Review

Neuropsychiatric Burden of SARS-CoV-2: A Review of Its

Physiopathology, Underlying Mechanisms, and
Management Strategies
Aliteia-Maria Pacnejer 1,2 , Anca Butuca 2, * , Carmen Maximiliana Dobrea 2 , Anca Maria Arseniu 2 ,
Adina Frum 2 , Felicia Gabriela Gligor 2 , Rares Arseniu 3 , Razvan Constantin Vonica 2 ,
Andreea Loredana Vonica-Tincu 2 , Cristian Oancea 4 , Cristina Mogosan 5 , Ioana Rada Popa Ilie 6 ,
Claudiu Morgovan 2 and Cristina Adriana Dehelean 1,7

1 Department of Toxicology, Drug Industry, Management and Legislation, Faculty of Pharmacy, “Victor Babeş”
University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timişoara, Romania;
[email protected] (A.-M.P.); [email protected] (C.A.D.)
2 Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania;
[email protected] (C.M.D.); [email protected] (A.M.A.); [email protected] (A.F.);
[email protected] (F.G.G.); [email protected] (R.C.V.);
[email protected] (A.L.V.-T.); [email protected] (C.M.)
3 County Emergency Clinical Hospital “Pius Brînzeu”, 300723 Timis, oara, Romania; [email protected]
4 Department of Pulmonology, Center for Research and Innovation in Personalized Medicine of Respiratory
Diseases, University of Medicine and Pharmacy “Victor Babes, ”, 300041 Timis, oara, Romania; [email protected]
5 Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Hatieganu”
University of Medicine and Pharmacy, 400029 Cluj-Napoca, Romania; [email protected]
6 Department of Endocrinology, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy,
3-5 Louis Pasteur Street, 400349 Cluj-Napoca, Romania; [email protected]
7 Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of
Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timişoara, Romania
* Correspondence: [email protected]

Citation: Pacnejer, A.-M.; Butuca, A.; Abstract: The COVID-19 outbreak, caused by the SARS-CoV-2 virus, was linked to significant neuro-
Dobrea, C.M.; Arseniu, A.M.; Frum, logical and psychiatric manifestations. This review examines the physiopathological mechanisms
A.; Gligor, F.G.; Arseniu, R.; Vonica, underlying these neuropsychiatric outcomes and discusses current management strategies. Primarily
R.C.; Vonica-Tincu, A.L.; Oancea, C.; a respiratory disease, COVID-19 frequently leads to neurological issues, including cephalalgia and
et al. Neuropsychiatric Burden of migraines, loss of sensory perception, cerebrovascular accidents, and neurological impairment such as
SARS-CoV-2: A Review of Its
encephalopathy. Lasting neuropsychological effects have also been recorded in individuals following
Physiopathology, Underlying
SARS-CoV-2 infection. These include anxiety, depression, and cognitive dysfunction, suggesting a
Mechanisms, and Management
lasting impact on mental health. The neuroinvasive potential of the virus, inflammatory responses,
Strategies. Viruses 2024, 16, 1811.
and the role of angiotensin-converting enzyme 2 (ACE2) in neuroinflammation are critical factors
https://doi.org/10.3390/v16121811
in neuropsychiatric COVID-19 manifestations. In addition, the review highlights the importance
Academic Editor: Daniele Focosi of monitoring biomarkers to assess Central Nervous System (CNS) involvement. Management
Received: 30 October 2024 strategies for these neuropsychiatric conditions include supportive therapy, antiepileptic drugs, an-
Revised: 20 November 2024 tithrombotic therapy, and psychotropic drugs, emphasizing the need for a multidisciplinary approach.
Accepted: 20 November 2024 Understanding the long-term neuropsychiatric implications of COVID-19 is essential for developing
Published: 21 November 2024 effective treatment protocols and improving patient outcomes.

Keywords: SARS-CoV-2; neuropsychiatric manifestations; COVID-19; neuroinflammation; pharma-

cotherapy; biomarkers; long COVID-19
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
1. Introduction
Attribution (CC BY) license (https:// In late 2019, several cases of an unknown form of pneumonia emerged in Wuhan,
creativecommons.org/licenses/by/ China, rapidly spreading across Asia and then all over the globe. The outbreak was ulti-
4.0/). mately confirmed to be caused by a new type of coronavirus [1–3]. It caused symptoms

Viruses 2024, 16, 1811. https://doi.org/10.3390/v16121811 https://www.mdpi.com/journal/viruses

Viruses 2024, 16, 1811 2 of 26

similar to those of the severe acute respiratory syndrome (SARS) in 2003, caused by severe
acute respiratory syndrome coronavirus 1 (SARS-CoV-1) [4]. The severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) virion has four structural proteins: the S (spike)
glycoprotein, responsible for the spikes of the virus; the envelope (E) protein; the mem-
brane (M) protein; and a nucleocapsid with helical symmetry (N) [5]. In vivo, SARS-CoV-2
interacts with the angiotensin-converting enzyme 2 (ACE2) via the outer membrane “S”
protein. Peripheral ACE2 contributes to angiotensin II conversion, impacting blood pres-
sure regulation, while in the central nervous system, ACE2 plays multiple roles in brain
injury recovery, stress response, and memory function [6,7]. The SARS-CoV-2 genome is a
single-stranded ribonucleic acid (RNA) molecule, which makes the virus more susceptible
to mutation and rapid adaptation, allowing it to spread from one species to another [8–11].
The genome sequence of SARS-CoV-2 can cause the dysregulation of cytokine activity,
i.e., an alteration of the immune response [11,12]. Also, several studies have shown that
patients infected with SARS-CoV-2 develop hyperinflammatory syndrome associated with
increased circulating cytokine levels, like TNFα and IL-6.
In February 2020, WHO named the SARS-CoV-2-induced infection as the “new Coron-
avirus Disease 2019” (COVID-19) [13]. Although COVID-19 is primarily classified as an
acute respiratory syndrome, it may also cause dysfunction of several organs and systems,
particularly the central and peripheral nervous systems, given the virus’s ability to impact
multiple organs. This happens particularly in patients who develop severe forms of the
disease, where an excessive inflammatory cascade can be observed, disrupting the function
of vital organs (cytokine storm), with subsequent bleeding disorder, low oxygen levels,
liver impairment, septicemia, and acute kidney impairment (AKI). As far as neurological
manifestations are concerned, these are often seen in COVID-19 patients, and range from
light and non-specific symptoms, like headache, dizziness, fatigue, myalgia, anosmia,
and ageusia, to more serious events such as stroke, delirium, coma, and encephalopa-
thy [14–23]. Further studies show that a considerable number of COVID-19 patients face
persistent neuropsychiatric alterations that can lead to mood changes like depression,
anxiety, post-traumatic stress disorder (PTSD), and decreased cognitive function [24–28].
Various neurological symptoms can represent initial signs of COVID-19 and can
develop in patients with or without underlying disease [29–31].
The development of neurological symptoms during hospitalization in patients with
severe SARS-CoV-2 infection, as well as a history of neurological conditions, are associated
with a higher mortality in COVID-19 disease [32–35]. Pre-existent metabolic syndromes,
older age, and a dysregulated immune response are also key risk factors for increased
severity and mortality due to COVID-19 infection [23]. The neuropsychiatric effects of
SARS-CoV-2, like depression and cognitive impairment, highlight the need for comprehen-
sive care, as similar inflammatory and lifestyle-related mechanisms are seen in conditions
such as ischemic heart disease. For example, inflammatory responses and stressors associ-
ated with COVID-19 disease can worsen mood disorders and cognitive function, just as
depression exacerbates outcomes in ischemic heart disease patients. This parallel suggests
that COVID-19 patients, especially those experiencing both neuropsychiatric and systemic
symptoms, could benefit from management strategies that address both mental health
and physical well-being [36,37]. However, the pathways leading to such neuropsychiatric
alterations in COVID-19 and their long-term consequences are still a topic for debate among
researchers [38–40].
Different studies suggested a higher negative impact on mental health during COVID-
19 in the low- and middle-income countries compared to high-income countries. Often,
poor mental health support facilities represent the main cause of the increased incidence of
neurologic and psychiatric disorders (e.g., depression, anxiety, neurocognitive disorders,
etc.) [41–43].
However, it was not only the infection that caused damage, but lockdown had a
negative impact on mental health during pandemic, too. Thus, a higher number of cases of
psychiatric disorders as depression, anxiety, insomnia, etc., were reported. Also, ADHD
Viruses 2024, 16, 1811 3 of 26

was reported more frequently in children because of school closures. Additionally, burnout
was frequently reported in healthcare professionals during this pandemic [44].

2. Classification and Underlying Factors of COVID-19 Disease

Neurological and neuropsychiatric involvement has been widely reported with
COVID-19 and can occur both in the acute phase of the disease and in the post-infection
recovery period. According to National Institute for Health and Care Excellence (NICE),
COVID-19 can be classified into three distinct phases, starting from the time of infection
and the onset of symptoms:
1. acute phase of COVID-19 infection: first 4 weeks after disease onset [45,46];
2. subacute phase of COVID-19: this includes manifestations occurring between weeks
4 and 12 after the onset of the acute phase [46,47];
3. chronic phase of COVID-19: this category includes symptoms that last for more than
12 weeks after the acute phase onset, and which are not consistent with a different
diagnosis [48,49].
Post-COVID-19 syndrome is an umbrella term for symptoms, signs, and conditions
persisting or appearing 4 weeks after the acute phase of infection. Patients experience
persistent symptomatology following the SARS-CoV-2 infection that cannot be related to
any other disease [46,49]. Post-COVID-19 syndrome is a complex condition with symptoms
and mechanisms that have yet to be fully understood. Some studies suggest that high levels
of D-dimer, C-reactive protein, and the presence of lymphopenia may be associated with
an increased susceptibility to develop post-COVID-19 symptoms [50–53]. An abundance
of studies has been identified in the literature which mention neurological symptoms of
post-COVID-19.
One of the most important determinants of the neurological and psychiatric outcomes
in COVID-19 patients is host immunity. The direct cytopathic effects of SARS-CoV-2
can lead to significant neurological damage and dysfunction, manifesting as a range of
neurological sequelae. These sequelae are often exacerbated by neuroinflammation, which
contributes to neurological and psychiatric symptoms.
Another key factor is the expression of ACE2 and other receptors. Systemic inflam-
mation and the cytokine storm induced by SARS-CoV-2 infection can cause endothelial
dysfunction and vasculopathy [54]. Dysregulation of the renin–angiotensin–aldosterone
system (RAAS) may also contribute to neurological manifestations. The SARS-CoV-2 virus
enters host cells by binding to the S protein and ACE2. This results in endothelial inflamma-
tion, endothelial and mitochondrial dysfunction, and inactivation of endothelial nitric oxide
synthetase (eNOS), the enzyme responsible for nitric oxide (NO) production [55]. This can
lead to the deregulation of the renin–angiotensin and kinin–kinase systems, affecting both
cardiovascular and cerebrovascular balance [56].
The endothelium dysfunction produced by SARS-CoV-2 infection can aggravate ad-
verse events such as inflammation and microvascular thrombosis in severe cases, including
pulmonary thrombosis complications [57].
Viral factors, such as mutations and variants of the SARS-CoV-2 virus, play an impor-
tant role too. These factors can lead to coagulopathy and thrombosis, which are critical
pathological processes underlying many neurological complications [58]. These complica-
tions include the same wide range of neurological symptoms seen in neuroinflammation
and RAAS dysregulation.
Other factors include pre-existing neurodegenerative diseases, like dementia or Parkin-
son’s disease, where the SARS-CoV-2 infection may exacerbate the underlying disease and
lead to more severe outcomes, such as cerebrovascular events, due to thrombotic microan-
giopathy and hypercoagulable state, and anxiety [59,60].
The main proposed pathways by which SARS-CoV-2 infection may lead to neuropsy-
chiatric manifestations, are summarized in Figure 1.
 Other factors include pre-existing neurodegenerative diseases, like dementia or Par-
kinson s disease, where the SARS-CoV-2 infection may exacerbate the underlying disease
and lead to more severe outcomes, such as cerebrovascular events, due to thrombotic mi-
croangiopathy and hypercoagulable state, and anxiety [59,60].
Viruses 2024, 16, 1811 The main proposed pathways by which SARS-CoV-2 infection may lead to neuro- 4 of 26
psychiatric manifestations, are summarized in Figure 1.

Figure 1. Proposed pathways of neuropsychiatric manifestations in SARS-CoV-2 infection.

Figure 1. Proposed pathways of neuropsychiatric manifestations in SARS-CoV-2 infection.
3. Physiopathology of Neuropsychiatric Presentations Associated with
3. Physiopathology
COVID-19 Disease of Neuropsychiatric Presentations Associated with
COVID-19 Disease
The pathophysiology of COVID-19 involves complex interactions between oxidative
stressTheandpathophysiology
inflammation, with of COVID-19 involves
viral binding complex
to ACE2 interactions
initiating betweenand
endothelial oxidative
mito-
stress anddysfunction
chondrial inflammation,thatwith viral binding
exacerbates to ACE2 initiating
the production endothelial
of reactive and mitochon-
oxygen species, further
drial dysfunction
promoting that exacerbates
a pro-inflammatory statethe
andproduction
endothelialofdamage.
reactiveTheoxygen species,
cytokine stormfurther pro-
observed
inmoting
severe acases
pro-inflammatory
of COVID-19 leadsstatetoand endothelial
a cascade damage.
of systemic The cytokine
inflammation, storm observed
endotheliosis, and
ain severe cases of
prothrombotic COVID-19 highlighting
environment, leads to a cascade
the roleofof
systemic
oxidative inflammation, endotheliosis,
stress and inflammation in
and a prothrombotic environment, highlighting the role of oxidative
the neurological and vascular complications associated with the disease [61]. stress and inflamma-
tionThe
in the neurologicalalterations
neurological and vascular complications
induced by COVID-19associated withare
disease thethe
disease
result[61].
of com-
The neurological
plex pathogenic alterations
mechanisms. Theseinduced
include byviral
COVID-19 disease are
neuroinvasion, the result
causing directofneuronal
complex
pathogenic
damage, mechanisms. These
cerebrovascular include
hypoxia, viral neuroinvasion,
ischemia, causing direct
increased inflammation, andneuronal
increased dam-
co-
age, cerebrovascular
agulability. hypoxia, ischemia,
Typical neurological findingsincreased
indicate inflammation,
damage to theand increased
nervous coagula-
system, both
bility. and
central Typical neurological
peripheral, findings
the most indicate damage
seen symptoms to the nervous
being dizziness, system,
headache, both central
hyposmia, and
Viruses 2024, 16, x FOR PEER REVIEW 5 of 28
and peripheral,
dysgeusia. Figurethe most seen
2 presents thesymptoms
impact of the being dizziness,infection
SARS-CoV-2 headache, onhyposmia,
the nervous and dys-
system
and its associated
geusia. manifestations.
Figure 2 presents the impact of the SARS-CoV-2 infection on the nervous system
and its associated manifestations.

Figure
Figure2.2.The
Theimpact
impactofofthe
theSARS-CoV-2
SARS-CoV-2infection
infectionon
onthe
thenervous
nervoussystem
systemand
andthe
theresulting
resultinginju-
injuries.
ries.

3.1. Experimental Studies

Animal studies have provided valuable insights into the mechanisms by which
SARS-CoV-2 may affect the CNS and contribute to neurological symptoms. Experiments
on mice, particularly those genetically modified to overexpress ACE2 receptors, allow re-
searchers to observe the virus s ability to invade the brain, disrupt the BBB, and impact
various neural cells. These studies are crucial for understanding the virus s neurotropism,
Viruses 2024, 16, 1811 5 of 26

3.1. Experimental Studies

Animal studies have provided valuable insights into the mechanisms by which SARS-
CoV-2 may affect the CNS and contribute to neurological symptoms. Experiments on mice,
particularly those genetically modified to overexpress ACE2 receptors, allow researchers to
observe the virus’s ability to invade the brain, disrupt the BBB, and impact various neural
cells. These studies are crucial for understanding the virus’s neurotropism, the immune
response within the CNS, and potential neurodegenerative effects, offering important
knowledge that can complement clinical findings in human studies.
Experiments in which the SARS-CoV-2 virus was administered intranasally to ACE2
overexpressing mice were able to demonstrate the neurotropism of the virus in the brain [62].
Furthermore, the spike protein of the virus crossed the blood–brain barrier (BBB) and
reached the parenchyma by adsorptive transcytosis, a vesicle-dependent transport mech-
anism [63]. Also, microglia have been found to play a role in the process of synapse
elimination that leads to memory deficits following a viral infection [64,65].

3.2. Clinical Studies

The literature describes various pathways for SARS-CoV-2 penetration into the Central
Nervous System (CNS), in particular, retrograde transport through peripheral nerves and
viruses entering the brain through the olfactory pathway that supposed the invasion of the
virus in the nasal neuroepithelium, the olfactory bulb, and its cortical projections [66–69].
After its binding by the olfactory nerve terminals, the virus is internalized by endocytosis.
Then, it is transported to different brain regions through the circulatory system crossing
the blood–brain barrier (BBB) [70,71].
This can be achieved either through the endothelial cells, through the migration of
infected leukocytes, or by reaching the cerebrospinal fluid (CSF) through the epithelial cells
of the choroid plexus [70].
Experiments in which SARS-CoV-2 was administered intranasally to ACE2 overex-
pressing mice were able to demonstrate the neurotropism of the virus in the brain [62].
In mice, the spike protein of the virus crossed the blood–brain barrier (BBB) and reached
the parenchyma by adsorptive transcytosis, a vesicle-dependent transport mechanism
(Figure 3) [63].
Certain studies suggest that SARS-CoV-2 may be responsible for infecting neurons
as well as astrocytes, therefore leading to neurodegeneration. Furthermore, extensive
protein expression and infectious viral fragments were found in SARS-CoV-2-infected
neutrospheres and brain organoids. This suggests that SARS-CoV-2 can not only infect
these cells, but also replicate within them, potentially leading to cell death and loss of
synapses in neurons. Most studies in the literature also indicate that brain infiltration by
the SARS-CoV-2 virus or its viral proteins might, potentially, cause neurological deficits in
infected individuals, although it is known that coronaviruses are not primarily neurotropic
viruses [25,62,72–74].
Viruses 2024, 16, x FOR PEER REVIEW 6 of 28

Viruses 2024, 16, 1811 individuals, although it is known that coronaviruses are not primarily neurotropic viruses
6 of 26
[25,62,72–74].

Figure 3. 3.
Figure Proposed underlying
Proposed mechanisms
underlying forfor
mechanisms thethe
neurological aspects
neurological ofof
aspects COVID-19 disease
COVID-19 [75].
disease [75].

Viralinfections
Viral infectionsofofthe thebrain
braincan
cancause
cause temporary
temporary or or long-term neurological
neurological or orpsychi-
psy-
atric dysfunction, like anxiety or depression, and motor deficits. Furthermore,
chiatric dysfunction, like anxiety or depression, and motor deficits. Furthermore, inflam- inflammation
in theinbrain
mation and an
the brain andabnormal
an abnormalinflammatory
inflammatory response
responsecan can
disrupt
disruptneuron function
neuron function and
cause
and causelong-term
long-term deficits,
deficits,resulting
resultingin impaired
in impaired synapses
synapses andandmemory
memory [64,65,76,77].
[64,65,76,77].
Microgliacells
Microglia cellsare
areaa type
type of
of glial
glialcell
cellfound
found throughout
throughout thethe
brain, spinal
brain, cord,cord,
spinal the retina,
the
and the olfactory bulb. They serve as the primary and most crucial
retina, and the olfactory bulb. They serve as the primary and most crucial line of active line of active immune
defensedefense
immune in the CNS in theandCNS areand
essential for normal
are essential CNS function,
for normal during both
CNS function, development
during both de-
and response to injury. They also regulate different inflammation
velopment and response to injury. They also regulate different inflammation responses, responses, including
repair, cytotoxicity, regeneration, and immunosuppression,
including repair, cytotoxicity, regeneration, and immunosuppression, through different through different activation
states or states
activation phenotypes [78–82]. [78–82].
or phenotypes
InIn thecontext
the contextofofneurodegeneration,
neurodegeneration, microglia
microglia areare involved
involved inin both
both protective
protective and
and
potentially harmful processes because they can release proinflammatory
potentially harmful processes because they can release proinflammatory cytokines, which cytokines, which
can
can contribute
contribute to to
thethe progression
progression of neurodegenerative
of neurodegenerative disease,
disease, but but
theythey can also
can also helphelp
to
to clear neuronal debris and damaged neurons, which is beneficial. Dysregulation of
clear neuronal debris and damaged neurons, which is beneficial. Dysregulation of micro-
microglial function has been implicated in several neurodegenerative diseases, including
glial function has been implicated in several neurodegenerative diseases, including Alz-
Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis [76,77,79,83]. Also, the
heimer s disease, Parkinson s disease, and multiple sclerosis [76,77,79,83]. Also, the pro-
process called “microglia priming” is the process by which microglial cells change their
cess called “microglia priming” is the process by which microglial cells change their mor-
morphology and become a primary source of inflammatory cytokines [84]. It is known that
phology and become a primary source of inflammatory cytokines [84]. It is known that
microglia and macrophages express ACE2 but most blood immune cells do not, suggesting
microglia and macrophages express ACE2 but most blood immune cells do not, suggest-
other receptors like toll-like receptors (TLRs) may be involved in the inflammatory response
ing other receptors like toll-like receptors (TLRs) may be involved in the inflammatory
in COVID-19 disease [85–87].
response in COVID-19 disease [85–87].
Another type of glial cell that contributes to the development of neurological injury
Another type of glial cell that contributes to the development of neurological injury
and age-related cognitive decline is the astrocytes, which have been shown to be incredibly
and age-related
diverse in theircognitive
functions. decline is the astrocytes,
This heterogeneity which
means thathave been shown
astrocytes to be incredi-
play different roles in
bly
brain health and pathology, and their functions may change as the brain ages [88].roles
diverse in their functions. This heterogeneity means that astrocytes play different Astro-
incytes
brainarehealth and pathology, and their functions may change as
involved in processes such as supporting neuronal function, contributing to the brain ages [88]. As-the
trocytes
integrityareofinvolved
the BBB,inregulating
processesblood
such as supporting
flow, neuronalregulation,
neurotransmitter function, contributing
neuronal repair to
the integrity
and scarring, of and
the BBB, regulatingfor
are responsible blood flow, neurotransmitter
producing neurotrophic factors regulation, neuronal re-
and anti-inflammatory
pair and scarring, and are responsible for producing neurotrophic
cytokines, like interleukin (IL)-10 [89–92]. On the other hand, reactive astrocytes factors and anti-inflam-
are astro-
matory
cytes that morphologically, molecularly, and functionally remodel in response toastrocytes
cytokines, like interleukin (IL)-10 [89–92]. On the other hand, reactive CNS injury
are
orastrocytes that morphologically,
infection, when molecularly,
certain proinflammatory and
factors arefunctionally
released in theremodel in response
microglia, to
specifically
complement component 1q (C1q), IL-1α and tumor necrosis factor alpha (TNFα). These
factors elicit the functional change of astrocytes into A1 reactive astrocytes, which are harm-
Viruses 2024, 16, 1811 7 of 26

ful and release a toxic factor which kills neurons and oligodendrocytes. This remodeling
has been known for over a century, but there is still uncertainty and controversy regarding
the role of reactive astrocytes in CNS disorders, recovery, and senescence [93–100].
SARS-CoV-2 infection has been shown in several brain autopsy studies to be respon-
sible for a local inflammatory response, microglial activation, signs of hypoxia, cerebral
infarcts, and infection of astrocytes, which may lead to impaired neuronal viability and
therefore explain some of the neurological symptoms associated with COVID-19, such
as fatigue, depression, and “brain fog” [25,62,101–104]. Astrocyte activation, along with
increased levels of biomarkers of CNS injury such as neurofilament light chain (NfL), glial
fibrillary acidic protein (GFAP) and total tau protein, were also observed in the CSF of
patients with COVID-19 and were correlated with disease severity and duration of intensive
care [105–108].
The CNS has unique immune responses compared to peripheral tissues due to its
specialized structure and function and the BBB plays a crucial role in shaping these re-
sponses [109]. As a response to the infection, proinflammatory cytokines are released
and several studies suggest that TNFα, IL-1β, and IL-6 are significantly increased during
infections and can cause learning and memory impairments. Also, TNF and IL-1β are
incriminated to disrupt the BBB, while IL-1β is linked to the degeneration of dopaminergic
neurons and cognitive impairments, highlighting the role of inflammation in neurodegen-
erative processes [109–111].
However, cytokines like interferon-gamma (IFN-γ) and IL-4 play an essential role
in maintaining normal cognitive and social behaviors. Disruptions in the balance of
these cytokines during infections can lead to behavioral alterations and neuropsychiatric
symptoms [112–114].
One of the most important proinflammatory cytokines involved in mediating the
inflammatory response within the CNS are TNFα and IL-6 [115–117]. TNFα acts through
two separate surface receptors (TNF-R 1 and TNF-R 2) and is responsible for the cellular
stress response mechanism [115,118]. Central upregulation of TNFα has been linked to
dopaminergic neuron death, cognitive dysfunction, memory impairment, and disruption
of the BBB, facilitating the entry of leukocytes into the CNS [64,117,119].
In brain homeostasis, IL-6 is present in low concentrations, but during CNS infection el-
evated IL-6 levels are responsible for memory and cognitive impairment [120,121]. In SARS-
CoV-2 infection, IL-6 and TNFα are linked to disease progression and severity, prompting
research into treatments targeting these cytokines [122,123]. Some findings suggest that
IL-6 can be a crucial biomarker for monitoring and potentially predicting the progression
of severe COVID-19 pneumonia [124–126]. The effects of key cytokines, including TNFα,
IL-1β, IL-6, IFN-γ, and IFN-α, on neurotransmitter pathways and neuronal activity during
SARS-CoV-2 infection are summarized in Supplementary Materials—Table S1 [127–136].

4. Inflammatory Response, Cognitive Impairment and Neuropsychiatric Manifestations

Associated with COVID-19 Disease
In 2020, the first retrospective analysis was conducted on 214 patients in Wuhan, which
found that 36.4% of patients exhibited neurological symptoms [137]. These symptoms were
classified into CNS, peripheral nervous system, and skeletal muscle injuries.
Neurological manifestations have been reported in around 80% of patients hospi-
talized with COVID-19 [138], and patients with severe COVID-19 are at a higher risk
of developing neurological complications, although the specific underlying mechanisms
remain unclear [16].
Psychiatric disorders such as schizophrenia augmented the risk of COVID-19 infection
and mortality, the risk of severe infections increasing during exposure to antipsychotic
drugs [139]. Moreover, schizophrenia could be one of the post-COVID-19 sequelae. Thus,
Baranova et al. suggested that the risk of schizophrenia was increased by 11% in severe
COVID-19 patients [140]. Also, different studies showed that patients with ADHD have an
increased risk of infection and of the severe COVID-19 symptoms [141,142].
 Psychiatric disorders such as schizophrenia augmented the risk of COVID-19 infec-
tion and mortality, the risk of severe infections increasing during exposure to antipsy-
chotic drugs [139]. Moreover, schizophrenia could be one of the post-COVID-19 sequelae.
Viruses 2024, 16, 1811
Thus, Baranova et al. suggested that the risk of schizophrenia was increased by 11% in
8 of 26
severe COVID-19 patients [140]. Also, different studies showed that patients with ADHD
have an increased risk of infection and of the severe COVID-19 symptoms [141,142].
Although in patients with autism, the long COVID-19 symptoms are difficult to di-
Although in patients with autism, the long COVID-19 symptoms are difficult to
agnose and manage [143]; aberrant behaviors of autistic patients are related to their
diagnose and manage [143]; aberrant behaviors of autistic patients are related to their
mother s anxiety level. Thus, a worsening of the behavior was correlated with a high level
mother’s anxiety level. Thus, a worsening of the behavior was correlated with a high level
of anxiety in the patients mothers [144].
of anxiety in the patients’ mothers [144].
Other retrospective studies reported that one in three COVID-19 survivors were di-
Other retrospective studies reported that one in three COVID-19 survivors were
agnosed with a neuropsychiatric condition within six months of infection, with 13% of
diagnosed with a neuropsychiatric condition within six months of infection, with 13% of
them being
them being first-time
first-time diagnoses
diagnoses [28,145].
[28,145].
In an
In an observational
observational study
study of
of 43
43 patients
patients infected
infected with
with SARS-CoV-2,
SARS-CoV-2, Paterson
Paterson etet al.
al.
described the main neurological symptoms of COVID-19 disease: encephalopathy,
described the main neurological symptoms of COVID-19 disease: encephalopathy, which which
is sometimes
is sometimes linked
linked to
to episodes
episodes ofof delirium
delirium andand psychosis;
psychosis; CNS
CNS inflammatory
inflammatory syndromes
syndromes
such as acute disseminated encephalomyelitis (ADEMs); parainfectious andand
such as acute disseminated encephalomyelitis (ADEMs); parainfectious postinfec-
postinfectious
tious encephalitis; myelitis; ischemic stroke commonly complicated by
encephalitis; myelitis; ischemic stroke commonly complicated by pulmonary thromboem- pulmonary throm-
boembolic
bolic events, events, and Guillain-Barré
and Guillain-Barré syndrome
syndrome (GBS)(GBS)
[146]. [146].
An Italian study reported that 78% of COVID-19 survivors
An Italian study reported that 78% of COVID-19 had cognitive
survivors had cognitive deficits,
deficits, and
and
36% experienced depressive symptoms linked to inflammation [26].
36% experienced depressive symptoms linked to inflammation [26]. The inflammatory The inflammatory re-
sponse is a common factor in neurodegenerative conditions and mood
response is a common factor in neurodegenerative conditions and mood disorders such as disorders such as
major depressive disorder, where stress can exacerbate inflammation.
major depressive disorder, where stress can exacerbate inflammation. The most frequentThe most frequent
neurological symptoms
neurological symptoms determined
determined by by the
the SARS-CoV
SARS-CoV infection
infection described
described in
in the
the literature
literature
are represented
are represented in in Figure
Figure 4.
4.

Neurological manifestations
Figure 4. Neurological manifestations of
of the
the SARS-CoV
SARS-CoV infection
infection described
described inin the
the literature.
literature.
disseminated encephalomyelitis;
ADEM—acute disseminated encephalomyelitis; AHLE—acute
AHLE—acute hemorrhagic leukoencephalitis;
leukoencephalitis;
MOGAD—myelin oligodendrocyte
MOGAD—myelin glycoprotein antibody-associated
oligodendrocyte glycoprotein antibody-associated disease;
disease; PIMS-TS—pediatric
PIMS-TS—pediatric
inflammatory multisystem
inflammatory multisystem syndrome;
syndrome; PRES—posterior
PRES—posterior reversible
reversible encephalopathy
encephalopathy syndrome.
syndrome.

Some studies in the literature reported that COVID-19 patients with neurological disor-
ders show anti-SARS-CoV-2 antibodies in the CSF [23,147,148]. For example, immunoglobulin-
G (IgG) antibodies were present in the CSF of all patients with encephalopathy [148], while
another study showed a low prevalence of anti-SARS-CoV-2 antibodies in COVID-19
patients [149].
Viruses 2024, 16, 1811 9 of 26

The role of BBB selectivity is to protect the brain from circulating blood cells and to
maintain CNS homeostasis. Systemic infection and inflammation can alter the permeability
of the barrier, allowing cytokines and inflammatory mediators to enter the CNS, promoting
neuroinflammation and neurodegeneration [150].
Some post mortem assays of COVID-19 patients have found undetectable or extremely
low concentrations of SARS-CoV-2 RNA in their CSF [63,151–155]. In addition, abnormali-
ties on brain magnetic resonance imaging (MRI), in particular leptomeningeal enhancement,
and increased inflammatory markers CSF, are common in COVID-19 patients with neuro-
logical symptoms [156]. Jarius et al. found dysfunction of the BBB in 50% of patients with
no history of CNS disease [157].
Exposure to the SARS-CoV-2 spike glycoprotein S1 in microglia, mononuclear blood
cells, and macrophages triggers the production of proinflammatory cytokines, such as
TNFα, IL-8, IL-1β, and IL-6 [158–160]. Furthermore, treatment with a TLR4 antagonist in
murine macrophages attenuated the proinflammatory cytokine induction and intracellular
signaling activation by S1, suggesting that TLR4 signaling appears to play a crucial role
in inducing inflammatory responses, including neuroinflammation [159,161–164]. Other
studies suggest that the “S” protein activates the nuclear factor kappa-B (NF-κB) pathway
via TLR2 in a MyD88-dependent manner. This pathway plays a crucial role in the cytokine
storm observed during COVID-19 [165,166].

5. Acute Neuropsychiatric Complications of COVID-19

In terms of severe acute COVID-19 complications, these comprise ischemic or hemor-
rhagic stroke, hypoxic-anoxic injuries, PRES, and acute disseminated myelitis, as well as the
occurrence of neuromuscular disorders, such as GBS, which can lead to persistent or even
permanent neurological impairment [138]. A study examining the medical records of more
than 40,000 COVID-19 patients revealed that 22.5% had neurological and/or psychiatric
complaints, of which anxiety and related disorders were the most common [167].
There are also reports in the literature of psychotic episodes in patients during the acute
phase of COVID-19. One study found that the most common neuropsychiatric syndrome
was early psychosis, followed by other associated psychiatric disorders [168,169]. In a
Spanish cohort of COVID-19 inpatients, approximately 20% presented neuropsychiatric
symptoms, including insomnia, anxiety, depression, and psychosis [17]. Case reports
have also documented the presence of manic and psychotic symptoms in patients with
COVID-19 who had no prior psychiatric diagnosis [170,171].
The most frequently reported acute symptoms of COVID-19 in the literature, together
with the possible associated pathophysiology, are presented in Table 1.

Table 1. Most common acute symptoms of COVID-19 disease.

Acute Symptoms of
Possible Associated Pathophysiology
COVID-19 Disease
Nasal congestion, resulting in the loss of fine olfactory receptor cell endings, making them unable to detect
odors [172–174];
SARS-CoV-2 virus predominantly colonizes the patients’ nasal cavity, triggering inflammation in the
Anosmia, Ageusia
olfactory nerves and causing structural damage to the receptors [173,175,176];
High expression of ACE2 receptors in the tongue cells as compared to other mouth tissues makes them
more susceptible to viral binding [177–179].
SARS-CoV-2 can infect nerve cells in the myelencephalon, which is responsible for regulating several basic
Neurogenic functions of the autonomic nervous system, including respiration, cardiac function and vasodilation [180];
respiratory failure Involved secondary mechanism due to increased inflammatory markers like TNFα and IL-8, which have
been associated with pleocytosis [181].
Viruses 2024, 16, 1811 10 of 26

Table 1. Cont.

Acute Symptoms of
Possible Associated Pathophysiology
COVID-19 Disease
GBS may be caused by the neuroinvasion of SARS-CoV-2, causing the side effect of
demyelination [18,182–184];
GBS The viral infection may trigger an exaggerated immune response via molecular mimicry, which leads to the
demyelination of peripheral nerves [185];
First GBS case in a COVID-19 patient reported in January 2020 [186].
The most common neurological complication seen in COVID-19 patients from Intensive C [18,187];
Symptoms: restlessness, confusion, delirium [188–190];
Can occur in less severe cases, affecting young adults [191];
The first case of acute necrotizing hemorrhagic encephalopathy associated with COVID-19 was reported in
Encephalopathy
2020 [192];
The base mechanism involves the onset of cytokine storm in the brain, leading to BBB dysfunction [193];
Cases of toxic metabolic encephalopathy were also reported in the literature [191], with risk factors
including age, male gender, diabetes, pre-existing conditions [194].

6. Chronic Neuropsychiatric Symptoms and Post-Recovery

There are several neurological and psychiatric diseases known to be mediated by a neu-
roinflammatory process, like the one described for COVID-19. The molecular mechanisms
causing this inflammation may have a considerable impact on the development and pro-
gression of neurodegenerative diseases, but also of psychiatric disorders, especially mood
disorders, as their pathogenesis also involves neuroinflammatory mechanisms. Research to
date has associated increased levels of C-reactive protein with the incidence of cognitive
deficits post-infection in patients who have recovered. This would suggest a possible role of
inflammation in the cognitive deficit reported by this group of post-recovery patients [195].
Maamar et al. found that patients who had elevated serum levels of inflammatory markers,
such as C-reactive protein, neutrophil-to-lymphocyte ratio, neutrophils, and fibrinogen
exhibited prolonged COVID-19 symptoms [196].
According to the National Academies of Sciences, Engineering, and Medicine in
2024, long COVID-19, also known as post-acute sequelae of SARS-CoV-2 infection, is
defined broadly as signs, symptoms, and conditions that continue or develop after the
initial phase of COVID-19 infection. These manifestations persist for four weeks or more,
can be multisystemic, and may exhibit a relapsing-remitting pattern with potential for
progression or worsening over time. This term encompasses various health issues that
might have different biological causes and risk factors and unfortunately, there are currently
no consensus-based diagnostic criteria for long COVID-19 [197].
Although evidence for a causal link between COVID-19-associated neuroinflammation
and the onset of psychiatric disorders remains limited, it is nevertheless possible that this
category of patients with neuroinflammatory impairment may be more likely to develop
depression, anxiety, and long-term PTSD [198–200].
One can also hypothesize about the long-term CNS effects of COVID-19 based on the
physiopathological mechanisms implicated in the development of long-term neuropsy-
chiatric disorders associated with SARS-CoV-1 and Middle East respiratory syndrome
(MERS). A study of SARS-CoV-1 survivors showed that 55% of them experienced PTSD,
39% developed depression, over 32% experienced panic disorder, and 15.6% exhibited an
obsessive-compulsive disorder [201].
Mood disorders, mainly depression, are also more common in post-infection COVID-
19 patients than in those recovering from influenza or other respiratory tract infections [28].
In patients with long COVID-19 syndrome, including those who have not been hospi-
talized, at least one persistent neuropsychiatric symptom has been reported [202].
In 2022, about 6.9% of adults and 1.3% of children in the U.S. experienced long COVID-
19 at some point. By January 2023, the prevalence among U.S. adults was recorded at
5.9%, which increased to 6.8% by January 2024, demonstrating a continuing and significant
Viruses 2024, 16, 1811 11 of 26

burden of the disease. Although the overall prevalence has decreased since mid-2022, long
COVID-19 still presents a substantial health burden. Approximately 22% of adults with
long COVID-19 reported significant activity limitations as of January 2024 [197]. The most
frequent long COVID-19 symptoms reported in the literature are presented in Table 2 [197].

Table 2. Common long COVID-19 symptoms reported in the literature according to the consensus
study report 2024 of the National Academies of Sciences, Engineering, and Medicine [197].

Category Long COVID-19 Symptoms

Cognitive dysfunction (brain fog);
Headaches;
Dizziness;
Concentration difficulties;
Memory impairments;
Mood changes;
Tinnitus;
Neuropsychiatric Visual disturbances;
Chronic fatigue syndrome;
Parosmia;
Anosmia;
Sleep disorders;
Anxiety;
Depression;
Fibromyalgia.
Shortness of breath;
Chronic cough;
Respiratory
Pulmonary complications;
Breathlessness.
Chest pain;
Palpitations;
Cardiovascular Tachycardia;
Endothelial dysfunction;
Coagulation disorders.
Nausea;
Diarrhea;
Loss of appetite;
Gastrointestinal Weight loss;
Gastroesophageal reflux disease;
Irritable bowel syndrome;
Gut dysbiosis.
Muscle weakness;
Musculoskeletal Joint pain;
Musculoskeletal pain.
Post-exertional malaise;
Rash;
Sore throat;
Hair loss;
Pins and needles sensation;
Painful lymph nodes;
Swelling in extremities;
Other Reduced exercise tolerance;
Bladder control issues;
Sexual dysfunction;
Persistent hiccups;
Endocrine dysfunction;
Kidney dysfunction;
Immune dysregulation;
Mast Cell Activation Syndrome.
Viruses 2024, 16, 1811 12 of 26

A retrospective cohort study was conducted in 1,284,437 COVID-19 patients over

two years. The study found that after six months, most patients still faced a significantly
increased risk of neurological damage. Additionally, there were but a few conditions, such
as encephalitis, GBS, nerve and plexus damage, and Parkinson’s disease that did not show
an increased incidence among COVID-19 patients. At the same time, the incidence of
cognitive deficits, dementia, psychiatric disorders, epilepsy, and seizures was still high
even after two years. Children were at greater risk of developing cognitive deficiencies,
insomnia, intracranial hemorrhage, ischemic stroke, nervous disorders, epilepsy, or seizures,
while adults were more likely to develop common psychiatric disorders [203]. As multiple
studies have shown, the symptoms of COVID-19 infection in children are less severe than
in the adult population. Also, older age is associated with an increased risk of long-term
symptoms [204]. Another characteristic of the pediatric population is that patients with
multisystem inflammatory syndrome (MIS) have a higher prevalence of long COVID,
including neurologic and psychiatric symptoms, compared to patients without MIS [205].
Over a longer follow-up period, neurological and psychiatric symptoms due to long COVID
were observed to decrease. Symptoms due to long COVID in children seem to be reversible,
even though in some cases it may take a long time [205].

7. Diagnosis of COVID-19 Neuropsychiatric Manifestations and Biomarkers Used to

Monitor Neurological and Psychiatric Alterations in COVID-19 Patients
Clinical assessment is an important step in diagnosing neuropsychiatric symptoms in
patients with COVID-19 disease. This involves a series of laboratory tests needed to rule
out other diagnoses such as metabolic disorders, CNS infections, and psychiatric disorders.
If the symptoms are consistent with focal neurological deficits, or if there is a suspicion
that they may be associated with COVID-19 disease, a brain MRI is strongly recommended.
As for the diagnostic criteria for mood disorders such as major depressive disorder
and anxiety disorders in COVID-19 patients, they do not differ from the standard criteria
used in their diagnosis.

7.1. Biomarkers
Monitoring neurological and psychiatric changes in patients with COVID-19 requires
a complex approach that includes clinical assessment, neuroimaging, and evaluation of spe-
cific biomarkers associated with CNS dysfunction and psychological distress. Biomarkers
play an important role in establishing the diagnosis, but also in predicting disease severity.
Multiple studies have examined serum biomarkers in order to evaluate the nature of
CNS injury. Plasma NfL (pNfL), an intra-axial structural protein, is a validated biomarker
for detecting neuro-axial injury, while plasma GFAP (pGFAP) is an astrocytic cytoskeletal
protein that is overexpressed in activated astrocytes [206–209]. Both markers, including
also other CSF biomarkers and ubiquitin C-terminal hydrolase L1 (UCH-L1), have been
shown to be elevated in the acute phase of SARS-CoV-2 infection, suggesting that CNS
damage is linked to neuronal impairment and astrocyte activation during acute infec-
tion [105,210–214].
Furthermore, additional studies in the literature support the relation between GFAP
levels and the development of severe disease in COVID-19 patients. GFAP is a glial
cytoskeletal protein mainly expressed in astrocytes, which regulates the morphology and
function of these cells in the CNS [215–217]. Serum levels of GFAP in healthy patients
are very low, but in case of neuronal injury, GFAP levels increase [99,216]. To date, there
are no specific biomarkers for the SARS-CoV-2 infection. However, several biomarkers
are commonly used to assess the severity of COVID-19, the inflammatory response and
potential complications. The most common non-specific biomarkers, used to monitor
neurological and psychiatric impairment in COVID-19 disease and that are described in
the literature, are listed in Table 3.
Viruses 2024, 16, 1811 13 of 26

Table 3. Non-specific biomarkers used to monitor neurological and psychiatric impairments in

COVID-19 disease.

Biomarker Description
Neurological Impairment
Neuronal cytoskeletal protein released into the CSF and blood following neuronal injury or
degeneration;
NfL
Elevated in COVID-19 patients with neurological complications;
Indicates CNS involvement and progression.
Calcium-binding protein expressed predominantly in astrocytes and oligodendrocytes;
S100B protein Increased levels indicate glial activation and neuroinflammation;
Reflects severity of neurological complications in COVID-19, including BBB dysfunction.
Includes protein levels, cell counts, and inflammatory markers like IL-6, IL-8, TNF-α;
Other CSF biomarkers
Diagnosis and characterization of neuroinflammatory disorders in COVID-19.
UCH-L1 levels were higher in patients needing ICU transfer;
UCH-L1
UCH-L1 linked to neuronal injury.
Psychiatric Impairment
Brain-derived neurotrophic factor Neurotrophin involved in neuronal survival, synaptic plasticity and mood regulation;
(BDFN) Low levels associated with psychiatric symptoms in COVID-19.
Elevated cytokine levels, including IL-6, TNFα, and IFN-γ were associated with mood
Peripheral cytokine profiles
disorders, cognitive impairment, and psychosis in COVID-19 patients.

7.2. Imagistic Investigations

Together with specific biomarkers, neuroimaging plays an important role in observing
microstructural changes with implications for cognitive function and neuro-psychiatric
outcomes. Thus, in COVID-19 patients with neurological manifestations, neuroimaging
could detect underlying causal pathology.
Neuroimaging helps specialists to observe the microstructural changes in cognitive
function and neurological outcomes in COVID-19 patients. Thus, different neuroimaging
techniques dominated by MRI, computed tomography (CT), and positron emission tomog-
raphy (PET) could be used in evaluating the abnormalities attributable to hypoxic, vascular,
and inflammatory pathology. Advanced neuroimaging revealed cerebral abnormalities
of olfactory system, cortical hypoperfusion, BBB leakage, white matter microstructural
integrity alterations, altered glucose metabolism in the COVID-19 brain, acute ischemic
stroke, cerebral venous thrombosis, and meningoencephalitis. [30,218–220].

7.3. Psychological Tools

Different tools were used for the evaluation of the mental status of the patients with
COVID-19 such as:
• COVID-19 Stress Scale for understanding the distress associated with COVID-19 and
for identifying people in need of mental health services. Based on 36 items, the scale
identifies 5 factors: (1) danger, (2) fears about economic consequences, (3) xenophobia,
(4) compulsive checking and reassurance seeking, and (5) traumatic stress symptoms
about COVID-19.
• Depression, Stress and Anxiety Scale 21, a self-report questionnaire based on 21 questions,
• Generalized Anxiety Disorder-7 questionnaire for evaluation of the generalized anxiety
symptoms during the 2 weeks (based on the Likert Scale),
• The COVID-19 Peritraumatic Distress Index contains 24 items regarding the anxiety,
depression, specific phobias, cognitive change, avoidant and compulsive behaviors,
physical symptoms and loss of social functioning in the past week (based on the Likert
Scale) [221,222].
Viruses 2024, 16, 1811 14 of 26

8. Pharmacotherapy of Neuropsychiatric Disorders and Management Strategies

Associated with COVID-19
The primary treatment for most neuropsychiatric events associated with COVID-19
is supportive therapy. A multidisciplinary approach is essential to effectively manage the
comorbidities of COVID-19 patients.
A retrospective UK study of 184,986 adult hospitalized patients revealed that patients
cotreated with dexamethasone and remdesivir experienced fewer neurological events such
as strokes, seizures, encephalitis, or meningitis compared with those receiving standard
treatment [223].
Also, in patients with severe COVID-19 who received either dexamethasone or remde-
sivir or their combination, a reduction in neurological manifestations was observed.
The effects of other drugs on reducing neurological impairment, such as tocilizumab,
ritonavir, baricitinib, or nirmatrelvir, which have been effective in treating SARS-CoV-2
infection, have not yet been reported. However, these drugs in turn target inflammation or
viral replication and are expected to have a similar effect on neurological complications.
Likewise, seizures were reduced in COVID-19 patients with severe disease who were
administered either dexamethasone or remdesivir or a combination of the two. Incidence of
meningitis and/or encephalitis events also decreased in the severe disease groups following
dexamethasone or combination therapy, which suggests the possible benefit of reducing
CNS inflammatory events.
Therefore, the management of neurological and psychiatric manifestations of COVID-
19 involves a tailored approach based on specific symptoms. In patients presenting with
acute neurological complications, such as encephalitis or stroke, antiepileptic drugs, an-
tithrombotic therapy, and supportive therapy, respectively, may be indicated depending
on the clinical presentation. Psychiatric symptoms, including anxiety, depression, and
psychosis, may require initiation of serotonin-norepinephrine reuptake inhibitors (SNRIs),
selective serotonin reuptake inhibitors (SSRIs), or antipsychotic drugs. However, particular
attention should be paid to potential drug interactions and adverse effects, especially in
patients with underlying medical conditions or who use concomitant medication [224].
However, more research is needed to corroborate this. Immunization programs have
been successful in significantly decreasing the incidence and severity of COVID-19 cases.
Several clinical studies performed in post-vaccination COVID-19 infections concluded that
the use of the vaccine is associated with a lower risk of hypercoagulopathy or venous
thromboembolism, seizures, or psychotic disorder especially after the second vaccine
dose [225]. Also, a reduction in the risk of neuropsychiatric disorders involved in post-
vaccinated COVID-19 patients was reported [226]. Moreover, the key finding of a recent
study published in June 2024, was that the median self-reported time to recovery from
SARS-CoV-2 infection was approximately 20 days, 1 in 5 COVID-19 patients had not fully
recovered from the infection after 90 days, and interestingly, vaccination before the infection
and infection with an Omicron variant was associated with shorter recovery times [227].
While adenovirus vaccines have been associated with a small number of neurological
disorders, such as GBS, studies suggest that the risk of neurological events caused by
SARS-CoV-2 infection greatly exceeds the risk following vaccination [228]. Evidence from
a recent meta-analysis suggests that vaccination lowers the risk of developing post-COVID-
19 disease, with patients who received two vaccine doses showing a significantly lower risk
compared to those who remained unvaccinated. Nevertheless, further investigations are
needed in order to improve the treatment of comorbidities associated with a severe form of
COVID-19 disease and thus to reduce the risk of neurological complications [229].
Figure 5 describes the management and diagnostic approaches for the key neurological
sequelae in SARS-CoV-2 infection (Supplementary Materials—Table S2) [230].
Viruses 2024, 16, x FOR PEER REVIEW 16 of 28
Viruses 2024, 16, 1811 15 of 26

Figure
Figure 5.
5. Management
Managementand
anddiagnostic
diagnosticapproaches
approachesfor
forneurological
neurologicalsequelae
sequelaeininSARS-CoV-2
SARS-CoV-2 infec-
infection
tion [224].[224].

9. Conclusions
9. Conclusions
The SARS-CoV-2
The SARS-CoV-2 virus virus has
has aa profound
profound impact
impact beyond
beyond its
its primary
primary respiratory
respiratory mani-
mani-
festations, significantly affecting the central and peripheral nervous systems.
festations, significantly affecting the central and peripheral nervous systems. This review This review
highlights the
highlights the wide
wide range
range ofof neurological
neurological andand psychiatric
psychiatric symptoms associated with
symptoms associated with
COVID-19, from
COVID-19, from mild
mild conditions
conditions such
such as
as headache
headache and
and anosmia
anosmia to to severe
severe complications
complications
such as stroke and encephalopathy. Long-term neuropsychiatric
such as stroke and encephalopathy. Long-term neuropsychiatric disorders, disorders, including
including cog-
cognitive dysfunction, anxiety, and depression, highlight the long-term
nitive dysfunction, anxiety, and depression, highlight the long-term consequences of consequences of
SARS-CoV-2 infection.
SARS-CoV-2 infection.
Understanding the underlying mechanisms of these neuropsychiatric manifestations
Understanding the underlying mechanisms of these neuropsychiatric manifestations
is critical. Key factors include the ability of the virus to invade the CNS, the resulting
is critical. Key factors include the ability of the virus to invade the CNS, the resulting in-
inflammatory response and the role of ACE2 receptors in neuroinflammation. The review
flammatory response and the role of ACE2 receptors in neuroinflammation. The review
also highlights the importance of specific biomarkers in diagnosing and monitoring CNS
also highlights the importance of specific biomarkers in diagnosing and monitoring CNS
involvement, which can guide treatment strategies.
involvement, which can guide treatment strategies.
Effective management of the neurological and psychiatric effects of COVID-19 requires
Effective management of the neurological and psychiatric effects of COVID-19 re-
a multidisciplinary approach combining supportive care with targeted pharmacological
quires a multidisciplinary approach combining supportive care with targeted pharmaco-
treatments. Further research into these mechanisms and management strategies is essential
logical treatments. Further research into these mechanisms and management strategies is
to improve patient outcomes and address the long-term mental health effects of COVID-19.
essential to improve patient outcomes and address the long-term mental health effects of
Neuropsyciatric implications must be considered when developing health strategies. Not
COVID-19. Neuropsyciatric implications must be considered when developing health
at least, further studies would be helpful to fill the gap regarding the developing of the
strategies. Not at least,
neuropsychiatric further
symptoms instudies would
different be helpful
populations, or to fill the gap
regarding theregarding the de-
neuropsychiatric
veloping
outcomesofinthe neuropsychiatric
vaccinated symptomspopulation
or non-vaccinated in differentcompared
populations, or regarding
to other the neu-
viral infections.
ropsychiatric outcomes in vaccinated or non-vaccinated population compared to other vi-
ral infections. Materials: The following supporting information can be downloaded at: https:
Supplementary
//www.mdpi.com/article/10.3390/v16121811/s1, Table S1: The effects of cytokines on neurotrans-
mitter pathways and neuronal activity; Table S2: Therapeutic management of COVID-19 disease,
according to NICE guidelines, version May 2024.
Viruses 2024, 16, 1811 16 of 26

Author Contributions: Conceptualization, A.-M.P., A.B., F.G.G., C.M. (Cristina Mogosan) and C.A.D.;
methodology, A.-M.P., A.B., A.F., C.M.D., A.M.A., A.L.V.-T., C.M. (Claudiu Morgovan) and C.A.D.;
software, A.-M.P., R.A., A.F., C.M.D., R.C.V., I.R.P.I. and C.M. (Claudiu Morgovan); validation, C.O.,
F.G.G., C.M. (Cristina Mogosan), I.R.P.I. and C.A.D.; formal analysis, A.-M.P., A.B., A.M.A., A.F. and
A.L.V.-T.; investigation, A.-M.P., A.B., A.F., C.M.D., R.A., R.C.V. and L.V; resources, A.-M.P., A.B.,
F.G.G. and C.A.D.; data curation, C.M.D., A.F., C.M (Claudiu Morgovan)., R.A., I.R.P.I., A.L.V.-T.,
C.M. (Cristina Mogosan) and C.A.D.; writing—original draft preparation, A.-M.P., A.B., C.M.D.,
A.F., A.M.A., R.A. and R.C.V. writing—review and editing, A.L.V.-T., C.O., F.G.G., C.M. (Cristina
Mogosan), C.M. (Claudiu Morgovan) and C.A.D.; visualization, A.-M.P., A.B., C.M.D., A.M.A., A.F.,
F.G.G., R.A., R.C.V., A.L.V.-T., C.O., C.M. (Cristina Mogosan), I.R.P.I., C.M. (Claudiu Morgovan)
and C.A.D.; supervision, C.O., F.G.G., C.M. (Cristina Mogosan) and C.A.D.; project administration,
A.-M.P., A.B. and C.A.D.; funding acquisition, A.-M.P., A.B. and C.A.D. All authors have read and
agreed to the published version of the manuscript.
Funding: The project financed by Lucian Blaga University of Sibiu through the research grant
LBUS-IRG-2023/No. 3523, 24 July 2023.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data contained within the article.
Conflicts of Interest: The authors declare no conflicts of interest.

Abbreviations

ACE2 angiotensin-converting enzyme 2

ADEM acute disseminated encephalomyelitis
AHLE acute hemorrhagic leukoencephalitis
AKI acute kidney injury
BBB blood-brain barrier
BDNF brain-derived neurotrophic factor
BP blood pressure
B12 vitamin B12
C1q complement component 1q
CNS central nervous system
COVID-19 Coronavirus Disease 2019
CRP C-reactive protein
CSF cerebrospinal fluid
CT computed tomography
CXR chest X-Ray
EEG electroencephalogram
EMG electromyography
eNOS endothelial nitric oxide synthetase
ESR erythrocyte sedimentation rate
FBC full blood count
GBS Guillain-Barré syndrome
GFAP glial fibrillary acidic protein
HbA1C hemoglobin A1c
IgG immunoglobulin G
ICU intensive care unit
IFN-γ interferon-gamma
IL interleukin
LFTs liver function tests
MERS Middle East Respiratory syndrome
MIS multisystem inflammatory syndrome
MOGAD myelin oligodendrocyte glycoprotein antibody-associated disease
MRI magnetic resonance imaging
NCS nerve conduction studies
NfL neurofilament light chain
Viruses 2024, 16, 1811 17 of 26

NICE National Institute for Health and Care Excellence

NO nitric oxide
OP opening pressure
PCR polymerase chain reaction
pGFAP plasma glial fibrillary acidic protein
PIMS-TS pediatric inflammatory multisystem syndrome
pNfL plasma neurofilament light chain
PRES posterior reversible encephalopathy syndrome
PTSD post-traumatic stress disorder
RAAS renin-angiotensin-aldosterone system
RNA ribonucleic acid
SARS severe acute respiratory syndrome
SARS-CoV-1 severe acute respiratory syndrome coronavirus 1
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
SNRI serotonin-norepinephrine reuptake inhibitors
SSRI selective serotonin reuptake inhibitors
TFTs thyroid function tests
TLR toll-like receptor
TNFα tumor necrosis factor-alpha
UCH-L1 Ubiquitin C-Terminal Hydrolase L1
U&Es urea and electrolytes
WCC white cell count
WHO World Health Organization

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