Neuropsychiatric Complications of SARS-CoV-2 Infection: Comparison
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Beginning with the various strategies of the SARS-CoV-2 virus to invade the bodies and manifest infection, and ending with the long COVID, people are witnessing the evolving course of the disease in addition to the pandemic. Given the partially controlled course of the COVID-19 pandemic, the greatest challenge currently lies in managing the short- and long-term complications of COVID-19.

  • COVID-19
  • complications
  • SARS-CoV-2

1. Introduction

Severe environmental stress associated with pandemics has affected the human population since the 19th century. In 1839, English physician Henry Holland claimed that influenza was “responsible for the impairment of mental functions”. Over the years, it has become clear that a combination of systemic infection, viral neurotrophy, and environmental factors can promote and even cause the development of psychiatric disorders [33][1]. A nationwide cohort study in Denmark showed that severe infections requiring hospitalization increased the frequency of subsequent psychiatric consultations by 84% and the need for psychotropic medication by 42%. Correspondingly, less severe infections also increased this risk by 40% and 22%, respectively [34][2].
The primary targets of SARS-CoV-2 are epithelial cells of the pulmonary and gastrointestinal tracts. However, the invasion of the virus is most likely not limited to these organs; it could enter the body through several pathways. The leading and most studied strategy is binding to human angiotensin-converting enzyme 2 (ACE2) as an entry receptor and human proteases as entry activators. ACE2 is expressed in many tissues, including the central nervous system [35,36][3][4].
Another postulated entry point for SARS-CoV-2 to the brain, with a little protection of the blood–brain barrier (BBB), is circumventricular organs, making it prone to various types of inflammation (including sepsis, stress, or autoimmune encephalitis).
An inflammatory storm and the massive release of inflammatory signaling factors (e.g., cytokines and chemokines) also contribute to the weakening of the BBB, which enhances the neuroinflammatory process [37][5].
Anosmia, which was one of the first described extrapulmonary manifestations of SARS-CoV-2, also raises the question of whether the virus is transported through the axons of olfactory bulb neurons and infects the brain via this pathway [38][6].
Whether SARS-CoV-2, like other coronaviruses (e.g., SARS-CoV-1 or MERS-CoV), is neurotropic requires further investigation. Other ss-coronaviruses have been found to extend their presence beyond respiratory cells and frequently affect the central nervous system [37][5].
Clinically, neurological and psychiatric signs or symptoms, for example headache, impaired consciousness, paresthesias, occur in 36.4% of hospitalized patients with COVID-19, with a higher incidence in patients with more severe disease [39][7].
Due to the clinical picture, neuropsychiatric complications of SARS-CoV-2 infection could be divided into two more distinct groups: psychiatric and neurological. Such a distinction may be useful in organizing specialist consultations and treatment procedures and may be related to the causes of the symptoms. In these two groups, symptoms may overlap and may be causally related.

2. Neurological Symptoms or Disorders

This subgroup of symptoms can also be divided into those that appear quickly, almost simultaneously with the early symptoms of systemic SARS-CoV-2 infection, the so-called acute symptoms, and symptoms that may develop slowly or appear later, but persist longer or even chronically even when the symptoms of the infection disappear. They can also be a consequence of brain damage.
The most common acute neurological symptoms include disturbance of the perception of smell and taste, and anosmia. Research is ongoing to find out the causes of its appearance in the early stages of COVID-19, as described above.
Interesting research results were presented by the authors of Douaud G et al., Nature (2022), that changes in the brain in patients appeared not only after severe SARS-CoV-2 infection, requiring hospitalization, but also in milder cases of the disease. These changes have been demonstrated using magnetic resonance imaging of the brain. In addition to lesions indicating tissue damage associated with the primary olfactory cortex, researchers noticed that the brains of people after SARS-CoV-2 infection showed a reduction in gray matter thickness and tissue contrast in the orbitofrontal cortex (related to emotions, reward, and decision-making) and in the parahippocampal gyrus (which plays a major role in encoding and memory retrieval). A greater reduction in overall brain size has also been shown. These were the differences from 0.2 to 2 percent in size compared with those in the control group who were not infected. Infected study participants also had poorer cognitive functions, and the negative effects described above were more pronounced in the elderly. The authors suggest that pathological changes in the brain are a sign of the degenerative spread of the disease following the immune response of the nervous system. However, it can also be influenced by the lack of sensory stimuli caused by anosmia. Yet, it is still unknown what exactly causes long COVID, or why it affects even people who have been mildly ill [40][8].
Except for anosmia, headache, dizziness, and impaired consciousness were the most commonly reported neurologic symptoms of COVID-19 [30][9]. Some patients present primarily with neurologic symptoms (e.g., stroke or epilepsy) without a typical history of respiratory distress with choking [41,42][10][11]. Such symptoms are not specific to SARS-CoV-2 infection and may occur in other viral infections and could also occur via indirect mechanisms of neuropathogenicity, e.g., as a result of respiratory distress, hypoxia, hypotension, dehydration, or fever during sepsis [42][11].
Delirium and memory loss observed in elderly patients recovering from pneumonia appear to be due to neuroinflammation, which has been well-described as a major component of neurodegenerative diseases [43][12].
In recent months, reports of meningitis, encephalitis, myelitis, or peripheral nerve damage have been published by COVID-19, suggesting that SARS-CoV-2 can directly infect structures of the nervous system. A 24-year-old adult from Japan was the first patient diagnosed with meningitis/encephalitis in March 2020 [42][11]. It was the first case in which SARS-CoV-2 RNA was detected in the CSF, demonstrating the neuroinvasive potential of the virus. Consequently, viral encephalitis as a complication of coronavirus infection is considered by clinicians to recognize the respiratory symptoms of encephalitic brainstem injury and as an independent disease.
In clinical practice, respiratory failure in some COVID-19 patients is manifested by decreased respiratory rate—a likely effect of the COVID-19-dependent alteration in baroreceptor function. Coronaviruses mainly affect neurons in the brainstem and damage sensitive cardio-respiratory control areas, exacerbating disease progression or even leading to respiratory failure [33][1].
Similar to SARS-CoV-1, SARS-CoV-2 can cause Guillain–Barre syndrome, which is characterized by weakness, difficulty walking and breathing, and difficulty weaning from artificial ventilation [41][10].
The increasing number of reports of COVID-19 patients with neurological problems and experimental models demonstrating neuroinvasion raise concerns that SARS-CoV-2 is a novel neuropathogen that remains underdiagnosed [44][13]. During the COVID-19 pandemic, it is also important to provide continuous care for people with chronic neurologic disorders.
In addition to neuroinvasion, COVID-19 infection triggered immunity and caused massive inflammation of the lungs and brain; the former is the main cause of death in COVID-19, and the latter can lead to brain hemorrhage. Hypercoagulation and aneurysm instability, partly due to systemic COVID-19 inflammation, may be the possible cause manifestation of neurological symptoms.
The neurological manifestations are currently supported by the following mechanisms, previously described in agreement with Heneka et al. (2020): (1) direct viral encephalitis, (2) systemic inflammation, (3) peripheral organ dysfunction (liver, kidney, lung), and (4) cerebrovascular changes. However, in most cases, the neurological manifestations of COVID-19 may result from a combination of the above factors [45,46][14][15]. Panariello et al. (2020) proposed a fifth possible mechanism related to the pathogenesis of SARS-CoV-2 infection or the binding of the virus to ACE2, leading to a downregulation of this receptor and a change in the dynamic balance between the two arms of the RAAS: (1) ACE/Ang II/AT1R with proinflammatory activity and (2) ACE2/Ang-(1-7)/MasR with anti-inflammatory properties [46][15].

3. Psychiatric Symptoms or Disorders

As previously mentioned in SARS-CoV-2 infection, symptoms of a mental disorder may overlap with neurological symptoms. Immune changes in the brain during an infection can also aggravate psychiatric problems that existed before the infection.
Inflammatory disorders are also responsible for many other neuropsychiatric disorders such as schizophrenia, depression, bipolar disorder, and multiple sclerosis [47][16]. Cytokine levels related to disease activity remain low in patients with unaffected mood but rise sharply in patients who resist treatment [48][17].
In COVID-19-positive patients with severe disease progression, an exaggerated host immune response is observed. An abnormally high serum level of IL-6 detected in patients with COVID-19 is an important inflammatory biomarker and could be used to predict disease severity [49][18]. Alterations in IL-6 levels are also observed in psychiatric disorders such as major depression, schizophrenia, or suicide attempts.
Following the research on other coronaviruses (SARS-CoV-1 and MERS-CoV), it is very likely that some people do not recover their mental state or cognitive abilities after recovery from a physical illness such as pneumonia [50][19]. In addition, the number of patients with severe COVID-19 increases rapidly beyond the age of 55, as does the mortality rate [51][20]. Aging is an important risk factor for cognitive impairment; in addition, systemic diseases and stress may accelerate the onset of the disease. COVID-19 pandemic-related reductions in interpersonal communication with subsequent alienation, especially among primarily vulnerable groups such as the elderly or teenagers, can lead to depression and anxiety and increase suicide risk [52][21]. This is not only due to the ability of the virus to invade the CNS and damage neuronal cells, but also because patients face an untreatable and potentially fatal disease that can cause persistent behavioral changes or exacerbate pre-existing mental illness. The long-term consequences will only become apparent in the coming months to years.
COVID-19 is associated with neuropsychiatric complications, of which anxiety is the most common. Several biological and psychosocial factors contribute to anxiety in COVID-19. Biological factors include stress, genetics, gender, immune system, resilience, anosmia, hypogeusia, direct central nervous system (CNS) infection with SARS-CoV-2, and comorbid psychiatric and general medical conditions, ARDS, and ICU stay. Anosmia and hypogeusia are COVID-19-specific risk factors for anxiety. Knowledge of anxiety risk factors is important to focus on timely interventions, as anxiety can exacerbate COVID-19 progression. There is an inverse correlation between resilience and anxiety due to COVID-19, and efforts should be made to increase resilience in COVID-19 patients. In COVID-19, one of the main causes of anxiety is neuroinflammation resulting from immune system activation and cytokine storm. The general approach to treating anxiety during COVID-19 should take a compassionate approach, similar to trauma or disaster, and attempt to provide a sense of hope and resilience. The choice of pharmacological treatment for anxiety should focus on the stress response and its effects on the immune system [53][22].
During the COVID-19 pandemic, individuals exhibited certain behaviors to reduce stress and anxiety. They were more likely to search the Internet for health information on wearing face masks or washing their hands. A healthy lifestyle and psychological interventions were recommended to strengthen the immune system against COVID-19. Although interdiction appears to be effective against COVID-19, it had profound effects on the social interaction and psychological well-being of the population [54][23].
The binding of SARS-CoV-2 to ACE2R decreases the availability of ACE2R, leading to a reduction in the downstream mechanism of CRH and lower glucocorticoid production. Consequently, fewer glucocorticoids are available to limit excessive inflammation, leading to a sustained stress response. Environmental conditions and comorbid psychiatric illness further exacerbate this cycle. SARS-CoV-2 infection and stress contribute to excessive inflammation, which can alter neurotransmitter signaling and compromise the structural integrity of neurons through multiple mechanisms. These changes can lead to abnormal levels of dopamine, glutamate, GABA, serotonin, and norepinephrine in various brain regions, including the ventral striatum, hippocampus, amygdala, raphe nuclei, and locus coeruleus, contributing to the development of psychotic, mood, and anxiety disorders or exacerbating preexisting conditions [55][24].
In two patients described from the psychiatric unit for COVID-19 emergencies at the College of Florence, anosmia and hyposmia were not limited to the sensory level. In both cases, patients reported a degree of depersonalization (“loss of oral cavity”) and derealization (“change in atmosphere”) [56][25]. Watson et al. studied 42 cases of psychosis in COVID-19-positive patients [57][26]. COVID-19-related psychoses were also described by Ferrando et al. in three patients (two of whom had a psychiatric history) who presented with new-onset severe panic attacks, paranoia, and disorganized thinking, without characteristic respiratory or gastrointestinal symptoms. Patients did not express COVID-19-related nervousness. Patients were physically healthy with minimal variation in laboratory tests except for inflammatory markers [58][27], which may support the theory that the cytokine storm is responsible for immune-mediated neuropsychiatric symptoms.
Both SARS-CoV-2 and the previous SARS-CoV infections are associated with an increase in pro-inflammatory cytokines and chemokines (cytokine storm). At the same time, the pathogenicity of MERS-CoV is based on its IFN antagonist proteins. Ongoing research shows that many psychiatric disorders are characterized by inflammation, and their treatments have different anti-inflammatory properties. The profound psychosocial impact of SARS-CoV-2 means that patients will receive standard antidepressants and antipsychotics for these disorders [55][24].
Direct CNS infection combined with systemic inflammation and hypoxia in COVID-19-positive patients can cause both immediate and long-term chronic neurological and psychiatric cognitive impairment. Therefore, the development of an appropriate therapeutic strategy, rapid recognition of the patient, and rehabilitation are only possible through a multidimensional, interdisciplinary team approach.

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