Damian Sendler: Neuropsychiatric symptoms after COVID-19 have not been demonstrated. Systematically measuring the incidence of neuropsychiatric symptoms in COVID-19 survivors helped improve mental health care planning throughout the recovery phase of the pandemic. We searched MEDLINE, EMBASE, CINAHL, and PsycINFO up to 20 February 2021, as well as our own curated database, for this pre-registered systematic review and meta-analysis (PROSPERO ID CRD42021239750).
Damian Jacob Sendler: Post-acute or later time points following infection with COVID-19 and control groups when available were taken into consideration in our peer-reviewed research reporting neuropsychiatric signs and symptoms. A minimum of two writers extracted the summary data for every research they worked on together. We used generalized linear mixed models to estimate the prevalence of each symptom. I2 was used to gauge heterogeneity. For COVID-19 hospitalization, severity, and follow-up length, subgroup analyses were undertaken. A total of 51 studies (n = 18,917 patients) were selected from a total of 2844 distinct titles. After COVID-19, the average follow-up period was 77 days (ranging from 14 to 182 days). Quality of the studies was generally mediocre. Sleep disruption was the most common neuropsychiatric symptom, followed by exhaustion, objective cognitive impairment, anxiety, and post-traumatic stress disorder. Only two studies documented symptoms in control groups, and both found that COVID-19 survivors had a greater frequency of symptoms than controls. This research has a significant degree of inter-study variability (I2 = 79%–98.6 %). There was no indication of a difference in symptom prevalence depending on hospitalization status, severity, or follow-up period.. After a COVID-19 recovery, it is not uncommon to have neuropsychiatric effects that continue for months or years. In the first six months following infection, sleeplessness, lethargy, cognitive impairment, and anxiety problems are most common, according to the research on the long-term effects of infection.
There were several neuropsychiatric symptoms associated with outbreaks of COVID-19 in the early stages of the pandemic.
Dr. Sendler: More recently, researchers have established that SARS-CoV-2 causes a wide range of neuropsychiatric symptoms, including exhaustion and headache, which were among the most frequently investigated in the early literature.
The frequency of depression, anxiety, and post-traumatic stress disorder in acute COVID-19 patients was shown to be higher than expected in several studies.3 Even after an infection had subsided, it was unclear how long neuropsychiatric symptoms would continue to exist.
Damian Sendler
Chronic symptoms after a COVID-19 sickness have been referred to as “Long COVID” in the medical community.
Between three and a half and a year after infection, Long COVID has been suggested to begin to appear.
8 Between 4 and 12 weeks following infection with COVID-19, symptoms are called ‘ongoing symptomatic COVID-19’ and ‘post-COVID-19 syndrome’, respectively, by the National Institute for Health and Clinical Excellence (NICE). Recurrent symptoms after COVID-19 are regarded to be multi-systemic in nature, with most likely numerous separate pathogenic processes at play. 9 10–12 The absence of systematized explanations of the many components of the disease and the early stage of our understanding regarding residual symptoms following COVID-19 are both reflected in these definitional, vocabulary, and mechanistic issues.
COVID-19 infection is associated with a significant rate of neuropsychiatric symptoms, according to recent research. Newly diagnosed mood or anxiety disorders, as well as dementia, are on the rise, according to these studies, as are symptoms of exhaustion, cognitive failure, and sleep difficulties. 13–15 We don’t know whether or how the severity of the original sickness or the length of time since COVID-19 affects these neuropsychiatric side effects. To get a clear picture of how widespread the effects of COVID-19 are, and to guarantee that those who have survived them have access to adequate medical care, we need to have these questions answered. 8,16,17 In the past, these consequences may have been overlooked because of the tremendous expansion in research. 19
Damian Jacob Markiewicz Sendler: In order to better understand the long-term effects of infection and to aid in service planning, we set out to find out how common persistent neuropsychiatric symptoms were among COVID-19 survivors. Secondary analyses were used to look for factors that might predict the prevalence of symptoms. COVID-19 survivors with a more severe disease (i.e., those who needed hospitalization or intensive care) were expected to have lasting neuropsychiatric symptoms, which would decrease in frequency as time went on.
Searched the Ovid MEDLINE® and Epub Ahead of Print, In-Process, and Other Non-Indexed Citations and Daily, EMBASE (through Ovid), APA PsycInfo (via Ovid), and CINAHL (via EBSCO) from January 1, 2020, through February 20, 2021, for articles that were relevant to our research. An existing librarian-designed search technique for post-acute, chronic or long-term COVID has been adopted for use in this study 21 Due to this, we did not include any neuropsychiatric keywords in our search method (Supplementary Methods). On top of that, we looked through the reference lists of relevant systematic reviews that were published at the time of our initial search in our weekly curated database of COVID-19 neurology and neuropsychiatry research22. 18,19
Adults (18 years and older) having a history of polymerase chain reaction (PCR)-confirmed or clinically suspected SARS-CoV-2 infection were included in our review. Our definition of ‘persistence’ differed across hospitalized and non-hospitalized populations. Patients who have been released from the hospital are regarded to have persistent symptoms since they are no longer in the acute phase of their disease. We defined persistent symptoms as those that lasted at least four weeks from the beginning of symptoms or a positive PCR test in community-based samples without a discharge date.
It was decided that we would use the term “neuropsychiatric” symptoms, as defined by patient-led research.
15 The following symptoms were investigated: affective symptoms (such as anxiety and panic attacks, depression, and manic episodes); hallucinations; sleep disturbances; objectively reported cognitive impairment (i.e., through standardized cognitive tests); subjectively reported cognitive impairment (such as patient reports of “brain fog” or other lay terms); sensorimotor symptoms (such as paraesthesia, numbness, or weakness in specific body parts); dizziness and vertigo; headache; shifts in sp PTSD/PTSS symptoms, which are often reported following COVID-19, were added to the list of possible side effects of long-term COVID treatment.
Damian Jacob Sendler
Major and secondary data extraction was our primary goal. There are many studies that give data on the general public as well as data on specific demographic subgroups, thus we extract each group (the general public, Subgroup 1, Subgroup 2, etc.) individually and enter it into our database. Only data from the whole population of each trial were included in the principal analyses. For a subgroup analysis, we took the conservative position that studies had to report extractable data on a completely homogeneous subgroup. For example, we would not label studies reporting a combined 95 percent community and 5 percent hospitalized patients as “community” samples; rather, such studies would be excluded from the ‘hospital vs. community’ secondary analysis. We only considered the longest follow-up time-point in studies that provided data from multiple time-points. Requests for clarification were made in cases where the data did not fit with our objectives.
Every neuropsychiatric symptom reported in three or more studies was analyzed in the main analysis. For each prevalence outcome, we calculated generalized linear mixed models using the metafor package23 in R version 4.0.2 before utilizing the inverse variance approach with the Freeman–Tukey double arcsine transformation to do a comparative analysis of the data. 26 Inter-study heterogeneity was evaluated using an I2 statistic. Forest plots with 95% confidence intervals were used as a means of interpreting the data (CIs).
Damien Sendler: Cognitive impairment was found in almost one-fifth of the studies that met the inclusion criteria. Cognitive impairment was subdivided into “objective” and “subjective” dysfunctions once the study was completed. As demonstrated by a cognitive assessment screening instrument, we identified objective cognitive impairment (e.g. Mini-Mental State Examination, Montreal Cognitive Assessment or similar). A patient’s self-report of memory issues, “brain fog,” or other subjective cognitive impairment was categorized as objective. More than one kind of cognitive dysfunction (for example, “memory problem” and “concentration disorder”) has been described in certain research, thus we included just the most common type of cognitive dysfunction.
After-the-fact examinations
Initially, we planned to conduct secondary analyses comparing the prevalence of neuropsychiatric symptom prevalence between COVID-19 patients and control groups, COVID-19 patients whose diagnosis was PCR-confirmed and those in whom it was not, COVID-19 patients who were hospitalized and those who were not, and different time points following a positive test for SARS-CoV-2 (specifying 12 weeks versus 12 or more weeks to align with a key time-point in NICE guidance for post-COVID-CoV-2 diagnosis).
9 A lack of studies with control groups or non-PCR-confirmed cases meant that I and (ii) couldn’t be done, and the phrasing of (iv) was excessively limited (excluding, for instance, the many studies measuring the duration of symptoms from the date of hospital discharge, rather than from the date of a positive test).
To take into account the rest of the research, we performed two additional post hoc quantitative secondary analyses. The first of them was an assessment of the severity of the condition. As a result of our research, we discovered that some studies compared ICU admission to non-ICU admission while others utilized the WHO severity scale. 28 The following is how we organized the research: WHO “critical” or “severe” COVID-19 was recorded in patients admitted to the intensive care unit (ICU), as opposed to hospitalized patients who were considered not to be in the ICU. When looking at the second analysis, we widened the scope of the term “duration” to encompass all of the 19 studies that focused on discharge (ie, those that were less than 12 weeks in length). For this reason, we did not merge studies that used the date of PCR testing with those using the date of hospital discharge since COVID-19 hospital admissions were so variable. It’s possible that the commencement of symptoms may have occurred at the same time as PCR testing, however we decided to combine these investigations after the fact. Scatterplots of reported symptom prevalence versus time (each for dichotomized 12/12+ weeks, mean duration and median duration for all symptoms) were examined in a post hoc qualitative analysis.
Neuropsychiatric problems after COVID-19 are widespread and persistent, according to this comprehensive review and meta-analysis. One in four individuals may be affected by sleep difficulties and exhaustion, which seem to be particularly common. Cognitive impairment is often detected and anxiety and post-traumatic stress disorder symptoms appear to be especially widespread. Symptoms such as dizziness and vertigo are less prevalent yet occur in a significant number of individuals. There seems to be no variation in the occurrence of these symptoms at various stages in the first six months, regardless of the severity of COVID-19. Patients who did not need hospitalization, ethnicity, and the course and frequency of symptoms in the long run are unknown implications of COVID-19.
It’s important to proceed with caution while analyzing these results. The NICE guideline recommends that post-acute symptoms should last no more than 12 weeks. Three of the five trials in our analysis met this requirement. 9 COVID-19 severity was shown to have a significant influence on the number of eligible community-based or ICU-admitted samples reporting our outcomes of interest. The term “Long COVID” may be better reserved for patients who were not hospitalized if data comparing hospitalized and non-hospitalized patients shows substantial clinical differences, or a subspecifier may be appropriate to indicate the severity of early respiratory and/or other symptoms. In this analysis, just 15.7 percent of patients were verified to be non-hospitalized, which reflects the early research concentration on hospitalized patients. However, a recent big study conducted by patients themselves found that non-hospitalized patients made up the vast majority (91.6 percent). Patient viewpoints on nomenclature for this patient-driven illness are equally important to doctors and researchers, according to our perspective. 15
Structured clinical evaluations were seldom used in the majority of investigations, instead relying on patient self-reports to describe results. In the meanwhile, the particular contribution of COVID-19 to these neuropsychiatric symptoms remains uncertain due to the absence of active control groups. Some of these symptoms could be normal throughout the healing process after a major viral disease such as the common cold. Neuropsychiatric symptoms were not described in terms of how many of them were new or relapses. We didn’t collect data on comorbidities to see whether particular preexisting diseases could render patients more prone to symptom recurrences. We also did not explicitly evaluate the eligibility of 15 research for which an English-language paper was not accessible.
However, our pooled findings suggest that COVID-19 survivors in the post-acute phase often suffer from neuropsychiatric morbidity. Recent research shows that COVID-19 is linked to a higher risk in the first six months of neuropsychiatric clinical diagnoses, such as insomnia, mood or anxiety disorders first-onset and dementia. 14 Other respiratory tract infections were not associated with an increased risk of such disorders, but the results of this research suggest at least portion of this apparent neuropsychiatric burden may be COVID-19-specific. It is noteworthy that the trend of new psychiatric diagnoses was only slightly flattened in the first 6 months, confirming the concept that neuropsychiatric symptoms remain in this period. According to the patient-led survey15, we found that tiredness, cognitive impairment, and other neuropsychiatric symptoms (e.g. dizziness) were widespread in 3762 mostly non-hospitalized COVID-19 patients. In this meta-analysis, the study population’s data would be ineligible to contribute to generalizable estimates of community prevalence because they were recruited primarily through Long COVID support groups and similar organizations; a characteristic that illustrates the difficulty of finding generalizable community-based samples. 79
It’s not clear how much of an influence neuropsychiatric symptoms have on clinical services, but Long COVID services’ proactive approach to identifying cases and providing treatment sounds like a good idea. This does not rule out a combination of pharmacological and rehabilitative treatments (e.g. physical and/or occupational therapy) for the most common symptoms (in decreasing order of frequency): insomnia, fatigue, cognitive impairment (e.g. Alzheimer’s), anxiety, post-traumatic stress disorder (PTSD). 80–84 There may be some instances where the symptoms that persist after COVID-19 may be linked to initial direct tissue damage mechanisms (such as inflammation) that overlap with other or additional mechanisms (such as cognitive) as seen in other complex disorders arising after an illness like chronic pain. Multidisciplinary techniques are typically suited for such disorders85 and include combinations of physiotherapy and occupational therapy as well as psychiatric care and psychological interventions. Planning for ‘Long COVID’ services should integrate such strategies.
In light of our findings, we have identified topics for additional investigation. To distinguish between the neuropsychiatric effects of viral infection in general and those that may be unique to COVID-19, further controlled investigations are needed. It’s yet unclear how ethnicity and the COVID-19 severity interact. In order to collect representative samples from the population, traditional epidemiological methods may be necessary, and long-term follow-up is needed. Chronic neuropsychiatric symptoms in individuals with COVID-19.86 are to be studied in prospective, long-term and multicenter research. Other medications that have been shown useful in the treatment of neuropsychiatric symptoms may also be examined in future studies.
After a COVID-19 recovery, it is not uncommon to have neuropsychiatric effects that continue for months or years. About a quarter of those who have survived the ordeal have reported having difficulty sleeping or feeling fatigued. Also prevalent in the first six months after recovery are cognitive impairment, anxiety, post-traumatic symptoms, and sadness There is currently no indication that these symptoms are related to the severity of the first illness or the time since the initial infection. More study is required, but these early signs imply that COVID-19 survivors have a significant burden of neuropsychiatric disorders. It is imperative that multidisciplinary services be adequately funded in the post-COVID period.
