Covid-19: Long-Covid Neuropsychiatric Symptoms Common, New Research Shows

It is increasingly clear that disorders such as sleep disturbance and post-traumatic stress are common post-acute symptoms of Covid-19, but little is known about the mechanism linking Covid to these and other neuropsychiatric disorders.

In an effort to identify these mechanisms and better address neuropsychiatric and other long-Covid symptoms, the National Institutes of Health is funding the multicenter Researching Covid to Enhance Recovery (RECOVER) initiative.

In a special communication published Wednesday in JAMA Psychiatry, researchers reported details of the initiative and highlighted what is and is not known about neuropsychiatric disorders associated with post-acute sequelae of Covid-19 (PASC).

"Despite rapidly emerging data, many gaps in knowledge persist related to the variable definitions of PASC, lack of standardized phenotyping of biomarkers, variability in virus genotypes, ascertainment biases, and limited accounting for social determinants of health and pandemic-related stressors," wrote Jennifer Frontera, MD, and Naomi Simon, MD, of the New York University Grossman School of Medicine.

Frontera and Simon noted that while the U.S. Centers for Disease Control and Prevention (CDC) defines post-Covid conditions as occurring 4 weeks or more following SARS-CoV-2 infection, the World Health Organization (WHO) definition describes symptoms occurring 3 months or more after initial infection that last 2 months or more.

Using the CDC definition, the researchers conducted a targeted rapid review of the literature published from January 2020-2022 to identify psychiatric and neurological symptoms commonly occurring post infection.

Their analysis confirmed that the most commonly reported neurologic symptoms occurring post-Covid were fatigue (33%), sleep disturbance (29%), headache (23%), and anosmia/dysgeusia (18%).

"Because at least 33% of individuals infected with SARS-CoV-2 are completely asymptomatic during the acute phase of infection, the association between SARS-CoV-2 and neuropsychiatric symptoms may be unrecognized, potentially leading to underestimates of PASC after asymptomatic or mild Covid-19," Frontera and Simon wrote.

Meta-analyses examining psychological symptoms have shown pooled prevalence rates as high as 45% for depression and 47% for anxiety, which are roughly double the rates reported among people without a history of Covid-19.

In a recently published prospective study, Frontera and colleagues examined long-term outcomes among patients hospitalized with Covid-19 with and without neurological complications.

They found that 91% of patients were still experiencing functional and cognitive abnormalities 6 months after hospital release, with 50% experiencing impaired cognition and 47% of those employed prior to hospitalization reporting that they had not yet been able to return to work.

In a study examining cognitive and psychological symptoms among non-hospitalized people with a recent history of Covid-19, also led by Frontera, 25% of those who had the disease reported prolonged cognitive and psychosocial symptoms 6 months later.

Across studies examining long-Covid neuropsychiatric symptoms, rates of cognitive abnormalities, sleep disturbance, anxiety, depression, PTSD, and related disorders were all higher in former Covid-19 patients than in people without a history of SARS-CoV-2 infection, the researchers wrote.

With regard to the mechanism linking neurological disorders to Covid-19, Frontera and Simon wrote that "the pathophysiology underpinning neuropsychiatric injury during acute infection is related to secondary effects of SARS-CoV-2, including hypoxemia, hyper-inflammation and hypercoaguability."

"Neuropathological evidence of acute hypoxic-ischemic brain injury exists in multiple Covid-19 autopsy cohorts," they wrote. "Additionally, elevations in proinflammatory cytokines, particularly IL-6, is a hallmark of moderate-severe acute Covid-19 known to promote endothelial dysfunction, vascular permeability and potentially blood-brain barrier (BBB) dysfunction."

They added that neuropathological studies involving Covid-19 fatalities have revealed "endothelial injury, microhemorrhages, disruption of the microvasculature basal lamina, and extravasation of fibrinogen into brain parenchyma, all suggestive of BBB disruption that may be mediated by Covid-19-related inflammatory state."

With regard to psychiatric disorders, autoimmune and viral mechanisms have been proposed, but Frontera and Simon wrote that "little is known regarding mechanisms of neuropsychiatric PASC, and it is likely that host, viral and environmental factors contribute to differing degrees depending on the PASC subphenotype."

The RECOVER initiative will include clinical cohort studies—involving both adult and pediatric patients, and subgroups such as pregnant women—as well as pathology studies and larger studies evaluating data from electronic medical records.

"The adult clinical cohort study is designed to assess disorders affecting multiple organ systems and is an ambidirectional, longitudinal meta-cohort study combining retrospective and prospective data with nested case-control studies," the researchers wrote.

The plan is to enroll 15,000 people with cases that met WHO criteria for suspected, probable, or confirmed SARS-CoV-2 infection on or after March 1, 2020, as well as 2,680 uninfected control patients recruited from inpatient, outpatient, and community-based settings.

The design calls for a 3-tiered approach to prospective data collection, with assessments from early tiers "setting gateways for later-tier testing across a broad range of potentially affected organ systems (e.g., cardiology, respiratory, neurologic, and psychiatric)," the researchers wrote.

Approximately 30% of patients in tier 1 will be included in tier 2, and 20% will go on to tier 3 testing for symptoms. Some uninfected participants and infected participants without relevant symptoms will also complete tiers 2 and 3 as part of a control group.

"Growing data support a high prevalence of PASC neuropsychiatric symptoms, but the current literature is heterogeneous with variable assessments of critical epidemiological factors," Frontera and Simon wrote. "By enrolling large, diverse patient samples across the age spectrum with varying levels of illness exposure and experiences, and conducting state-of-the-art assessments, RECOVER will help clarify PASC epidemiology, pathophysiology, and mechanisms of injury, as well as identify targets for therapeutic intervention."

Both Frontera and Simon receive funding as co-investigators for the RECOVER initiativefrom the NIH. Frontera reported receiving consulting fees from Thieme and speaking fees from Physician Education Resource unrelated to this correspondence. Simon reported receiving grants from the NIH, Patient-Centered Outcomes Research Institute, Department of Defense, American Foundation for Suicide Prevention, Cohen Veterans Network, and Vanda Pharmaceuticals and consulting fees from Vanda Pharmaceuticals, Bionomics Limited, BehavR LLC, Praxis Therapeutics, Cerevel, Genomind, and Engrail Therapeutics.

Frontera JA, Simon NM "Bridging knowledge gaps in the diagnosis and management of neuropsychiatric sequelae of Covid-19" JAMA Psychiatry 2022; DOI: 10.1001/jamapsychiatry.2022.1616.