key: cord-0925064-330nadvs
authors: Damiano, Rodolfo Furlan; Caruso, Maria Julia Guimarães; Cincoto, Alissom Vitti; de Almeida Rocca, Cristiana Castanho; de Pádua Serafim, Antonio; Bacchi, Pedro; Guedes, Bruno F.; Brunoni, André R.; Pan, Pedro Mario; Nitrini, Ricardo; Beach, Scott; Fricchione, Gregory; Busatto, Geraldo; Miguel, Euripedes Constantino; Forlenza, Orestes V.
title: Post-COVID-19 psychiatric and cognitive morbidity: Preliminary findings from a Brazilian cohort study
date: 2022-01-06
journal: Gen Hosp Psychiatry
DOI: 10.1016/j.genhosppsych.2022.01.002
sha: 88c01ad915ce0479b678d168db2b722941022a71
doc_id: 925064
cord_uid: 330nadvs

OBJECTIVE: The present study aims to investigate the occurrence of psychiatric and cognitive impairments in a cohort of survivors of moderate or severe forms of COVID-19. METHOD: 425 adults were assessed 6 to 9 months after hospital discharge with a structured psychiatric interview, psychometric tests and a cognitive battery. A large, multidisciplinary, set of clinical data depicting the acute phase of the disease, along with relevant psychosocial variables, were used to predict psychiatric and cognitive outcomes using the ‘Least Absolute Shrinkage and Selection Operator’ (LASSO) method. RESULTS: Diagnoses of ‘depression’, ‘generalized anxiety disorder’ and ‘post-traumatic stress disorder’ were established respectively in 8%, 15.5% and 13.6% of the sample. After pandemic onset (i.e., within the previous year), the prevalence of ‘depression’ and ‘generalized anxiety disorder’ were 2.56% and 8.14%, respectively. Memory decline was subjectively reported by 51.1% of the patients. Psychiatric or cognitive outcomes were not associated with any clinical variables related to the severity of acute-phase disease, nor by disease-related psychosocial stressors. CONCLUSIONS: This is the first study to access rates of psychiatric and cognitive morbidity in the long-term outcome after moderate or severe forms of COVID-19 using standardized measures. As a key finding, there was no significant association between clinical severity in the acute-phase of SARS-CoV-2 infection and the neuropsychiatric impairment 6 to 9 months thereafter.

There is an urgent need for a better characterization of the profile of acute and chronic psychiatric and neuropsychological morbidity among COVID-19 victims and the role played by multiple pathophysiological components related to disease severity/staging and individuals' clinical characteristics. Cross-sectional studies addressing the incidence of psychiatric and cognitive abnormalities in the acute and severe cases of SARS-CoV-2 infection highlight the occurrence of delirium, encephalopathy, cognitive impairment, J o u r n a l P r e -p r o o f Journal Pre-proof insomnia, psychosis and mood symptoms [1] . Regarding chronic symptoms, longitudinal studies conducted in post-COVID-19 cohorts have presented preliminary evidence of a high prevalence of psychiatric symptoms in the 'long phase' of the disease, namely anxiety, depression, fatigue, and post-traumatic stress disorder (PTSD) [2] [3] [4] [5] [6] , though recent studies indicated that these symptoms tend to wane in the following months [7] . These large longitudinal studies are important but fail in differentiating infected from non-infected individuals as well as patients with asymptomatic, mild, moderate, and severe cases, who might present with different phenomenological characteristics [8, 9] .

Psychiatric and cognitive morbidity following SARS-CoV-2 infection may emerge from multiple factors as part of what is being referred to as post-acute COVID-19 syndrome (PACS) or "long COVID" [10] . Psychosocial stress represents an important mechanism that predisposes COVID-19 victims to emotional suffering, some of whom will ultimately present with signs and symptoms of major psychiatric disorders [11] . However, recent evidence indicates that neuropsychiatric outcomes may also represent features of systemic and central nervous system (CNS) involvement in the pathophysiology of COVID-19, resulting largely from indirect mechanisms mediated by inflammation, hypercoagulability, vascular, and immunological pathways, in addition to possible direct invasion of the brain by the coronavirus [4, 12] . According to current knowledge, the interaction of multiple COVID-19related pathophysiological mechanisms disrupts brain homeostasis, causing dysfunctions/injuries that will ultimately present as symptoms of mental and cognitive impairment ('neurocovid') [13] . A recent perspective piece suggested that, in vulnerable populations (particularly the elderly), SARS-CoV-2 infection may hasten underlying brain pathologies and increase the risk of late-life cognitive decline and progression to dementia [14] .

The available knowledge on the so-called 'neurocovid' hypothesis was largely built from the clinical analysis of case series and uncontrolled studies conducted amidst the pandemic. In spite of the inherent methodological difficulties of carrying out research in this context, the current body of evidence about COVID-19-related neuropsychiatric morbidity does encourage the implementation of more refined symptom assessment protocols to address this matter in greater depth. Most studies so far have methodological limitations, such as crosssectional design [15] and lack of standardized SARS-CoV-2 infection determination [16] and lack of severity markers [17] . Furthermore, the assessment of the mental state has been generally based on small arrays of neuropsychiatric symptoms [18] , frequently assessed by self-report questionnaires [19] , electronic databases [20] , or by the attending physician's clinical impression [1] , therefore restricted to dimensional or non-validated symptomatic scales [5, 7, 21] . Finally, most of the available literature was published in populations from Eastern and European countries, which may constrain the generalizability of findings [5] .

The primary objective of the present study is to ascertain the mental and cognitive state of COVID-19 survivors after 6 to 9 months of the acute episode, with emphasis on the assessment of patients who recovered from moderate or severe forms of the disease requiring hospitalization, using a comprehensive protocol composed by objective and validated psychometric instruments. As a secondary and exploratory goal, we determined the extent to which these impairments were correlated with the severity of the acute disease, as well as with the occurrence of stressful events related to the COVID-19 pandemic, trying to predict potential variables associated with a worse neuropsychiatric morbidity.

J o u r n a l P r e -p r o o f Journal Pre-proof

The study was conducted at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), a tertiary, university-based medical facility that is responsible for providing care for moderate and severe cases of the COVID-19 in Brazil. The 'HCFMUSP post-COVID-19 cohort' was constituted to facilitate multidisciplinary studies addressing long-term medical, functional and neuropsychiatric outcomes among adults and elders who survived moderate or severe forms of COVID-19. Subjects were assessed 6-9 months after hospital discharge (mean interval of 207 days, SD 20.4) through structured interviews and assessment protocols pertaining to an interdisciplinary medical team. A full description of our methodology as well a flowchart can be seen at Busatto et al. [22] . In the present communication, we will report on the assessment of psychiatric and cognitive outcomes.

This research protocol has been approved by the Ethics Committee at HCFMUSP (CAPPesq-HC), and registered at the Brazilian Registry of Clinical Trials (ReBEC) under the registration number 4.270.242 (RBR-8z7v5wc) and will be reported according to The

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement. [23] Participants:

All patients hospitalized at HCFMUSP for at least 24 hours due to moderate or severe forms of COVID-19 between March and September 2020 (n=3,751) were regarded as eligible for this 'post-COVID-19 cohort'. The requirement of hospital treatment was used to ascertain moderate forms of COVID-19, and the need of intensive care unit (ICU) treatment was used to define severe cases. We present herein a preliminary analysis of the first 2,009 individuals who were invited to participate (compared with the total cohort sample described above and in Busatto Filho et al, 2021). From hospital registries, we ascertained all patients aged 18 years or older who were discharged from hospital in this time period, excluding the deceased J o u r n a l P r e -p r o o f (n=1,803). Diagnostic confirmation was based on clinical presentation combined with Polymerase Chain Reaction (PCR) tests to detect viral RNA or enzyme-linked immunosorbent assays to detect the presence of anti-SARS-CoV-2 serum antibodies (in subjects for whom a RT-PCR test collected up to the 10th day of symptom onset was not available). We also included 6 patients with highly suspected COVID-19 (based on clinical and chest-CT findings) without PCR confirmation. These patients were contacted by telephone and enrolled in this follow-up study. In case of acceptance, an appointment was made at an outpatient clinic dedicated to the assessment of this cohort. From all contacted patients, a small number of patients declined participation, reporting being too impaired to visit the clinic (n=18). Further exclusions were due to failed telephone contact (n=645), refusal to participate in the study as expressed by the patient or his/her informant upon telephone contact (n=297), inability to comply with the assessment protocol due to preexisting dementia or severe intellectual deficiency (n=10), or unknown reasons (i.e., subjects who did not show at the scheduled appointment) (n=408). A total of 425 volunteers signed informed consent and completed neuropsychiatric assessments between October/2020 and January/2021. A flow-chart can be seen in Supplementary Figure 1 .

A set of data relative to the acute stage of the disease was retrieved from hospital charts and databases, providing baseline information on duration of hospital stay; requirement/duration of ICU care; requirement of orotracheal intubation, mechanical ventilation, or dialysis; and any available information about previous diagnoses, comorbidities, and relevant clinical symptoms. There was no systematic capture of neuropsychiatric and/or cognitive symptoms at baseline, except for recorded information about incident delirium, seizures, or any signs suggestive of encephalopathy or cerebrovascular events during the acute phase of the disease. Evaluation of mental state and global cognitive function was done in face-to-face interviews   by a dedicated team of psychiatrists, psychologists, neuropsychologists, and undergraduate   medical students using the following instruments (details provided on Supplementary Table   1 predicting new data with small error [24] . LASSO is reputed as a very sensitive machine learning method for increasing the quality of prediction by shrinking regression coefficients [25] . Each LASSO was repeated at least ten times in order to reduce its instability and possible effect of confounding factors.

After LASSO, the following variables were included as possible predictors: age, education level, temporo-spatial orientation score in Mini Mental State Examination (MMSE), general health status (GHS) and pre-/post-COVID-19 frailty (CFS), persistent cough, duration of hospitalization during acute phase of infection, length of stay in ICU, requirement of haemodialysis or orotracheal intubation, and presence of medical/neurological comorbidities (such as systemic arterial hypertension, diabetes mellitus, cancer, hepatic steatosis or cirrhosis, chronic renal disease, gastric ulcer, bleeding ulcer, rheumatoid arthritis, rheumatological disease, stroke and dementia).

Data from an interim sample of 425 patients were used in the present analysis. The mean age of participants was 55.7 years (median 56.4), and 51.5% were women. Overall educational level was low, with 55.5% of participants not having completed high school (less than 12 years of education) ( Table 1) . Table 2A Table 2 describes the clinical profile of patients during hospital stay, with emphasis on the diagnosis of medical comorbidities and the requirement of intensive-care treatment. Table 1 also presents an estimate of their subjective memory complaints (MCS score). The characterization of symptoms according to psychometric scales (HADS, ASQ, AUDIT, MCS) and cognitive screening tests (MMSE-orientation, TMT-A and VFT) at 6-month follow-up after COVID-19 infection is summarized in Table 2B . Table 3 presents the diagnostic classification according to CIS-R, SCID-5-RV (for the assessment of psychotic symptoms) and changes in substance use behaviour. Notably, we found evidence of psychotic symptoms according to SCID-5-RV schedule, with 8.7% of participants reporting hallucinations and 12.5% reporting delusions of any kind lifetime. Furthermore, we calculated both chronic diagnosis (all time) and new diagnosis (symptoms starting within less than one year). Noteworthy, when looking only to new diagnosis, we found a prevalence of 2.56% of 'depression' (1.16% severe depression), 2.79% of 'specific phobia', 8.14% of 'generalized anxiety disorder' and 1.4% of 'obsessive-compulsive disorder'. Table 4 displays linear regression analyses searching for predictors of the psychiatry outcomes 'anxiety' and 'depression' according to HAD, and Table 4B displays predictors of the CIS-R outcome 'common mental disorder' (please see a complete definition in Supplementary Table 1) , six months after the acute phase of COVID-19. In all instances, only two variables were able to predict the occurrence of these psychiatric diagnoses, namely 'current frailty' (according to CFS) and 'general health status' (GHS scale). 'Common mental disorder' was positively associated with GHS across all levels, i.e., better general health associated with better psychiatric outcomes. As compared to those with 'very bad' general health, patients with 'regular' health were 86% less likely to be diagnosed with a 'common J o u r n a l P r e -p r o o f mental disorder' (p=0.016), similar to those with 'good' (91.5%, p=0.003) and 'very good' general health (94.4%, p=0.003). The same was true for frailty scores, where each additional point on the CFS increased the chance for having a 'common mental disorder' in 32.5% (p=0.006). The Area under the ROC curve of 0.72, indicating good quality of the model.

Regarding 'depression' and 'anxiety', the occurrence of symptoms within these affective domains was associated with a worse estimate of general health (i.e., lower GHS) and frailty (i.e., higher CFS scores) (Table 4A ). Psychiatric symptoms could not be associated with any clinical measure at the time of COVID-19 infection or psychosocial variables related to effect of COVID-19 pandemic. Table 5 summarizes data relative to linear regression analysis addressing the effect of sociodemographic and clinical variables on the prediction of cognitive outcomes, i.e., temporospatial orientation (MMSE), attention (TMT-A) and verbal fluency (VFT with semantic restriction). Previous history of stroke or pre-existing dementia at baseline assessment (i.e., prior to the acute phase of COVID-19) were associated with worse performance in the orientation task of the MMSE (R 2 = 0.283). Older age and disorientation (according to MMSE) were associated with a worse performance in the TMT-A (R 2 =0.114). Finally, older age, higher frailty (CFS) scores prior to COVID-19 and temporo-spatial disorientation (MMSE) in the current assessment were associated with a worse performance in the VFT; as opposed to that, higher education was (as expected) associated with better performance in the VFT. Curiously, individuals who had been submitted to hemodialysis due to COVID-19 complications during hospitalization had a better performance in this cognitive task. The Finally, the comparison of baseline (in-hospital) clinical and sociodemographic variables of participants and non-participants showed striking similarities in mean age (55 years in both groups), gender distribution (53% and 51% of males, respectively), body mass index (32,5 and 30,8) and duration of symptoms upon hospital admission (8 days for both groups).

Participants had in fact a higher number of medical comorbidities, longer hospital stay (14 vs. 9 days) and a higher proportion of them required ICU treatment (65% vs. 42%) or orotracheal intubation (43% vs. 29%), subsuming that the actual participants had experienced more severe forms of the acute disease as compared to non-participants (data not shown).

The present study provides original data highlighting the high prevalence of neuropsychiatric impairment in the long-term outcome of moderate or severe forms of SARS-CoV-2 infection.

To the best of our knowledge, the objective assessment of mental state with the aid of validated diagnostic instruments is a relevant and original contribution in the characterization of psychiatric and cognitive impairments among COVID-19 survivors; most of the previous studies dedicated to the assessment of long-term post-COVID-19 neuropsychiatric morbidity were based solely on unstructured questionnaires, self-report tests, telephone-based interviews or other forms of remote assessment, yielding at best a preliminary overview of complaints and symptoms. Moreover, studies that proposed to assess potential predictors of J o u r n a l P r e -p r o o f psychiatric and cognitive morbidity included only a few variables, most of them assessed retrospectively. The protocol that we used in the present study was built to provide diagnostic classification and to depict a more detailed symptomatic profile of post-COVID-19 psychiatric and cognitive morbidity. A comprehensive array of clinical and functional variables that had been previously tabulated during hospital treatment, along with a set of COVID-19 related psychosocial stressors, were used to evaluate the contribution of these acute-phase variables to the long-term psychiatric outcomes.

The CIS-R diagnoses of 'common mental disorder', 'anxiety' and 'PTSD' were highly prevalent. Also, we found that roughly one-third of the new diagnoses of 'depression' and 'obsessive-compulsive disorder', and the majority of diagnoses of 'generalized anxiety disorder' were established within the previous year in our sample of post-COVID-19

survivors. This is in line with previous studies that called attention to the high prevalence of mental health problems in the course of COVID-19 [26, 27] . The prevalence of 'common mental disorder' in this post-COVID-19 cohort (32.2%) was higher than previously reported in the Brazilian general population (26.8%), as indicated by epidemiological studies using the CIS-R schedule , [28] . Regarding the CIS-R diagnosis of 'depression', prevalence in the present sample (8.0%) was higher than expected in epidemiological studies concerning highand low-income countries (respectively 5.5% and 5.9%, 12-month prevalence), as well as in general Brazilian population using the same instrument (around 4 and 5 %) [29] . The CIS-R diagnosis of 'generalized anxiety disorder' (GAD) in the present sample (14.1%) was considerably higher than the 12-month prevalence in the European general population (0.2-4.3%) [30] , in Brazilian general population (9.9%) and in Brazilian individuals with coronary heart disease (10.2%), both using the same instrument [31] . A recent study using the same structured interview (CIS-R) in representative sample of Brazilian general population during COVID-19 pandemic found lower rates than reported in this manuscript, with 21.1% of J o u r n a l P r e -p r o o f common mental disorders, 2.8% of depressive disorders and 8% of anxiety disorders, highlighting high prevalence in our sample [32] .

Even though the cross-sectional nature of the psychiatric data acquisition precludes the assessment of incidence rates, we were able to determine the prevalence of new psychiatric diagnoses. Our data indicate a high prevalence of new diagnoses of 'depression', 'generalized anxiety disorder' and 'obsessive compulsive disorder', contrasting with the findings of a recent meta-analysis of longitudinal studies that found only a small increase on mental health issues among general population pre-and post-COVID-19 pandemic [33] . Noteworthy, our sample is older and represented by COVID-19 survivors, and therefore more prone to be clinically impaired. We understand that the high proportion of new psychiatric diagnoses in our sample can be related to the severity of COVID-19 morbidity, but may also contain an indirect effect of controversial policies in Brazil during the COVID-19 crisis [34] , given that the appropriateness of public policies has been shown to moderate mental health burden in the general population during COVID-19 pandemic [35] . The impact of the actual COVID-19 infection on new psychiatric diagnoses was challenged by a recent meta-analysis, although not controlling for the severity of the acute disease [36] .

We found high rates of lifetime delusions (8.7%) and hallucinations (12.5%) in the present sample. Even though there are some reports of psychotic symptoms following COVID-19 [37] , there are several reports indicating high rates of lifetime psychotic symptoms in the general population, ranging from 7.2 to 12.5% [38, 39] , consistent with our findings. In our study, 'delusions of religious content' accounted for a substantial proportion of the latter classification (6.15%), and we perceived that, in many such cases, non-delusional religious beliefs (e.g., acknowledging any form of spiritual interference or guidance as key to surviving the disease) could have led to an overestimation of this item. Therefore, after withdrawing J o u r n a l P r e -p r o o f 'delusions of religious content' from the former estimate, the overall prevalence of delusions was downgraded to 6.35%. Impairments in several cognitive domains were found in our sample, especially executive and attentional deficits. Likewise, previous studies in COVID-19 survivors have pointed out to impairments in several cognitive domains in acute forms of the disease [4, 40] , particularly logical memory and executive functions (attention and cognitive flexibility), which were interpreted as possibly related to the systemic inflammatory process [40] . Long-term studies following patients with severe acute illnesses and acute respiratory distress syndrome point to cognitive decline and executive dysfunction as well [41, 42] . Contrary to what we expected, cognitive morbidity after six months of SARS-CoV-2 infection was unrelated to any of the multiple clinical parameters relative to the acute phase of the disease, nor to any of psychiatric diagnoses that were established after six months of hospital discharge.

Disorientation was only associated with pre-existing dementia or stroke, presumably reflecting cognitive impairment prior to COVID-19. Older age and disorientation (according to MMSE) were associated with worse performance in attention and verbal fluency tasks, and lower scores in verbal fluency were associated with frailty. In a recent study, Jaywant et al. [43] evaluated cognitive impairment prior to hospital discharge in a cross-section of 57 inpatients recovering from severe COVID-19, and, similar to our findings, the authors found high rates of attention and executive dysfunction unrelated to clinical severity. Conversely, Taquet et al. [20] in a large retrospective cohort study, found a positive association between disease severity and neuropsychiatric symptomatology using a large electronic health record.

The presence and severity of psychiatric manifestations were unrelated to two important psychosocial stressors (i.e., 'death of a close relative' or 'financial loss'), nor to any of the multiple clinical parameters relative to the acute phase of the disease. Psychosocial stressors J o u r n a l P r e -p r o o f [11] such as death of a close relative [44] or major financial loss [45] are reputed to be powerful triggers of psychiatric morbidity; however, these variables were not associated with a worse neuropsychiatric outcome in our sample. In the absence of any such associations between risk factors and observed outcomes, psychiatric and cognitive impairments observed in the long-term after moderate or severe COVID-19 could be viewed either as an expression of SARS-CoV-2 effects on brain homeostasis or a representation of non-specific psychiatric manifestations secondary to diminished general health status, given that these disorders are correlated with general health status regardless of the cause of diminished general health [46] . Surprisingly though, patients who had been submitted to hemodialysis during ICU treatment for COVID-19 performed better on the verbal fluency test. We do not have a prompt interpretation for this putative 'protective' effect of hemodialysis on this specific cognitive domain, although the beneficial effect of dialysis on the clearance of systemic toxins could be regarded as advantageous in relation to severely ill patients who remained at pre-dialytic states. Previous studies have shown that individuals discharged from ICU [47] (especially those with acute respiratory distress syndrome) may present with symptoms compatible with post-intensive care syndrome (PICS) [48] , which consists in a combination of psychological, physical and cognitive impairments following conditions that did require critical care, and may persist for up to five years after ICU discharge [49] .

We must also acknowledge the limitations of the present study. First, the assessment of psychiatric and cognitive impairment in this cohort was performed after 6-9 months of the acute episode, in the absence of a similar protocol implemented at baseline, and thus precludes the characterization of changes secondary to this viral disease. However, it is noteworthy that a myriad of detailed information regarding clinical, laboratory and supplementary tests were accessible at baseline. Second, selection bias might remove relevant J o u r n a l P r e -p r o o f cases from the study sample, given that patients with more severe consequences of the disease may be less prone to accept enrolment to the study and/or to comply with the procedures. Regarding psychiatric diagnoses, we acknowledge that the CIS-R interview focuses predominantly on mood and affective symptoms, without covering other relevant psychiatric domains. Because of that, we tried to buffer our assessment battery with other questionnaires and psychometric tests. In this regard, the assessment of psychotic symptoms based on the SCID-5-RV (Module B, Psychotic and Associated symptoms) may have been too specific to be implemented in a non-psychiatric sample. Even though all raters were trained for reliability, it is plausible that the lack of experience in the assessment of psychotic patients may have biased the completion of this questionnaire, particularly among less educated patients, to whom culture-bound and religious beliefs may have influenced their responses, causing the over-rating of psychotic symptoms. Also, we did not include preexisting psychiatric illness in our analysis due to lack of availability in the current dataset, though we plan to include this parameter in future analyses. Furthermore, comparison of these results to general population prevalence rather than to the prevalence of these conditions in other patients recovering from serious illness limits one's ability to assess the specificity of these findings. Furthermore, the category of 'new diagnosis' might be biased by memory recall bias. Finally, 6 patients with high clinical suspicion of COVID-19, but without laboratory confirmation by PCR, were included. These individuals had been admitted as inpatients within the first 6 weeks after the initial preparation of HCFMUSP as a COVID-only facility, and the decision to include them was based on the fact that the in-hospital RT-PCR testing setup was not yet fully operational at that time. Nonetheless, the clinical picture of these cases was highly compatible with COVID-19 and they were treated as such throughout hospitalization.

In summary, we found a high prevalence of psychiatric and cognitive impairments following SARS-CoV-2 infection, specifically common mental disorders, depression, anxiety, PTSD, executive and attentional cognitive impairments. These deficits seem unrelated to psychosocial stressors or clinical risk factors documented in the acute-stage of COVID-19.

The present findings should encourage longitudinal studies addressing changes in mental and cognitive state among COVID-19 survivors across distinct ranges of severity.

We J o u r n a l P r e -p r o o f Journal Pre-proof Table 4 . J o u r n a l P r e -p r o o f The assessment of psychotic symptoms was done with the aid of an excerpt of the SCID-5-RV schedule, i.e., Module B, Psychotic and Associated Symptoms (items B2 to B19). The SCID-5-RV is a semi-structured psychiatric interview that follows the diagnostic criteria established by the American Psychiatric Association (APA)'s Diagnostic and Statistical Manual for Mental Disorders, 5th Edition (DSM-5). Given that the target population comprised subjects with no (a priori) previous history of psychotic disorders, and to render the interpretation of responses easier for the examiners, this assessment was limited to nineteen objective questions yielding yes/no answers (i.e., symptom present or absent). Thirteen of those questions address different types of delusions, while the remaining six assess auditory, visual, tact, taste, olfactory and somatic hallucinations. (1995) . The HAD is a widely used reliable instrument to determine the levels of anxiety, depression and emotional disorders in hospitalized and post-hospitalized patients, due to its focus on psychological rather than somatic symptoms of depression. The scale is composed of 14 questions scored from 0-3, subdivided in two domains (anxiety and depression) of seven questions each. Total score ranges from 0 to 21, higher scores indicating more severe symptoms. We used cut off of ≥8 for both subscales, which supposedly yields 82% sensitivity for the identification major depressive disorder (MDD) and 78% for generalized anxiety disorder (GAD), along with 74% specificity for MDD and GAD. The AUDIT is a widely used instrument developed by the World Health Organization to estimate Alcohol Use Disorder (AUD). It is a comprehensive 10-item self-report screening tool, with total score ranging from 0 to 40, indicating 'low risk' (0-7), 'increasing risk' (8) (9) (10) (11) (12) (13) (14) (15) , 'higher risk' (16) (17) (18) (19) and 'possible dependence' (20 or The MCS carries out a systematic search for memory complaints. It is composed of seven self-reported items with graded responses where higher scores indicate greater intensity (0, 1 and 2). The memory complaints are ranked as 'absent' (0-2), 'mild' (3) (4) (5) (6) , 'moderate' (7) (8) (9) (10) and 'severe' (11) (12) (13) (14) . This instrument explores the frequency and the degree to which the memory complaints impact on daily activities; compares the current memory to that of a younger age, and to that of others within the same age range. The scale has two identical versions (A and B), the latter dedicated to capture the informant's report (if available) about the subject's memory complaints. Previous research suggested that subjective memory complaints may be a proxy of poor cognitive function in older adults. After completion of the MCS schedule, participants were additionally asked to rank their overall memory performance in the light of COVID-19. This study utilizes the temporal and spatial orientation section of the mini-mental state examination (MMSE) composed of 10 questions for which answers were classified as either correct or incorrect (range 0-10). It is asked that the patient specify the day of the week, the day of the month, which month, which year and at what time the interview is being conducted. The spatial orientation is determined by assessing if the patient is able to correctly name the following items: the specific location the interview is being conducted at; the building he or she is in; the neighborhood or any close by streets; the country and the state. The choice for this part of the instrument was meant to discriminate severe forms of dementia, which could impact our final outcome and interpretation. The TMT was initially developed for utilization in the U.S. Army Test Battery Since then, it has had wide use in neuropsychological tests and researches, being able to identify several different neurological impairments and symptoms. It consists of two parts (TMT-A and TMT-B). Only the TMT-A was included as an instrument in this project, due to the difficulties in TMT-B in having good accuracy in individuals with low levels of education.51 In TMT-A, the patient is instructed to connect, with a continuous drown line, a randomly placed sequence of circled numbers ranging from 1 to 25, following the number sequence while being timed. The score is set based on the amount of time taken to complete the task and how many mistakes have been made. Multiple cognitive functions are involved in TMT execution, such as visual search; scanning; speed of processing; mental flexibility; and executive functions. We chose a fluency test with semantic restriction (animals) in order to access individuals' verbal production, semantic memory and language. In this test, the subject is asked to name as many animals as possible in one minute. Score is based on the number of animals correctly named, if there are non-animal words included (mistakes) and if repetition of the same animals occurs (perseverance). This test is less influenced by age and gender, and is capable to identify initial forms of mild cognitive impairment and other cognitive issues. The CFS was developed for use in the Canadian Study of Health and Aging (CSHA), and described by Rockwood et al. It is composed of a 7-item scale that clinicians have to ascertain for the vulnerability of each patient, where 1 represents very fit (robust, active, energetic) and 7 severely frail (completely dependent). It has demonstrated good accuracy, being able to predict death or entry in institutional care of elderly individuals. In order to characterize both preand post-COVID19 frailty, clinicians were asked to grade both in accordance to patients' clinical status at each time point (currently and retrospectively). 

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The continuum of psychotic symptoms in the general population: a cross-national study

An updated and conservative systematic review and metaanalysis of epidemiological evidence on psychotic experiences in children and adults: on the pathway from proneness to persistence to dimensional expression across mental disorders

The landscape of cognitive function in recovered COVID-19 patients

Clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: a prospective cohort study

Long-term cognitive impairment after acute respiratory distress syndrome: a review of clinical impact and pathophysiological mechanisms

Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19

Complicated grief after death of a relative in the intensive care unit

Prevalence of mental disorders after catastrophic financial loss

Health status and risk for depression among the elderly: a meta-analysis of published literature

Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort study

Psychiatric morbidity in survivors of the acute respiratory distress syndrome: A systematic review

Psychiatric symptoms after acute respiratory distress syndrome: a 5-year longitudinal study

Intensive Care Unit; CFS, Clinical Frailty Scale; HADS, Hospital Anxiety Depression Scale; ASQ, Ask Suicide-Screening Questions; AUDIT, Alcohol Use Disorder Identification Test; MCS

Mental State Examination; TMT, Trail Making Test; VFT, Verbal Fluency Test (animals)

Brazilian norms and effects of age and education on the Hayling and Trail Making Tests

Dados normativos para o teste de fluência verbal categoria animais em nosso meio