including the central nervous system (CNS). It is not well understood how the virus affects the CNS and how frequently it happens. Our review pro- vides insight into the occurrence of mental disorders in Corona Virus Disease 2019 (COVID-19) patients. We also collected information about the biological basis of the susceptibility of brain cells to SARS-CoV-2 and its implication to psychiatric manifestations. We included 24 publications in our review, reporting psychiatric manifestations published between 31 December 2019 and 30 July 2020, using the Preferred Reporting Items for Systemic Review and Meta-Analysis state- ment. Mental disorders occurred in up to one-fifth of patients during the acute phase of the infec- tion. The most common disorders included anxiety-related disorders, mood-spectrum disorders, impaired consciousness, confusion, delirium and psychosis. The onset of psychiatric manifesta- tions is not always preceded by respiratory symptoms, but occurs initially in COVID-19 patients. Long-term manifestations are mainly depression and post-traumatic stress symptoms. The ob- tained data allow the statement that direct infection of the CNS by SARS-CoV-2 could be respon- sible for the observed findings. To further investigate long-term psychiatric manifestations, randomised controlled studies must be initiated. Key words: mental disorders, psychiatry, brain changes, Covid-19, susceptibility, SARS-CoV-2. INTRODUCTION place in Wuhan, China and the virus was named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS- Since the beginning of the 21st century, an animal beta- CoV-2), causing the Coronavirus Disease 2019 (COVID- coronavirus underwent a successful crossover to humans 19) (Fu et al., 2020). SARS-CoV-2 is closely related to three times, causing severe respiratory diseases. The first SARS-CoV and utilises the same cellular receptor, event took place in China in 2002, when an acute severe angiotensin-converting enzyme 2 (ACE2) for cell entry. respiratory disease was seen in people without known The cellular co-factor needed for cell entry is transmem- cause. Later, this coronavirus was named Severe Acute Res- brane protease serine 2 (TMPRSS2), which facilitates piratory Syndrome Coronavirus (SARS-CoV). The second SARS-CoV-2 spike protein priming (Heurich et al., 2014; outbreak took place in 2012 in Saudi-Arabia, showing al- Hoffmann et al., 2020). The most common symptoms of most identical symptoms, but the responsible agent was COVID-19 patients include fever, cough, fatigue, headache, only related to SARS-CoV and therefore named Middle sore throat, myalgia and dyspnea. A subset of COVID-19 Eastern Respiratory Syndrome Coronavirus (MERS-CoV) patients also manifest severe pneumonia, leading to respira- (Singhal, 2020). In December 2019, the third event took tory failure and death (Fu et al., 2020; Singhal, 2020). How- Proc. Latvian Acad. Sci., Section B, Vol. 74 (2020), No. 6. 347 ever, complications of COVID-19 are not limited to the res- ria. Data extraction of eligible articles was also done inde- piratory system. There are reports of a wide variety of pendently by the same investigator. extrapulmonary and systemic manifestations, including gas- trointestinal symptoms, renal failure, liver damage, cardiac Every article, published in either English or German lan- injury, sepsis and shock, often leading to fatal outcome. In guage and reporting the occurrence of mental disorders in addition, involvement of the central nervous system (CNS) patients with COVID-19 or reporting structural brain has been reported, thought to be mediated by either direct changes or susceptibility of brain areas for COVID-19 in- neuronal damage through SARS-CoV-2 or by host immune- fection, was included. Exclusion criteria comprised studies, mediated damage due to pathogenic levels of inflammatory which included participants < 18 years old, participants mediators (Alam et al., 2020; Zaim et al., 2020). There are with diagnosed mental disorders prior to the infection with publications addressing direct neurological manifestations SARS-CoV-2, and participants that were not tested positive in COVID-19 patients, such as taste and smell disorders and for COVID-19. In addition, articles, which did not report headache (Chen et al., 2020; Leonardi et al., 2020; Zubair any psychiatric symptoms or had results indirectly related to et al., 2020). Other publications are addressing the indirect the COVID-19 infection, were excluded. Furthermore, we psychological impact of the pandemic (e.g., due to social re- excluded articles, which had no freely accessible full text or strictions) on the general population (Amerio et al., 2020; were not original research. Loades et al., 2020; Pfefferbaum and North, 2020; Rajku- mar, 2020). Interestingly, we could identify only two sys- Characteristics of research studies. We identified 6669 tematic reviews on the direct impact of COVID-19 infection articles through the initial database search. 3071 articles on the mental state and the occurrence of psychiatric symp- were from PubMed, 2820 from the medRxiv preprint server toms. One review included 12 publications (Rogers et al., and 778 from the bioRxiv preprint server. After removal of 2020) and the second review included only two articles the duplicates via EndNote X9, 6657 articles underwent quanti- reported psychiatric symptoms in COVID-19 patients (Vin- tative screening, from which 6519 articles were excluded degaard and Benros, 2020). after screening of title and abstract. 138 articles were as- sessed for eligibility, from which 114 articles were excluded In October 2020, more than 41 500 000 cases of COVID-19 on the base of the exclusion criteria. Twenty-four articles were registered worldwide. Also, Latvia is currently in mid- were included in the qualitative synthesis. The PRISMA stream of the ‘second wave’ and new registered cases in- flow diagram is shown in Figure 1. The characteristics of crease day by day (Anonymous, 2020). Hence, it is impor- the included studies are presented in Tables 1–3. Of the 24 tant to investigate the potential impact of COVID-19 on the studies, eight were retrospective studies, one was a cross- mental state of infected patients. The aim of this systematic sectional study, one was a surveillance study, one a point review is to provide evidence of occurrence of mental disor- prevalence study, one a self-report study and one had a ba- ders as a direct result of COVID-19. These include psychi- sic research design, and eleven were case reports or case se- atric symptoms occurring during the acute phase of illness, ries. Overall, 20 of 24 studies were peer-reviewed journal as well as after resolved infection. In addition, we want to articles and four were published preprints. hypothesise about potential psychiatric long-term outcomes in patients who survived COVID-19. Furthermore, we want to investigate the susceptibility of the CNS, when it comes MENTAL DISORDERS DURING THE ACUTE PHASE to the infection with SARS-CoV-2 and structural changes of OF COVID-19 INFECTION the CNS, which are associated with COVID-19. A surveillance study from the UK utilised 153 rapid reports and defined 39 (31%) cases with an altered mental status. LITERATURE RESEARCH STRATEGY They attributed the alteration of the mental state to neurop- sychiatric disorders in 23 (59%) cases: psychosis (ten This systematic review made use of the PRISMA statement cases), neurocognitive disorder (six cases) and other psychi- in concomitance with the flow diagram, to depict the flow atric disorders (seven cases). Other psychiatric disorders in- of information throughout the review. However, there was cluded depression (three cases), personality change (two no registered study protocol (Liberati et al., 2009). cases), catatonia (one case) and mania (one case) (Varatha- PubMed, the preprint servers medRxiv and bioRxiv were raj et al., 2020). screened systematically for related articles, published be- tween the 31 December 2019 and 30 July 2020. The follow- A retrospective study from the UK reviewed the clinical ing key words and Boolean operators were applied for the picture of 43 patients. Of these, ten patients (mostly > 50 search inquiry: ‘Covid-19’ OR ‘sars-cov-2’ OR ‘2019- years old) had an unspecified encephalopathy (para- -ncov’ AND ‘mental disorders’ OR ‘mental health’ OR infectious or septic encephalopathy) with delirium. One pa- ‘clinic’ OR ‘depression’ OR ‘delirium’ OR ‘hallucinations’ tient also manifested a psychosis, which was characterised OR ‘anxiety’ OR ‘cognitive dysfunction’ OR ‘psychotic by visual and auditory hallucinations, delusions of persecu- disorder’ OR ‘CNS’ OR ‘neurology’ OR ‘brain changes’ tion, Capgras delusion and complex systematised delusional OR ‘brain