Journal of Psychiatric Research
Short communication
Neurocovid-19: A clinical neuroscience-based approach to reduce
SARS-CoV-2 related mental health sequelae
Stefano Pallantia,b,c,*, Eleonora Grassib, Nikos Makrisd,e, Gregory P. Gasicf, Eric Hollanderg
a Careggi University Hospital, Florence, IT, Italy
b Istituto di Neuroscience, Florence, IT, Italy
c Albert Einstein College of Medicine, USA
d Department of Psychiatry, Massachusetts General Hospital, MA, USA
e Harvard Medical School, MA, USA
f Department of Physics, University of Houston, TX, 77204, USA
g Autism and OCD Spectrum Program, Psychiatric Research Institute of Montefiore Einstein, Albert Einstein College of Medicine, NY, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2, is a disaster due to not only its psychosocial
COVID-19
impact but it also to its direct effects on the brain. The latest evidence suggests it has neuroinvasive mechanisms,
SARS-COV-2
in addition to neurological manifestations, and as seen in past pandemics, long-term sequelae are expected.
Psychosocial support
Specific and well-structured interventions are necessary, and that’s why it’s important to ensure a continuity
Mental health
between primary care, emergency medicine, and psychiatry. Evidence shows that 2003 SARS (Severe Acute
Coronavirus
Respiratory Syndrome) survivors developed persistent psychiatric comorbidities after the infection, in addition to
Neurocovid
Chronic Fatigue Syndrome. A proper stratification of patients according not only to psychosocial factors but also
an inflammatory panel and SARS-Cov-2’s direct effects on the central nervous system (CNS) and the immune
system, may improve outcomes. The complexity of COVID-19’s pathology and the impact on the brain requires
appropriate screening that has to go beyond the psychosocial impact, taking into account how stress and neu
roinflammation affects the brain. This is a call for a clinical multidisciplinary approach to treat and prevent Sars-
Cov-2 mental health sequelae.
COVID-19, a unique disaster - The outbreak of Coronavirus Disease
IFNs (IFNγ), upregulate ACE2 in airway epithelial cells, and SARS-CoV-2
(2019) (COVID-19), caused by Severe Acute Respiratory Syndrome -
may be using the IFN response for its benefit (Ziegleret al., 2020). Acute
Coronavirus-2 (SARS-CoV-2), can be considered as a unique disaster
inflammation is part of innate immunity’s response to harmful stimuli,
(from Latin: Astrum + dis, “bad star”), where individuals in a large
and triggers adaptive immunity, whereas excessive or chronic inflam
population are randomly exposed to the trauma of a virus that has direct
mation causes disease.
effects on the Central Nervous System (CNS), and subsequently induces
How the virus enters the CNS - In patients diagnosed with viral
an immunological response (Troyer et al., 2020).
encephalitis, gene sequencing showed SARS-CoV-2’s presence in the
SARS-Cov-2 mechanism and multi-organ targeting - SARS-CoV-
cerebrospinal fluid, confirming its neuroinvasive potential (Zhou et al.,
2’s mechanism of infection exploits the virus’ strong binding affinity to
2020). Several hypotheses have been advanced to explain how
the angiotensin-converting enzyme-2 (ACE2) to gain entry into cells
SARS-CoV-2 enters the CNS: hematogenous dissemination, neuronal
(Wang et al., 2020a). This receptor is expressed in lungs, heart, kidneys,
retrograde transport and the passage via the nasal cavity across the
testicles, venous endothelial cells and small intestinal enterocytes (Zou
cribriform plate that supports the olfactory bulb (Zhou et al., 2020). The
et al., 2020). ACE2 is also widely expressed in the mouse and human
virus can be disseminated throughout the body via the bloodstream, and
brain although current human evidence is strongest for its expression on
across vascular beds of different organs by disrupting ACE2 bearing
endothelial and smooth muscle cells
(Xia and Lazartigues,
2008).
endothelial cells (Varga et al., 2020). The presence and persistence of
Moreover, type I interferon IFNs (IFNα), and to a lesser extent Type II
human coronaviruses in the brain have been proposed to cause acute
* Corresponding author. Istituto Di Neuroscienze, Via Lamarmora 24, 50121, Florence, IT, Italy.
Received 1 July 2020; Received in revised form 6 August 2020; Accepted 12 August 2020
Available online 15 August 2020
0022-3956/© 2020 Published by Elsevier Ltd.
S. Pallanti et al.
Journal of Psychiatric Research 130 (2020) 215-217
and long-term sequelae, whereas their activities in prodromal or
pregnancy is associated with the later development of neuropsychiatric
asymptomatic phase are still unknown.
disorders in human offspring (Gumusoglu and Stevens, 2019).
COVID-19’s neurological symptoms - Approximately 40%-88% of
During infection, fetal villous tissues secrete a number of inflam
severe COVID-19 patients present with neurological symptoms (Mao
matory and immunoregulatory cytokines and chemokines, contributing
et al., 2020), along with neurodegeneration, neuroinflammation and
to their presence at the fetal-maternal interface. SARS-CoV-2 infection
demyelination signs (Zanin et al., 2020). However, we cannot assume
during pregnancy and childhood may lead to the manifestation of neu
that all neurological symptoms are a consequence of direct CNS
rodevelopmental disorders. Individuals exposed to SARS-CoV-2, as well
involvement and new sudden onset neurological manifestation should
as offspring of exposed mothers, should be assessed for neuropsychi
be considered. A Predominant Organ’s Involvement Model is necessary
atric, neuroimmune and inflammatory status in longitudinal studies to
to provide specific and timely interventions (Troyer et al., 2020). The
better understand the pathophysiology, and to allow for early
complexity of COVID-19’s pathology requires appropriate screening for
intervention.
neurological and psychosensorial manifestations in individuals testing
Neuro-behavioral sequelae and psychosocial support - Functional
positive for SARS-CoV-2, whether they have respiratory symptoms or
disability after Acute Respiratory Distress Syndrome represents a well-
are asymptomatic. One third of COVID-19 positive patients exhibit
known hazard (Margaret et al., 2011) but the neuro-behavioral sequa
anosmia, hyposmia and hypogeusia, occurring even in otherwise
lae of SARS-CoV-2 may not be detected by the common psychological
asymptomatic patients. Clinicians need to consider SARS-CoV-2’s direct
assessment and the concomitant support may be not enough. To counter
effects on the CNS and immune system.
the direct and indirect CNS harm inflicted by this virus including stress
Patient stratification: an important step forward
- Patients
and inflammation, a continuity between primary care, emergency
should be stratified according to neurological, psychosensorial, and in
medicine, inpatient treatment, and psychiatry is needed using clinical
flammatory status irrespective of the psychosocial consequences of
assessment at specific phases and stages (Fava et al., 2012). Studies
quarantine. Inflammatory markers should be assessed, including CBC
suggest that psychotherapy leads to measurable neuroimaging changes
with differential, hsC-reactive protein, D-dimer, lactate dehydrogenase,
associated with functional improvement (Barsaglini et al., 2014) and
transaminase, azotemia (uremia), creatinine, creatine kinase and IL-6.
psychosocial interventions may be associated with an improvement of
Peripheral cytokines involved in anti-viral responses may elicit neuro
beneficial immune system function and a decrease in harmful immune
psychiatric symptoms and neuroinflammatory responses (Troyer et al.,
system function, with changes persisting for at least 6 months following
2020). An increased secretion of pro-inflammatory cytokines and che
treatment (Shields et al., 2020)As seen in SARS (Severe acute respiratory
mokines such as IL-6, IFNγ, MCP1 and IP-10 are found in the blood of
syndrome) survivors, Ho-Bun Lam and colleagues (Lam et al., 2009)
COVID-19 patients (Tay et al., 2020). Hyperketonemia has also been
showed that many SARS survivors developed psychiatric morbidity that
reported. Interleukin (IL)-6, Tumor Necrosis Factor (TNF)-alpha, IL-8,
persisted at 4 year follow up, and many psychosocial factors (such as
IL-10, and IL-2R are significantly higher among fatal COVID-19 cases
being a health care worker at the time of infection, being unemployed
as reported for SARS-CoV-1’s infection (Tay et al., 2020; Yang et al.,
after recovery and having perception of social stigmatization) increased
2020). T-lymphocytes, expressing ACE2 Wang et al., 2020b, play a
the risk of developing psychiatric morbidity. More specifically, only
decisive role in maintaining immune homeostasis: lymphopenia and
3.3% of the SARS survivors who participated to the study had a history
increased neutrophil-lymphocyte ratio have been seen in approximately
of psychiatric disorders before contracting SARS; otherwise many pa
80% of SARS-CoV-2’s patients (Tay et al., 2020). Type I IFN deficiency is
tients experienced at least one psychiatric illness after SARS infection
a hallmark of severe COVID-19 and is present before their decline. These
(42.5%) and the main diagnoses included posttraumatic stress disorders
COVID-19 patients might benefit from IFN administration and from the
(54.5%), depression (39%), somatoform pain disorder (36.4%), panic
concomitant
exacerbated
inflammation
combined
with
disorder (32.5%) and obsessive-compulsive disorder (15.6%). The study
anti-inflammatory therapies targeting IL-6 or TNF-α. This intervention
suggests the use of specific instruments and trained personnel to
may serve as an example for why stratification of patients with markers
improve diagnostic evaluation and stratification. Even if the long-term
of their immune response is advantageous (Hadjadj et al., 2020).
outcome of Covid-19 is unknown at this time, patient stratification
Given all of the above evidence, it would be useful to search for
will allow for assessment of anti-inflammatory interventions (such as the
antibodies in the cerebrospinal fluid of those patients where CNS
use of fluoxetine, fluvoxamine, SSRI and trazodone) and a reduction of
involvement is strongly suspected.
stigma associated with mental health sequela of the disorder. Such
Basal ganglia dysfunction and related disorders as COVID-19
stratification utilizing an inflammatory panel, may help to tailor
sequelae - SARS-Cov-2 a beta-Coronavirus, which is in the order of
appropriate therapeutic and rehabilitative programs. While this was not
Nidovirales, member of the family Coronaviridae and subfamily Corona
done for SARS survivors, it is now time to do so for COVID-19 patients.
virinae
(Park, 2020), is associated with such central and peripheral
Also, psychosocial support should be an essential part of the patient’s
neurological effects as dizziness and headache as well as hypogeusia and
overall multidisciplinary medical treatment, and this would also reduce
hyposmia respectively (Dickman, 2001). Although different in mecha
the stigma of mental health treatment. Many individuals subject to
nism of action and clinical manifestations, an interesting parallelism in
lockdowns and social distancing may succumb to loneliness-associated
the neurological domain, could be drawn with other viruses, which are
elevated levels of markers for inflammation and an increased sensi
known for being associated with neurological symptomatology as in
tivity to negative social experiences (Eisenberger and Moieni, 2020).
Spanish Influenza Pandemic of 1918, and Encephalitis Lethargica, first
Although SARS-CoV-2 may stress several systems of the body in the
described by Constantine von Economo (Steardo et al., 2020). The
process of overcoming the infection including the brain, an individual’s
long-term sequelae of COVID-19 are still unknown but Basal Ganglia
response need not be pathological (Tedeschi and Calhoun, 2004). The
dysfunctions and related disorders seem to be present as outcomes,
net stress experienced by a given individual is not deterministic, but
given that basal ganglia and other structures are likely to be affected by
their response defines “subjective vulnerability” and “resilience char
aberrant hemorrhagic (Franceschi et al., 2020) or neuroinflammatory
acteristics” or what is called “post traumatic growth”.
processes in the central nervous system (Dickman, 2001).
Where do we go from here? - As of May 21st, there have been more
Implications of immune-inflammatory signaling
- Elevated
than 5.2 million cases (and 330 thousand deaths) worldwide resulting
immune-inflammatory signaling is a relevant mechanism to the patho
from the SARS-CoV-2 pandemic, and an effective vaccine is badly
etiology of mood disorders (Pfau and MénardScott, 2018). Another
needed. In developed nations with resources that are not available in
threat to the CNS is represented by inflammatory factors that specifically
most of Africa, some parts of Asia, and Latin America, it is time to utilize
impact neurodevelopment (Khandaker et al., 2014); convergent evi
all of the tools of modern medicine to assess the effects of this devas
dence suggests that exposure to the mother to inflammation during
tating virus on the human brain and it’s neurological, psychiatric, and
216
S. Pallanti et al.
Journal of Psychiatric Research 130 (2020) 215-217
psychosocial consequences (such as suicide prevention of COVID 19-
Mao, L., Jin, H., Wang, M., et al., April 10, 2020. Neurologic manifestations of
hospitalized patients with coronavirus disease 2019 in wuhan, China. JAMA Neurol.
infected healthcare workers, economic impact, and grief response in
family members). The direct effects of the virus (viremia), immune-
Margaret, S Herridge, Catherine, M Tansey, Matté, Andrea, George, Tomlinson, Diaz-
mediated response, and sequelae from ACE2 positive cell destruction
Granados, Natalia, Cooper, Andrew, Guest, Cameron B., Mazer, C David,
Mehta, Sangeeta, Stewart, Thomas E., Paul, Kudlow, Cook, Deborah, Arthur, S
(blood clots, stroke) need to be considered. Beyond testing for viral RNA
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Park, S.E., 2020. Epidemiology, virology, and clinical features of severe acute respiratory
dinated response by the different branches of medicine. “After 40 years,
syndrome - coronavirus-2 (SARS-CoV-2; Coronavirus Disease-19). Clin Exp Pediatr
psychiatry is becoming more mindless than brainless, perhaps digital
phenotyping will help the pendulum swing back toward a fresh look at
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behavior, cognition, and mood” (Insel, 2017). There is no better time
disorders: therapeutic opportunities. Mad. Ann. Rev. Pharmacol. Toxicol. 58,
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Oct 6.
Shields, Grant S., Spahr, Chandler M., Slavich, George M., 2020. Psychosocial
Author contribution
interventions and immune system function: a systematic review and meta-analysis of
SP developed the idea, and all authors made a substantial contri
Steardo, L., Steardo Jr., L., Zorec, R., Verkhratsky, A., 2020. Neuro infection may
bution to the development and writing of this article. SP, acting as
contribute to pathophysiology and clinical manifestations of COVID-19. Acta
corresponding author, had the final responsibility for the decision to
Tay, M.Z., Poh, C.M., Rénia, L., MacAry, P.A., Ng, L.F.P., 2020. The trinity of COVID-19:
submit for publication.
immunity, inflammation and intervention. Nat. Rev. Immunol. 1-12. https://doi.
Declaration of competing interest
Troyer, E.A., Kohn, J.N., Hong, S., 2020. Are we facing a crashing wave of
As authors, we declare no competing interests.
neuropsychiatric sequelae of COVID- 19? Neuropsychiatric symptoms and potential
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