COVID-19 and the Brain – Pathogenesis and Neuropsychiatric Manifestations of COVID-19

MECHANISMS OF VIRUS ENTRY

As viruses are acellular, they do not grow through cell division, but rely on the host cell machinery for replication.

There are 6 stages in a virus life cycle

1. Attachment
2. Penetration
3. Uncoating
4. Replication
5. Assembly
6. Release.

Viruses have multiple entry mechanisms with the common ones shown below: [Viral Pathogenesis, Third edition, 2016]

Once inside the cell, viruses will go through a  process of uncoating by which the viral capsid is removed, ,and the viral genome is released.

The viral genome will then replicate in the nucleus or cytosol. The viral mRNA ‘hijacks’ the host cell machinery to make new virus particles.

These viral particles are then released by a process of budding (blebbing) or lysis of the cell and go on to infect new cells.

STRUCTURE OF SARS-COV-2

SARS-CoV-2 belongs to the β-coronavirus family and exists in the form of RNA. It has nearly 30000 nucleotide base pairs that hold the genetic code for viral production. The number is 3 times compared to HIV and Hep-C and twice that of influenza.

The virus has an average diameter of 100 nm and is spherical or oval. The virus has large spikes of viral membrane glycoproteins on the surface.

The birth of coronavirus ranges from 10000 yrs to 300 million years.

It is partially related with SARS-CoV (~79% similarity), MERS-CoV (~50% similarity), 90% to pangolin CoV and has 96% similarity to a bat CoV found in a cave in Yunnan according to genome sequencing (raising the possibility that that SARS-COV-2 was transmitted from bats in China). [Zhou P et al., 2020]

The intermediate host is currently unknown.

PATHOGENESIS OF SARS CoV-2

SARS-CoV-2 Entry

Two specific nose cells (goblet and ciliated cells) that express the ACE-2 receptor have been identified as likely infection points for the SARS-CoV-2.  [Waradon S et al., 2020]

At the microscopic level, the SARS-CoV-2 engages ACE2 as an entry receptor and employs the host cell enzyme, Transmembrane Serine Protease 2 (TMPRSS2) or furin for spike protein priming. [Wrapp D et al., 2020]

Priming of the spike protein occurs by cleavage of the spike protein (by host cell enzymes), exposing fusion peptides (that fuse the viral membrane with the host cell).

Once fusion occurs, the virus can enter the cell.

Viral replication

Once inside the host cell, the foreign viral RNA ‘hijacks’ the host cell machinery inducing it to produce RNA and proteins that produce new viral particles.

These viral particles will then exit the cell to infect new cells.

The ACE2 receptor is broadly expressed in vascular endothelium, respiratory epithelium, alveolar monocytes, macrophages, neurons, and glial cells, oral and nasal mucosa, nasopharynx, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, and kidney.

Clinical presentation:

The symptoms of COVID-19 infection usually appear after an incubation period of about five days.

The most common symptoms of COVID-19 illness are fever, cough, dyspnoea, and fatigue; other symptoms include headache, hemoptysis, among others.

In severe cases, patients may develop pneumonia, acute respiratory distress syndrome, acute cardiac problems, and multiorgan failure.

A meta-analysis of 38 studies including 3062 patients showed: [Zhu J et al., 2020]

Fever (80.4%), fatigue (46%), cough (63.1%) and expectoration (41.8%) were the most common clinical manifestations. Other common symptoms included muscle soreness (33%), anorexia (38.8%), chest tightness (35.7%), shortness of breath (35%), dyspnea (33.9%). Minor symptoms included nausea and vomiting (10.2%), diarrhea (12.9%), headache (15.4%), pharyngalgia(13.1%), shivering (10.9%) and abdominal pain (4.4%).

Normal leukocytes counts (69.7%), lymphopenia (56.5%), elevated C‐reactive protein levels (73.6%), elevated ESR (65.6%) and oxygenation index decreased (63.6%) were observed in most patients.

About 37.2% of patients with elevated D‐dimer, 25.9% of patients with leukopenia, along with abnormal levels of liver function (29%) and renal function (25.5%).

Other findings included leukocytosis (12.6%) and elevated procalcitonin (17.5%). Only 25.8% of patients had lesions involving single lung and 75.7% of patients had lesions involving bilateral lungs.

Pathophysiology of COVID-19

The severe cases show the following key pathophysiological processes:

• Progressive increase of inflammation
• Unusual trend of hypercoagulation
• Decrease in lymphocyte count and a significant elevation of neutrophils.

EVIDENCE FOR CNS INVOLVEMENT

The first case of viral encephalitis associated with SARS-CoV-2 was reported on March 4, 2020, at Beijing Ditan Hospital. The researchers confirmed the presence of SARS-CoV-2 in the cerebrospinal fluid (CSF) by genome sequencing. [Xiang P et al., 2020]

Subsequently, another case of SARS-CoV-2 encephalitis was reported in Japan, where SARS-CoV-2 was identified in the CSF without nasopharyngeal positivity.  This raised the possibility of direct infection or alternate routes of transmission, such as the haematogenous route.[Moriguchi T et al., 2020]

Since then, there have been numerous cases of neurological involvement associated with SARS-CoV-2.

Recently, transmission electron microscopy of the brain tissue of a 74-year-old male with SARS-COV-2 showed evidence indicating the neuroinvasive nature of the virus and the likely routes of transmission to the CNS. [Paniz-Mondolfi A et al., 2020]

• Frontal lobe sections showed the presence of 80 to 110 nm viral particles
• Spherical viral-like particles were observed individually and in small vesicles of endothelial cells.
• Blebbing of viral particles in/out of the endothelial wall indicative of viral entry-transit across the brain microvascular endothelial cells into the neural system.
• Neural cell bodies exhibited distended cytoplasmic vacuoles containing enveloped viral particles with distinct stalk-like projections.

However, this neuroinvasive potential has been disputed by a systematic review on neuropathological findings in covid-19, which found no evidence for direct brain invasion. The review found greater evidence for brain inflammatory reaction and hypoxic-ischemic damage involved in pathogenesis rather than neuronal viral load. [Cosentino et al., 2021] 

PATHOPHYSIOLOGY OF CNS INVOLVEMENT

SARS-CoV-2 can take two pathways to involve the brain; direct and indirect pathways. [Wu Y et al., 2020]

Postulated Direct pathways –

1. The haematogenous route

• The virus gains access by infecting endothelial cells of the blood-brain-barrier, epithelial cells of the blood-cerebrospinal fluid barrier in the choroid plexus, or using inflammatory cells as Trojan horses to gain access to CNS (myeloid cell trafficking).
• Observation of viral-like particles in brain capillary endothelium and actively budding across endothelial cells strongly suggests the hematogenous route as a highly likely pathway for SARS-CoV-2 to the brain.

2. Neuronal transport

• The virus can use retrograde axonal transport (travel from axon terminals across the axon) to reach the neuron cell bodies in the central nervous system.
• Retrograde axonal transport may occur through the olfactory, respiratory, and enteric nervous system networks.

Olfactory network:

Retrograde neuronal transport via the olfactory pathway (across the cribriform plate of the ethmoid bone to the olfactory bulb situated in the forebrain) is a likely route given the proximity to the brain but also due to the presence of ACE2 receptors on olfactory cilial cells.

The virus can reach the CSF and brain through olfactory nerve and bulb within 7 days and can cause inflammation and a demyelinating reaction.  Removal of the olfactory bulb in mice resulted in the restricted entry of COV-2 into CNS. [Bohmwald K et al., 2018]

Intact CoV particles together with SARS-CoV-2 RNA have been found in the olfactory mucosa, as well as in neuroanatomical areas receiving olfactory tract projections and may suggest SARS-CoV-2 neuroinvasion occurring via axonal transport. [Meinhardt J et al., 2020]

Respiratory network

The virus may also enter via retrograde neuronal transport via axons from the peripheral nerves of the respiratory network into the medulla oblongata, where respiratory rhythm is generated and regulated [Li et al. 2020].

Gut-Brain Axis:

Viral shedding in faeces is known to occur up to 5 weeks post-infection [Wu Y et al., 2020].

The gut is postulated as a key entry point due to the following factors:

• The higher relative expression of ACE-2 receptor in enterocytes than lungs
• Evidence that SARS-CoV-2 can directly infect and replicate in intestinal cells
• The worse clinical outcome of COVID-19 patients with concomitant GI symptoms with increased acute respiratory distress and need for mechanical ventilation.

The enterocytes are connected to the enteric nervous stem and may provide a source of entry to the brain.

The enteric glial cells act as antigen-presenting cells (APC’s) to immune cells housed in the gut-associated lymphoid tissue (GALT). An infection of the gut may trigger a peripheral immune response such as a cytokine storm and also facilitate enteric neuroinflammation.[Esposito G et al., 2020]

Once inside the brain, the virus can activate the immune cells of the brain to start a cascade of neuroinflammation.

Postulated Indirect Mechanisms of Brain Involvement include:

Cytokine dysregulation

• Pro-inflammatory cytokines (e.g., IL-6 and TNF-α) are significantly higher among deceased COVID-19 patients, which has previously been linked to cytokine storm syndrome-related encephalitis [Huang et al 2005].

Peripheral immune cell transmigration

• Human coronaviruses may play a possible role in the development of psychiatric symptoms via the opportunistic infection of peripheral myeloid cells (Trojan Horse mechanism), which are then trafficked to the brain causing neuroinflammation and virus-induced neuropathology. [Desforges et al 2019]

Neuroinflammation

• Cytokines released through peripheral inflammation may increase the permeability of the BBB providing a pathway for the virus to enter the brain.
• Once in the CNS, it can infect of astrocytes and microglia activating the cascade of neuroinflammation and neurodegeneration through the release of TNF, cytokines, ROS and other inflammatory mediators.

Post-infectious autoimmunity

• Viral infections have been suggested to induce auto-reactive processes that can potentiate the development of an autoimmune response in susceptible individuals.
• In fact, the literature has already described cases of autoimmunity following a SARS-CoV-1 or MERS-CoV infection. [Tsai et al 2004], [Kim et al 2017]

The mechanisms of viral CNS autoimmunity include: [Getts D et al., 2013]

1.Molecular mimicry:

• Potential for T-cell receptors (TCRs) specific for certain microbial epitopes to potentially cross-react with self-antigens that have similar molecular patterns or mimics.

2.Bystander activation of immune cells:

• Overactive response to virus results in the release of self-antigens that trigger off the immune response by processing antigens by inflammatory monocyte-derived APCs to autoreactive T cells

3.Epitope spreading:

• In the context of antiviral immunity, activation of a broad set of viral-specific T cells is potentially a helpful event. However, destruction of host tissue and autoimmunity may result should the spread happen to include epitopes expressed by host tissues.

Hypoxic injury

• Hypoxia in the brain may occur via direct infection of the lung tissue but may also occur due to the neuroinvasive potential of the virus directly affecting the medullary cardiorespiratory centre. [Li Y et al., 2020]
• Hypoxia of the brain increases anaerobic metabolism in the mitochondria of the brain cells, and the resultant lactic acid leads to cerebral oedema, reduced blood flow, raised intracranial pressure, which can clinically present with a range of neuropsychiatric symptoms.

Immunomodulatory treatments

• There is evidence that some patients have been treated with high dose corticosteroids during the acute phase.
• Unfortunately, this type of therapy is linked to acute neuropsychiatric effects such as sleep disturbances, delirium, mania, depression, and psychosis. [Warrington and Bostwick 2006]

Gut Microbiome translocation [Gao Q et al., 2020]

• Inflammation disrupts the intestinal barrier resulting in ‘gut leak’ causing bacterial translocation into circulation and secondary systemic infection.
• Increased intestinal permeability leads to the influx of large amounts of lipopolysaccharides which in turn causes the release of TNFα, IL-1β, and IL-6, further exacerbating systemic inflammation
• It will be of interest to determine whether the infection causes any change to microbial composition in the gut which may be linked to psychiatric disorder

Angiotensin-converting enzyme 2 (ACE-2) receptor involvement [Vaduganathan M et al., 2020]

• The virus uses the ACE2 receptor for entry into cells and results in the destruction of ACE2 producing tissues.
• ACE2 is thought to be an essential regulator of the renin-angiotensin system (RAS) essential for cardiac function and blood pressure control. ACE-2 is a negative regulator of the RAS.
• ACE2 cleaves Ang I and Ang II into the inactive Ang 1-9 and Ang 1-7, respectively preventing hypertension.
• Loss of ACE2 can be detrimental, as it leads to the functional deterioration of the heart and progression of cardiac, renal, and vascular pathologies.

Hypercoagulability

Hypercoagulability is seen in more severe cases of COVID-19. The persistent inflammatory status in severe and critical COVID-19 patients acts as an important trigger for the coagulation cascade. Potential mechanisms include [Cao W & Li T, 2020] :

• Certain cytokines, including IL-6, could activate the coagulation system and suppress the fibrinolytic system.
• Pulmonary and peripheral endothelial injury due to direct viral attack.
• Endothelial cell injury can strongly activate the coagulation system via exposure of tissue factor and other pathways.
• Dysfunctional coagulation may exacerbate an aggressive immune response setting up a vicious cycle
• Thrombotic microangiopathy caused by endotheliopathy with a haemorrhagic predisposition [Hernández-Fernández F et al., 2020]
• Production of anti-cardiolipin and anti-β2GP1 antibodies (Zhang Y et al. 2020]
• The pathogenesis of neuropsychiatric involvement via antiphospholipid antibodies [Rege S & Mackworth-Young C,  2015] may provide some clues towards the pathogenesis of brain involvement in COVID-19.  (see below)

NEUROPSYCHIATRIC MANIFESTATIONS

A study of 214 hospitalised patients in Wuhan, China showed that 36.4% had neurologic manifestations. Patients with more severe infection were more likely to have neurological involvement, such as acute cerebrovascular diseases, impaired consciousness, and skeletal muscle injury. [Mao L et al.,2020]

The most common symptoms at onset of illness were fever (61.7%), cough (50.0%), and anorexia (31.8%).

Seventy-eight patients (36.4%) had nervous system manifestations: CNS (24.8%), PNS (8.9%), and skeletal muscle injury (10.7%).

In patients with CNS manifestations, the most common reported symptoms were dizziness (16.8%) and headache (13.1%).

In patients with PNS symptoms, the most common reported symptoms were taste impairment (5.6%) and smell impairment  (5.1%).

Most neurologic manifestations occurred early in the illness (the median time to hospital admission was 1-2 days).

In a French case series of 58 intensive care patients with COVID-19,  69% were encephalopathic with agitation or confusion, including 67% with corticospinal tract signs. 33%  who had been discharged had a dysexecutive syndrome. [Helms J et al., 2020]

In the first 3 weeks of UK-wide surveillance system, 153 cases were notified with a median (range) age 71 (23-94) years. 77 (62%) had a cerebrovascular event: 57 (74%) ischemic strokes, nine (12%) intracerebral haemorrhages, and one CNS vasculitis.

The second most common group were 39 (31%) who had altered mental status, including 16 (41%) with encephalopathy of whom seven (44%) had encephalitis.

The remaining 23 (59%) had a psychiatric diagnosis of whom 21 (92%) were new diagnoses; including ten (43%) with psychosis, six (26%) neurocognitive (dementia-like) syndrome, and 4 (17%) an affective disorder. [Varatharaj A et al., 2020]

A retrospective study of 236,379 patients diagnosed with COVID-19 showed the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 33·62% with 12·84% receiving their first such diagnosis. For those admitted to an ITU the estimated incidence of a diagnosis was 46·42% and for a first diagnosis was 25·79%. [Taquet et al., 2021]

• 0·56% for intracranial haemorrhage
• 2·10%  for ischaemic stroke
• 0·11% for parkinsonism
• 0·67%  for dementia
• 17·39%  for anxiety disorder
• 1·40%  for psychotic disorder

ITU admission outcomes

• 2·66% for intracranial haemorrhage
• 6·92% for ischaemic stroke
• 0·26%  for parkinsonism
• 1·74% for dementia
• 19·15% for anxiety disorder
• 2·77% for psychotic disorder.

A systematic review and meta-analysis of neuropsychiatric manifestations of COVID-19 revealed there was evidence for delirium (confusion) in 65% of intensive care unit patients and altered consciousness in 21% of patients who subsequently died in another study. [Rogers J et al., 2020]

Immunologic test results from COVID-19 patients show that CNS symptoms such as headache, dizziness, and ataxia are linked to significantly lower blood lymphocyte counts, platelet counts, and higher blood urea nitrogen levels compared to those without CNS symptoms [Mao et al. 2020]. Lymphopenia has been suggested to be indicative of immunosuppression in patients with CNS symptoms.

Clinical presentations:

Headache:

• The incidence of headache as a symptom has been variable with studies showing rates from 8-70% [Lechien J et al., 2020]
• A meta-analysis showed the prevalence of headache at 12% [Borges do Nascimento I et al., 2020]

Acute cerebrovascular disease

• Both ischaemic and haemorrhagic strokes have been described.
• Hypercoagulability is associated with stroke in younger individuals. [Oxley T et al. 2020]
• A case series of 221 patients with COVID-19 showed 11 (5%) developed acute ischemic stroke, 1 (0·5%) cerebral venous sinus thrombosis (CVST), and 1 (0·5%) cerebral haemorrhage [Li Y et al. 2020 ]

Intracranial infection-related symptoms

Encephalopathies

• Persistent (>24 hr) alterations in consciousness are common in severe cases and may be related to the cytokine storm [Troyer et al. 2020]

Meningoencephalitis:

• Clinical features include acute onset, fever (high grade), vomiting, seizures and abnormal consciousness.
• Meningitis may have additional signs of neck rigidity.
• It is important to recognise that in some cases, as neuronal death in COVID-19 is not always accompanied by signs of inflammation, the usual clinical picture may be absent. [Baig A., 2020]

Infectious toxic encephalopathy (Acute toxic encephalitis) :

• It has been suggested that this viral infection causes pulmonary, metabolic dysfunction and systemic inflammatory processes that not only result in acute respiratory distress syndrome but also encephalopathy. [Chen et al. 2020]
• Patients may present with headache, confusion, delirium, psychiatric illness and in extreme cases may progress to loss of consciousness, coma and paralysis.

Anosmia and ageusia :

• The loss of smell and taste has been strongly associated with COVID-19 patients [Bénézit F et al., 2020]
• In a European study, olfactory dysfunction was reported for 357 (85.6%) of 417 COVID-19 patients, including 284 (79.6%) with anosmia; 342 (88.8%) reported gustatory disorders. [Lechien J, et al. 2020]
• It is hypothesised that infiltration of the vagus nerve, olfactory network and higher-order chemosensory processing structures in the brain may underlie these symptoms.
• The American academy of otolaryngology-head and neck surgery released a statement noting that anosmia and dysgeusia be added to the list of screening tools for COVID-19 infection.
• Anosmia, in particular, has been seen in patients with no other symptoms who ultimately tested positive for the virus.

Survivors of SARS-CoV-1 were clinically diagnosed with PTSD (54.5%), depression (39%), pain disorder (36.4%), panic disorder (32.5%), and obsessive-compulsive disorder (15.6%) at 31 to 50 months post-infection, a dramatic increase from their pre-infection prevalence of any psychiatric diagnoses of 3% (Lam, 2009).

Depression and anxiety:

• The psychological effects of SARS-CoV-1 and MERS-CoV on healthcare workers have been linked to an increase in psychiatric diagnoses, especially mood disorders [Lin et al. 2007], [Lee et al. 2018]. However, it is unknown whether this is due to exposure to the virus or is linked to the host immune response.
• Increased prevalence of depression has been identified in patients who experienced COVID-19 infection, while the prevalence of anxiety was not statistically different. [Zhang J et al. 2020]
• Prevalence of depression in COVID-19 is associated with low health literacy.[Nguyen HC et al., 2020]
• Seropositivity for a Human CoV strain (HCOV-NL63) has been associated with mood disorder but not its polarity. [Okusaga O et al., 2011]

Psychotic disorders: 

• Immunoreactivity to the human coronavirus, HCoV-NL63, has been reported in patients that have had a recent psychotic episode.  [Severance et al. 2011]
• Furthermore, some patients that were confirmed to have been exposed to MERS-CoV have reported hallucinations and psychotic features. [Kim et al. 2018]
• COVID-19 has been linked to an increase in the incidence of first-episode presentations of schizophrenia with a shift towards late age onset. [Hu W et al., 2020]
• Patients may present with delusional themes related to the pandemic.

PTSD

• A cross-sectional study of 714 recovered and clinically stable COVID-19 inpatients showed that 96% had significant posttraumatic stress symptoms. [Bo H et al., 2020]
• Evidence from previous pandemics points towards higher rates of PTSD in health care workers. See mental health challenges for health care workers in COVID-19

Neuromuscular complications :

• Peripheral neuropathy, myopathy, Bickerstaff brainstem encephalitis, and Guillain-Barre syndrome are rare nerve diseases linked to demyelination that have previously been observed in some patients after both SARS-CoV-1 and MERS-CoV [Tsai et al. 2004], [Kim et al. 2017].
• Neuralgia has been described in COVID-19.
• Several cases of Guillain–Barré Syndrome (GBS) have been associated with SARS-COV-2. [Toscano G et al., 2020]
• It is still unclear if GBS is a typical presentation of COVID-19. However, GBS is known to occur post-infection as in the case of Zika virus.
• Other neuromuscular complications described are Myasthenia gravis, transient cortical blindness and acute disseminated encephalomyelitis.
• Muscular complications include soreness, fatigue and raised muscle enzymes.

Neurodegenerative disorders: 

• There is no current clear evidence of neurodegenerative considerations associated with SARS-COV-2. However, experience from past pandemics shows that the lag period may be months to years for the onset of neurodegenerative illnesses when associated.
• Anti-CoV Abs have been identified in cerebrospinal fluid (CSF) of individuals with Parkinson’s disease. [Fazzini et al., 1992]
• The Braak hypothesis of Parkinson’s disease (PD) proposes that a neurotropic virus invading neural tissue through the nasal cavity and the gastrointestinal tract causes α-synuclein to turn into a promiscuous binder and be transmitted, prion-like, to key areas such as the substantia nigra. [Santos S et al., 2019]
• Given that neural and immune cells can serve as reservoirs of latent CoV, it is plausible that this could contribute to delayed neurodegenerative processes, but this also remains to be seen in COVID-19. [Desforges M et al., 2019]

Our last concern is around the potential chronic neurological consequences of this pandemic. The sheer volume of those suffering critical illness is likely to result in an increased burden of long-term cognitive impairment.

In addition, there also remains the as yet unquantified risk of both “common” para-infectious processes such as acute disseminated encephalomyelitis, as well as atypical disorders akin to encephalitis lethargica, which continues to be linked to the 1918 H1N1 pandemic, though this link remains unproven. [Needham E et al., 2020]

Post-acute COVID-19 (Long Covid):

Approximately 10% of patients with the infection remain unwell beyond three weeks, and a smaller proportion for months. [Greenhalgh T et al., 2020]

Symptoms include:

• Shortness of breath
• Chest pain
• Headaches
• Neurocognitive difficulties
• Muscle pains and weakness
• Gastrointestinal upset
• Rashes
• Metabolic disruption
• Thromboembolic conditions
• Depression and other mental health conditions
• Skin rashes (vesicular, maculopapular, urticarial, or chilblain-like lesions on the extremities (covid toe))

PREGNANCY AND NEURODEVELOPMENTAL IMPACT

The presence of ACE2 receptors on the placenta raises the possibility of vertical transmission which can affect the fetus and potentially have longer-term neurodevelopmental consequences.

A systematic review of 108 pregnancies concluded: [Zaigham M & Andersson O, 2020]

Although the majority of mothers were discharged without any major complications, severe maternal morbidity as a result of COVID-19 and perinatal deaths were reported. Vertical transmission of the COVID-19 could not be ruled out. Careful monitoring of pregnancies with COVID-19 and measures to prevent neonatal infection are warranted.

Evidence of IgM, IgG antibodies and elevated cytokines have been reported in fetuses which indicates a combination of placental transfer and fetal production of antibodies.

A negative RT-PCR test in neonates does not rule out SARS-CoV-2 infection and antibody testing may provide some certainty.

Literature includes case reports of infants with neurological symptoms. [Nathan N et al., 2020]

Maternal infections are known to activate an immune response that can impact on the neurodevelopment of the fetus altering the neurodevelopmental trajectory. [Meyer U., 2019]

The virus has been detected in semen samples suggesting the possibility of transmission from paternal infection to offspring. [Li D et al., 2020]

The long term effects if COVID-19 on the fetus are as of yet unknown and longitudinal studies will be needed to identify any neurodevelopment impact. [Pantelis C et al., 2020]

ROLE OF THE PSYCHIATRIST

COVID-19 pandemic has the potential to result in a significant burden of psychiatric illness even after the pandemic has been controlled. A range of biological, psychological, and social factors interact to increase the psychiatric burden of disease. [Huremović D. 2019]

Specific Mental health aspects of the pandemic include:

• Mental health burden in health care workers
• Psychological effects of quarantine
• Neuropsychiatric sequelae in survivors
• Managing concerns, fears, and misconceptions at the local community and broader public level

Role of the psychiatrist

Biological perspective:

Diagnostic

• The psychiatrist will play an essential role in differentiating between organic and functional psychiatric illness.
• Previous experience from other forms of encephalitis highlights the important role of the psychiatrist.

See treatment principles in management

Psychosocial perspective:

• Providing important tips to manage the consequences of isolation in the short term
• Early identification, prevention, and treatment of mental health conditions
• Psychological first aid can be administered to patients by public health and public behavioural health workers.
• Identification and management of relapses or exacerbation  of illness due to the pandemic in a vulnerable population and
• In the long term, manage the consequences of losses e.g. employment, financial distress, bereavement, etc).
• Acting as an important part of the multidisciplinary team to manage exacerbation of psychiatric and behavioural disturbances arising from neuropsychiatric complications
• In the aftermath of pandemics, increased psychiatric screening and surveillance is recommended to address acute stress disorder, posttraumatic stress disorder, depressive disorders, and substance abuse.
• Working with key decision-makers at a systemic level to devise a meaningful mental health response to an impending potential mental health catastrophe.
• At a systemic level, the psychiatrist can assist in prevention and data collection to design services to combat pandemics in the future.

DIAGNOSTIC AND BIOCHEMICAL MARKERS OF SEVERITY

Inflammatory markers are common in severe cases of COVID-19 and appear to correlate with the severity of the symptoms and clinical outcome. [Xie P et al., 2020]

• Elevated levels of IL-6, CRP and procalcitonin
• Lymphopenia appears to predict morbidity and mortality even at early stages. [Fei et al., 2020]
• Elevation in lactic acid levels
• Imaging results showing bilateral or multilobar infiltration, pleural effusion, or short-term increase in lesions
• Thrombocytopenia and elevated D-dimer levels may be indicative of coagulopathies. [Fogarty et al., 2020]
• Neutrophil-to-lymphocyte ratio (NLR).  Patients aged ≥50 years and with NLR ≥3.13 tend to develop severe COVID-19 and should be admitted to the ICU immediately [Xie P et al., 2020]
• PCR testing of SARS-CoV-2 in CSF. Many cases described in the literature have known to be N-P swab positive and CSF negative although cases of N-P swab negative and CSF positivity have also been described.

Neurological Imaging findings: [Coolen T et al., 2020], [Kandemirli S et al., 2020], [Helms J et al., 2020]

• MRI brain abnormalities were found in 44% of ICU patients

Findings on MRI and perfusion imaging described in the literature

• Cortical signal abnormalities on FLAIR images
• Leptomeningeal
• Bilateral frontotemporal hypoperfusion
• Focal hyperintensities indicative of acute and sub ischaemic strokes
• Hemorrhagic and posterior reversible encephalopathy syndrome (PRES) -related brain lesions in non-survivors of COVID-19 that might be triggered by the virus-induced endothelial disturbances.

Another single-centre neuroradiological analysis of intracranial findings from 3403 patients concluded: [Sawlani V et al.,2020]

Various imaging patterns on MRI were observed including acute haemorrhagic necrotising encephalopathy, white matter hyperintensities, hypoxic-ischaemic changes, ADEM-like changes, and stroke. Microhaemorrhages were the most common findings. Prolonged hypoxaemia, consumption coagulopathy, and endothelial disruption are the likely pathological drivers and reflect disease severity in this patient cohort.

MANAGEMENT

The management of neuropsychiatric complications of COVID requires a multidisciplinary team input due to the multisystemic nature of the illness, particularly in severe cases.

The current therapeutic strategies available in COVID-19 are: [Vabret N et al.,2020]

Anti-Virals

• Broad-spectrum anti-virals – (e.g acyclovir, famciclovir etc)
• Protease inhibitors – nelfinavir, lopinavir, ritonavir, saquinavir, atazanavir, tipranavir, amprenavir, darunavir, and indinavir
• RdRp (RNA-dependent RNA polymerase) inhibitors – e.g. Remdesivir, ribavirin
• Anti-fusion – Arbidol

Immunomodulators

Chloroquine and Hydroxychloroquine (CQ and HCQ)

• CQ and HCQ increase the pH within lysosomes, impairing viral transit through the endolysosomal pathway.
• CQ and HCQ augment antigen processing for presentation on MHC complexes and increases cytotoxic T-lymphocyte-associated protein 4 (CTLA4) expression, which acts as an immune checkpoint and downregulates the immune response.
• There is controversy regarding treatment with CQ and HCQ with no clear evidence for efficacy.
• The combination of HCQ and Azithromycin (AZ) is being used in the treatment of COVID-19.
• The clinical trials performed thus far to evaluate the efficacy of HCQ ± AZ for COVID-19 have not demonstrated clear evidence of clinical benefit in patients with severe disease.

Corticosteroids

• Corticosteroids are used for their anti-inflammatory properties; ; however, there are concerns that they may interfere with the development of an immune response against the virus.

Cytokine directed therapy

• Recombinant IFN as an antiviral treatment

Cytokine blockade

• Anti-IL-6R antibody therapies – Tocilizumab,  sarilumab,
• Anti-IL-6 antibody – Siltuximab
• GM-CSF inhibitors – Gimsilumab

Cytotoxic medications

• Cyclophosphamide

Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells.

Ivermectin

It is an anti-parasitic drug that has been shown to halt the replication of SARS-CoV-2 in vitro. It also shows broad-spectrum anti-viral activity. The reliable evidence available does not support the use of ivermectin for the treatment or prevention of COVID-19. [Popp et al., 2021]

Neutralising Antibodies and Convalescent Plasma Therapy

Vaccine development

• S-protein as a vaccine target
• While the S protein is the most immunodominant protein in SARS-CoV- 2, the M and N proteins also contain B and T cell epitopes.

The main mechanisms in vaccine development are as follows:

• Inactivated or live attenuated viruses
• Protein sub-unit
• Virus-like particles (VLP)
• Viral vector (replicating and non-replicating)
• DNA
• RNA
• Nanoparticles

The Pfizer and Moderna vaccines are mRNA vaccines while the Oxford-Astra Zeneca is a viral vector vaccine. A discussion about the various mechanisms is out of the scope of this article. We refer readers to the article by Kaur and Gupta.  [Kaur and Gupta, 2020]

There is emerging evidence of the role of Vitamin D which has anti-viral, immunomodulatory and anti-inflammatory properties. There are suggestions for using Vitamin D as an adjuvant in reducing complications attributed to unregulated inflammation and cytokine storm. [Daneshkhah A et al., 2020]

Some important points related to treatment [Needham E et al., 2020]

1. Routine use with corticosteroids to be avoided as evidence from previous coronavirus outbreaks suggests that viral shedding may be prolonged.
2. Second-line treatments like IVIg or Plasma exchange (PLEX) are less likely to delay viral clearance and may be beneficial in sepsis. IVIg may be associated with an increased risk of thromboembolism.
3. Third line immunotherapies such as cyclophosphamide and rituximab are high-risk treatments and are only considered if other treatments fail.
4. Due to the high rates of thromboembolism, prophylactic anticoagulation is being considered as it is associated with decreased mortality in high-risk patients. [Tang N et al., 2020]

In our center, given the benefits and risks of each option, high-dose intravenous immunoglobulin treatment at 0.3–0.5 g per kg weight per day for five days was recommended to interrupt the inflammatory flare at an early stage. Meanwhile, we recommend early anticoagulation therapy, preferably low-molecular-weight heparin (LMWH) when D-dimer level is 4 times higher than the upper limit of normal range, unless there is contraindication. A take-home message here is that timing is extremely important in this group of patients, regardless of what treatment might be used. [Cao W & Li T et al., 2020]

In Iran, according to the recent version of guidelines published by Iran’s Ministry of Health, prescription of anticoagulants in patients with COVID-19 is considered as follows: [Aghamohammadi M et al., 2020]

• Prophylaxis with Enoxaparin at a dose of 40 mg daily subcutaneously or heparin at a dose of 5000 units subcutaneous twice daily or three times daily is recommended in all patients admitted to the hospital with a diagnosis of COVID-19
• In patients who are prohibited from taking anticoagulants, the use of mechanical prophylactic methods such as compressive stocking is recommended.

GENERAL PRINCIPLES OF PSYCHIATRIC MANAGEMENT IN COVID-19

• Recognising neuropsychiatric manifestations of COVID -19 and liaising with relevant medical professionals
• Managing acute behavioural disturbance using bio-psychosocial strategies. Judicious use of medications as patients with organic brain illness may be more susceptible to side effects
• Differentiating between ‘normal’ and pathological responses to the pandemic
• Treatment for grief and loss
• Treatment of PTSD
• Diagnosis and treatment of clinical depression
• Mirtazapine 7.5–45 mg may be a good choice in patients with postinfectious cachexia and exhaustion as it promotes weight gain. Its sedative properties may help patients suffering from insomnia.
• Tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors are useful if there is also concurrent neuropathic pain or a lingering inflammatory process that persists following some viral infections ( amitriptyline 10–400 mg at bedtime, duloxetine 60–120mg/day).

Side effects of medications used in the treatment of COVID-19

• Exposure to CQ and HCQ was associated with a statistically significant high reporting of amnesia, delirium, hallucinations, depression, and loss of consciousness, however, there was no link with increased risk of suicide, psychosis, confusion, and agitation [Sato K et al., 2020]
• Corticosteroids can be associated with a range of psychiatric disturbances ranging from mania to psychosis.

Drug-Drug and Cytochrome P450 interactions

Interactions between SSRIs and Anti-Retrovirals

• Decreased levels of sertraline and citalopram by ritonavir (metabolised by CYP3A4 and CYP2D6; inhibits CYP2D6 and CYP2C19)
• Decreased levels of fluvoxamine and fluoxetine by nevirapine (potent inducer of CYP3A4).
• Fluoxetine (CYP2D6 inhibitor) and fluvoxamine (CYP1A2 inhibitor) can both increase the levels of amprenavir, delavirdine, efavirenz, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, and saquinavir.
• Increased levels of all TCAs by ritonavir except desipramine which is decreased.
• Increased levels of trazodone by ritonavir and darunavir

Antivirals such as amantadine have been associated with psychosis and delirium and interferon treatment is frequently associated with depression.

Antimalarials have been shown to increase the levels of phenothiazine neuroleptics.

Clarithromycin and erythromycin (CYP3A4 inhibitors) can increase carbamazepine, buspirone, clozapine, alprazolam, and midazolam levels.

Quinolones may increase clozapine and benzodiazepine levels but reduce the benzodiazepine effect via the GABA receptor.

Severe systemic inflammation can increase clozapine levels, in part due to cytokine-mediated inhibition of CYP1A2. [Clark S et al., 2018]

Risk of QTc prolongation with erythromycin, azithromycin, hydroxychloroquine or with combinations. SSRIs such as escitalopram and citalopram can be associated with QTc prolongation and if used with the above antibiotics can increase the risk of Torsades de Pointes.

Fluvoxamine may be used early in the course of the COVID-19 infection to prevent more severe complications like cytokine storm by activating the sigma -1 receptor. Adult outpatients with symptomatic COVID-19 treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. [Lenze et al., 2020]

Potential mechanisms include: [Sukhatme et al., 2021]

• Inhibitory effect on platelet aggregation through reduced serotonin uptake by platelets.
• Reduced histamine release by mast cells.
• Reduced Lysosomal trafficking of virus
• Interferes with lysosomal binding
• Activation of sigma-1 receptor and anti-inflammatory effects
• Increases melatonin levels by inhibiting melatonin breakdown.

Clozapine and COVID: 

The Australian Commission on Safety and Quality in Healthcare position statement suggests that during the COVID-19 pandemic, to ensure uninterrupted supply of clozapine:

The frequency of Absolute Neutrophil Count (ANC) monitoring may be reduced to every 3 months for people fulfilling all of the following criteria:

1. Continuous clozapine treatment for >1 year
2. Have never had an ANC <2000/μl (or <1500/μl if history of benign ethnic neutropenia)
3. No safe or practical access to ANC testing

According to guidance from the RCPsych

It appears likely that patients with COVID-19 infection will have a low WCC. This seems to be largely due to reduced lymphocytes.

As the monitoring parameters for clozapine include total WCC, a reduction may result in patients registering results that, under normal circumstances, require interruption of clozapine treatment. However, the purpose of interrupting clozapine treatment is to protect patients from neutropenia and agranulocytosis.

Where a low WCC count occurs in the presence of a normal or non-dangerous neutrophil level in the context of COVID-19 infection, it is reasoned that clozapine can be safely continued. It is also important to consider the risk of discontinuing an effective antipsychotic treatment such as clozapine at a time when uncontrolled psychotic symptoms (which are unlikely to be treated by other drugs) may present challenges in safely managing an infected patient. So, continuation of clozapine treatment is the imperative unless low neutrophil counts dictate treatment cessation.

Guidance for the management of Clozapine and blood dyscrasias in patients with coronavirus: [RCPsych]    BEN= Benign Ethnic Neutropenia

2.0 (BEN: > 1.5) AND drop in WCC is temporally consistent with the onset of COVID-19 symptoms. (Values are 1o^9 /l)

• Continue Clozapine and monitor FBC as normal:

< 2.0 (BEN: < 1.5) 

• STOP Clozapine
• Monitor FBC TWICE WEEKLY.
• Restart clozapine when two consecutive ANC results are > 2.0 unless there is a clear contraindication to doing so

Clozapine Patients on weekly monitoring

2.0 (BEN: > 1.5) AND drop in WCC is temporally consistent with the onset of COVID-19 symptoms

• Continue clozapine with weekly monitoring

1.5 – 2.0 (BEN: 1.0 – 1.5) AND drop in WCC is temporally consistent with the onset of COVID-19 symptoms

• Continue clozapine Monitor FBC TWICE WEEKLY until two consecutive ANC results are > 2.0

<1.5 (BEN: < 1.0)

• STOP clozapine
• Monitor FBC TWICE WEEKLY.
• Restart clozapine when two consecutive ANC results are >1.5, but only after consultation with COVID physician

Clozapine patients on 2 weekly or monthly monitoring

2.0 (BEN: < 1.5) AND drop in WCC is temporally consistent with the onset of COVID-19 symptoms

• Continue clozapine and continue to monitor FBC as normal

1.5 – 2.0 (BEN: 1.0 – 1.5) AND drop in WCC is temporally consistent with the onset of COVID-19 symptoms

• Continue clozapine
• Monitor FBC TWICE WEEKLY until two consecutive ANC results are > 2.0

<1.5 (BEN: < 1.0)

• STOP clozapine
• Monitor FBC TWICE WEEKLY.
• Restart clozapine when two consecutive ANC results are >1.5, but only after consultation with COVID physician

Covid-19 infection can increase clozapine levels due to smoking cessation and /or downregulation of CYP1A2. With inflammation, cytokines are increased, and interleukin 1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), interferon-α (IFN-α), and IFN-γ, in particular, seem to inhibit the activity of CYP1A2. [Tio et al., 2021]

All clozapine patients with symptoms of COVID-19 must have a blood sample taken immediately for WCC and ANC, and for clozapine plasma concentration.

Vaccines and Clozapine:

• Most of the COVID-19 vaccines could downregulate CYP1A2 and CYP3A4 enzymes both of which are involved in clozapine metabolism and could increase clozapine levels.
• A case study showed that the administration of mRNA COVID-19 vaccine (BNT162b2) could cause increased clozapine and CRP levels. [Thompson et al., 2021]
• Clinicians should thus be vigilant following COVID-19 vaccine administration, of such potential interactions and monitor absolute neutrophil counts and clozapine serum concentrations closely in patients using clozapine.[Bayraktar et al., 2021] 

CONCLUSION

The current pandemic is unprecedented in modern medicine, and its effects on human mental health are likely to be heterogenous, extensive, and long term.

The causality and etiopathogenic mechanisms of CNS involvement in SARS-CoV-2 are still being studied.

Early research into SARS-CoV-2, along with data from SARS-CoV-and MERS-CoV, suggests a neurotropic and neuroinvasive property of the SARS-COV-2 suggesting a possible substantial global neuropsychiatric burden from COVID-19.

COVID-19 challenges the mind-body dichotomy. Psychiatrists will play an important role in bridging the gap by addressing the short and long term biological, psychological and social consequences of the condition. A truly multidisciplinary effort is required.

It would be prudent to heed Plato’s age-old advice.

The greatest mistake in the treatment of diseases is that there are physicians for the body and physicians for the soul, although the two cannot be separated.

Keep track of all the new developments in neuropsychiatry of COVID-19 by following this link which is regularly updated.

Read more: 

1. The psychological impact of quarantine
2. Mental health challenges for healthcare workers during the COVID-19 pandemic – Impact and management strategies

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