The scope, magnitude and speed of the COVID-19 pandemic have been staggering and continue to evolve rapidly. To date, more than 80 million people have been infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) worldwide and at least 1.7 million have died.
Consequently, the full impact of this global infectious disease catastrophe may not be appreciated for years to come. Early in the pandemic, public and scientific attention focused on the acute morbidity and mortality associated with COVID-19. However, several months into the pandemic, reports emerged describing persistent physical and neuropsychiatric sequelae after SARS-CoV-2 infection.
While residual or persistent neuropsychiatric symptoms are not uncommon in critically ill survivors after admission to an intensive care unit (ICU), follow-up studies after COVID-19 reveal that mild and even asymptomatic infection can lead to cognitive impairment , delirium, extreme fatigue, and clinically relevant mood symptoms.
These descriptions reflect historical reports of post-pandemic neuropsychiatric complications such as encephalitis lethargica, as well as descriptions of sequelae from other respiratory disease pandemics.
Recent evidence suggests that psychiatric illness is both a risk factor and a consequence of COVID-19.
In a large electronic health record (EHR)-based cohort study of more than 60,000 COVID-19 cases, a documented psychiatric diagnosis in the previous year was associated with a 65% increased risk of COVID-19 compared to a cohort of patients with physical health problems without psychiatric diagnoses. Additionally, during the 3 months following COVID-19 diagnosis, 18% of patients were given a psychiatric diagnosis, with almost 6% representing a new diagnosis (e.g., dementia, anxiety, and insomnia).
Czeisler et al., who also noted that specific populations were disproportionately affected (e.g., young adults, Hispanic and Black patients, essential workers, unpaid caregivers, and people with pre-existing psychiatric conditions).
| Purpose of the review |
Our objectives are to describe the post-acute neuropsychiatric complications of COVID-19, the possible etiologies of these persistent central nervous system (CNS) symptoms, and to provide recommendations for the psychiatric evaluation and treatment of recovering COVID-19 patients presenting in primary care centers.
| Recent findings |
More than 30% of patients hospitalized with COVID-19 may present with cognitive impairment, depression and anxiety that persist for months after discharge. These symptoms are even more common in patients who required intensive care due to severe effects of the virus.
In addition to psychological stress related to the pandemic, multiple biological mechanisms have been proposed to understand the neuropsychiatric symptoms observed with COVID-19.
Given limited research regarding effective interventions, we recommend pharmacological and behavioral strategies with established evidence in other medically ill populations.
Clinical vignette A 62-year-old man with a history of osteoarthritis, but no formal medical or psychiatric history, presented to the emergency department (ED) with a chief complaint of hip pain. In the emergency department, physical and mental status examination was relatively normal. Specifically, the patient was afebrile, lung examination was normal, and his mental status was not significantly altered. Imaging and laboratory studies revealed acute kidney injury (AKI, serum creatinine 1.7 mg/dl), which led to hospital admission. The COVID-19 test was performed as part of their intake lab and was positive. The family noted that one of the patient’s children had recently been exposed to COVID-19 at work and later tested positive. They also reported that the patient had been “confused” in the days prior to his presentation. Within hours of admission to the COVID-19 unit, the patient’s creatinine normalized, but he quickly became belligerent, refusing interventions, and demanding to be discharged. The hospital consultant psychiatrist diagnosed the patient with acute delirium and, based on history obtained from his family, a pre-existing mild neurocognitive disorder. Risperidone 0.5 mg per night was recommended for agitation, which gradually improved over the 5 days of hospitalization. At discharge, the patient was connected for follow-up in a post-COVID clinic for ongoing management of his persistent neuropsychiatric symptoms, potentially precipitated by SARS-CoV-2 infection. |
| Etiologies of neuropsychiatric symptoms |
SARS-CoV-2 is a positive-screen, single-stranded, enveloped RNA virus with a crown-shaped morphology. It is a human coronavirus (HCoV) in the beta genera of the coronaviridae family.
During cell entry, SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) on the surface of the target cell to facilitate fusion of the viral and host membranes. ACE2 exists in the cell membranes of the lungs, gastrointestinal (GI) tract, myocardium, renal tubules, and bladder. Consequently, coronaviruses are traditionally considered lung diseases, often accompanied by gastrointestinal symptoms.
However, patients with COVID-19 have demonstrated a high prevalence of neuropsychiatric symptoms. Of note, both SARS-CoV-1 and MERS-CoV have demonstrated the ability to infect the CNS, especially the brainstem. Our knowledge of SARS-CoV-1 and MERS-CoV has contributed to four proposed mechanisms of CNS involvement by SARS-CoV-2.
First, the neuropsychiatric symptoms of COVID-19 are most often due to a wide variety of biological and environmental factors, including electrolyte abnormalities, liver inflammation, impaired kidney function, impaired oxygenation, hyperinflammation, and isolation due to to public health problems that lead to multifactorial delirium.
Elderly persons are at increased risk of delirium due to these multiple contributors and may experience both acute and long-term neuropsychiatric effects following an episode of delirium.
Second, virus-induced immune reaction and autoimmunity (during or after acute infection) provide another route by which SARS-CoV-2 can affect CNS function.
Third, SARS-CoV-2-induced coagulopathy has caused a wide variety of organ failures. Viral invasion of the vascular endothelium leading to activated thrombotic and inflammatory cascades amid a hypercoagulable state can lead to cerebrovascular events. Stroke is the most common neurological finding on images of patients hospitalized with SARS-CoV-2.
Stroke may even be a presenting symptom, although it is more typically part of multi-organ involvement . Furthermore, stroke itself is a risk factor for depression, and COVID-19 patients with stroke are at significantly increased risk of unfavorable outcomes.
Finally, direct viral invasion of the CNS has been demonstrated, although this aggression appears to be uncommon. Some reports have identified the virus in the CNS, but this is rare, even among patients with severe symptoms. Due to the prevalent and well-documented loss of taste and smell in infected patients, direct invasion of the CNS by SARS-CoV-2 through olfactory axonal migration was proposed.
However, subsequent work has shown that it is actually the olfactory epithelial cells that provide metabolic support to the olfactory sensory neurons, rather than the neurons themselves that are likely involved.
Therefore, direct SARS-CoV-2 invasion of the CNS is most likely to occur at the blood-brain barrier (BBB) through (1) transcellular migration (through host endothelial cells); (2) paracellular migration (through tight junctions); and (3) a “Trojan horse” cell of the immune system that passes through the BBB.
| Neurocognitive disorders |
There is little data on the long-term cognitive consequences of COVID-19. A study of 279 patients hospitalized with COVID-19 found that 34% reported memory loss and 28% described altered concentration approximately 3 months after discharge.
Similar findings have been observed after infection with other coronaviruses, with 20% reporting cognitive deficits months to years after initial infection. In the large EHR study by Taquet et al, new onset dementia after hospitalization for COVID-19 was 2 to 3 times more common than what was observed after hospitalization for other medical events.
In the most severe cases of COVID-19, long-term cognitive deficits are likely to be the sequelae of delirium experienced during the acute phases of the illness. Particularly in older patients, as in our illustrative case, delirium is one of the most common symptoms in patients with COVID-19 presenting to the emergency department, and may be the only or main symptom of SARS infection. CoV-2.
Delirium occurs in at least 30% of hospitalized patients with COVID-19 and is substantially more common in those requiring ICU admission.
Of interest, delirium has also been described in COVID-19 patients who do not experience serious medical complications (also as depicted in our case), and there have been reports of "brain fog" among patients experiencing milder symptoms that were never hospitalized and presumably did not experience delirium.
Common principles for the treatment of neuropsychiatric complications of COVID-19 in primary care settings • Consider SARS-CoV-2 infection, in addition to pandemic-related stress, as a possible causative factor for new or worsening neuropsychiatric symptoms. • Recognize that patients with pre-existing psychiatric illnesses are more likely to be infected with SARS-CoV-2, experience the neuropsychiatric consequences of COVID-19, and suffer worse medical outcomes. • Symptoms should be monitored longitudinally, at regular intervals, using validated rating scales and questionnaires to detect depression, anxiety, post-traumatic stress, substance use, suicidality, and cognitive concerns. • Evidence-based behavioral and pharmacologic therapies used to treat symptoms in other medically ill populations may be used in the setting of active or resolving SARS-CoV-2 infection, but providers should be aware of the possible drug interactions, particularly the proinflammatory, prothrombotic and arrhythmogenic effects of COVID-19. • Given the multiple organ systems affected by COVID-19, we recommend highly coordinated care in conjunction with other specialists (e.g., cardiology, nephrology, infectious diseases, pulmonology, neurology, rehabilitation medicine). • Telehealth represents an opportunity to expand access to mental health care while mitigating the spread of the virus; However, providers should consider the limited research regarding the effectiveness of telepsychiatry for certain populations (e.g., psychotic disorders) and develop plans for necessary face-to-face care (e.g., medication management). long-acting injectable medications, methadone treatment programs). |
| Mood and anxiety disorders |
During and after COVID-19 infection, patients are at increased risk of depression and anxiety. Approximately one month after infection, 31-38% of patients report depressive symptoms, 22-42% report anxiety symptoms, and 20% report obsessive-compulsive symptoms.
Rates vary depending on the population studied, the methods used to assess symptoms, and the time since symptoms of infection were assessed. Most studies are cross-sectional and most are from China.
While symptoms of depression and anxiety are more common than formal anxiety or mood diagnoses in COVID-19 survivors, a non-negligible proportion of patients meet diagnostic criteria for a psychiatric disorder.
Suicidal ideation also increases after COVID-19 diagnosis. In one study, 3.5% of respondents reported suicidality 1 month after infection. There have been numerous case reports of COVID-19 patients attempting suicide during or before hospitalization. However, it remains prudent to withhold final judgment on the relationship between COVID-19 and suicide until definitive epidemiological studies can be completed.
| Post-traumatic stress disorder |
Post-traumatic stress disorder (PTSD) was one of the most common psychiatric disorders diagnosed among SARS and MERS survivors, with a prevalence of almost 40% at 6 months after discharge. Not surprisingly, the prevalence of PTSD among COVID-19 survivors is at least as high as in previous coronavirus outbreaks.
Of interest, many risk factors for COVID-19 are also risk factors for PTSD. Specifically, high rates of obesity, diabetes, metabolic syndrome, cardiovascular diseases, and autoimmune diseases are observed in patients with PTSD [54-56].
Patients with COVID-19 also have disproportionately high rates of medical comorbidities, including obesity, diabetes, chronic lung and heart diseases, as well as immune dysfunction [57-59]. Delirium and ICU-level care, both common complications of COVID-19 [16, 26, 60], are also risk factors for PTSD/PTSS, with approximately 20% of critical care survivors experiencing PTSS. 12 months after discharge.
To our knowledge, specific pharmacological treatment for COVID-19-related PTSD/PTSS has not been studied. However, as discussed in our recommendations for the management of anxiety and depression, the basic principles of treatment for PTSD can be applied to patients with medical illnesses, considering potential drug interactions and potential organ dysfunction when selecting medications. and the doses.
While evidence supports the use of the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine and SSRIs for PTSD in patients with medical illnesses, the potential risks should be carefully considered on a case-by-case basis.
Again, paroxetine is not recommended in medically ill patients due to its short half-life, anticholinergic side effect profile, and increased risk of drug-drug interactions. Several studies have shown a reduction in the frequency and intensity of nightmares, as well as an improvement in other PTSD symptoms, in patients prescribed the alpha-1 receptor blocker prazosin.
There is some evidence that psychoeducational services provided online to COVID-19 survivors with PTSS have been helpful, although restricted Internet access and the poor health status of many affected patients make in-person psychological interventions preferred when may be possible.
Exposure-based cognitive behavioral therapy (CBT) has the highest level of evidence in those with PTSD, while supportive counseling, resilience training, and psychological first aid have some evidence in the treatment of PTSD. Of note, psychological questioning is not beneficial for PTSD, can cause harm, and should be avoided.
| Psychotic disorders |
Beginning with the Spanish influenza pandemic in 1918, higher rates of psychosis have been observed during many pandemics or epidemics. Early in the COVID-19 pandemic, an observational study from China reported a 25% increase in the incidence of psychotic disorders.
This relationship has largely been attributed to the considerable psychosocial stress of the pandemic, but, as described above, more direct mechanisms have also been suspected. Of interest, 0.9-4% of people exposed to viral infections develop psychosis, which is much higher than the incidence in the general population of 15.2 per 100,000 people.
There have been several cases from various countries detailing first-episode psychotic symptoms in COVID-19 patients. There is insufficient data to clarify a typical presentation of COVID-19 psychosis, but features of notable disorganization and confusion have been described.
Compared to patients who develop psychosis precipitated by pandemic-related stress, these patients are less likely to endorse paranoia or delusional content about COVID-19. They are also less likely to have a family history of psychosis and are more likely to present at an atypical age with subacute onset and relatively rapid recovery after treatment with low doses of antipsychotics.
COVID-19 treatment can also precipitate psychosis. Specifically, chloroquine and hydroxychloroquine, previously mainstays of COVID-19 care, can cause hallucinations and other psychotic symptoms.
This risk is exacerbated in patients receiving lopinavir/ritonavir combination therapy due to CYP3A4 inhibition. High-dose corticosteroid administration, which remains one of the few effective treatments for severe COVID-19 infection, can lead to psychotic symptoms, which have also been specifically described in the context of the treatment of viral diseases.
| Substance use disorders |
When COVID-19 was declared a global pandemic, the United States was already in the midst of another public health crisis: the opioid epidemic. In June 2020, the CDC reported that approximately one in 10 Americans had begun using illicit substances or had increased the amount and/or frequency of substance use due to the COVID-19 pandemic. Unsurprisingly, it is predicted that there will be more drug overdose deaths in 2020 than in any previous year.
| Post-COVID clinical infrastructure |
Interdisciplinary post-COVID-19 clinics are currently being established at multiple medical centers. At the University of North Carolina at Chapel Hill, a “COVID Recovery Clinic” was recently created.
Since COVID-19 affects multiple organ systems and will require follow-up care in multiple specialties, this clinic aims to provide care in a systematic and carefully coordinated manner. The purpose of the clinic is to assist adult COVID-19 survivors who are experiencing ongoing medical complications, residual symptoms, and/or loss of functional independence.
The clinic integrates providers with complementary expertise to enhance patient care and provide educational outreach to healthcare professionals and the community. The clinic’s main specialty is Physical Medicine and Rehabilitation.
The core clinical group is made up of doctors from internal medicine, psychiatry, neuropsychology, physical therapy, occupational health and speech therapy. There is also a collaborative group that includes cardiology, nephrology, infectious diseases, pulmonary, geriatrics, neurology, nutrition and other specialists.
Patients are screened by telephone with a battery of validated instruments and, as indicated, evaluated in person in the clinic for further evaluation and treatment. In addition to the goal of providing exceptional clinical care to patients affected by the aftermath of COVID-19, the clinic has been designed to facilitate unique teaching and research opportunities.
| Conclusion |
Scientific understanding of the impact of COVID-19 continues to evolve rapidly. There are emerging data related to a wide range of neuropsychiatric sequelae after SARS-CoV-2 infection. Due to the complexity of COVID-19 and its treatment, affected patients may require more appropriate longitudinal follow-up performed by multidisciplinary teams.
To accelerate medical knowledge about the long-term effects of COVID-19, it would be extremely beneficial for these post-COVID clinics to pool data into shared databases. Clinical trials are also urgently needed to clarify optimal treatment strategies for the neuropsychiatric and other potentially long-term impacts of COVID-19.
It is important to consider COVID-19 as a cause of new-onset psychotic symptoms. Patients with COVID-19-related psychosis may present with elevations in CRP, ferritin, LDH, and D-dimer, as well as elevated or depressed levels of leukocytes or platelets.
Low-dose antipsychotic medications may be helpful, and patients hospitalized with severe COVID-19 can present to primary care settings with antipsychotics started during the acute period.
It is important to note that antipsychotics increase the risk of QT prolongation and Torsades de Pointes , particularly when used together with other medications that prolong the QT interval (e.g., Azithromycin). Furthermore, COVID-19 infection itself is pro-arrhythmogenic. Similarly, cerebrovascular complications are extremely common in severe COVID-19, and exposure to antipsychotics may exacerbate this risk.
While telehealth is an invaluable way to provide care to patients during the pandemic, patients with psychotic disorders use fewer mobile phones and technology compared to the general population and there is a paucity of research on telepsychiatry interventions for patients with psychotic disorders. psychotic.
