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International Journal of Psychiatry in Clinical Practice
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ijpc20
Presentation and management of anxiety
in individuals with acute symptomatic or
asymptomatic COVID-19 infection, and in the post-
COVID-19 recovery phase
Genoveva Uzunova, Stefano Pallanti & Eric Hollander
To cite this article: Genoveva Uzunova, Stefano Pallanti & Eric Hollander (2021): Presentation
and management of anxiety in individuals with acute symptomatic or asymptomatic COVID-19
infection, and in the post-COVID-19 recovery phase, International Journal of Psychiatry in Clinical
Practice, DOI: 10.1080/13651501.2021.1887264
To link to this article: https://doi.org/10.1080/13651501.2021.1887264
Published online: 26 Feb 2021.
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REVIEW ARTICLE
Presentation and management of anxiety in individuals with acute symptomatic
or asymptomatic COVID-19 infection, and in the post-COVID-19 recovery phase
Genoveva Uzunova
a
, Stefano Pallanti
b,c
and Eric Hollander
d
a
Psychiatric Research Institute at Montefiore-Einstein, Albert Einstein College of Medicine, Bronx, NY, USA;
b
Istituto di Neuroscienze, Firenze,
Italy;
c
Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA;
d
Autism and Obsessive Compulsive Spectrum Program,
Department of Psychiatry and Behavioral Sciences, Psychiatric Research Institute at Montefiore-Einstein, Albert Einstein College of Medicine,
Bronx, NY, USA
ABSTRACT
COVID-19 is associated with neuropsychiatric complications, the most frequent one being anxiety.
Multiple biological and psychosocial factors contribute to anxiety in COVID-19. Among the biological fac-
tors, stress, genetics, gender, immune system, resilience, anosmia, hypogeusia, and central nervous system
infection with SARS-CoV-2 are key. Anxiety is a complication of COVID-19 that may exacerbate the infec-
tion course, and the infection may exacerbate anxiety. We present the mechanisms of anxiety in symp-
tomatic or asymptomatic COVID-19. We discuss the presentation of anxiety in patients without or with
prior psychiatric illness, and with co-morbidities. Timely diagnosis and management of anxiety in COVID-
19 patients is important. Given the frequent complication of COVID-19 with Acute Respiratory Distress
Syndrome and Intensive Care Unit stay, anxiety may be a long-term complication. We review the diagnos-
tic tools for anxiety in COVID-19, and summarise pharmacologic and non-pharmacologic treatments. We
provide recommendations for diagnosis, treatment, prevention and follow up of anxiety in COVID-19.
KEY POINTS
Patients with COVID-19 (symptomatic or asymptomatic) exhibit a high frequency of neuropsychiatric
complications with highest percentage attributed to anxiety.
Multiple biological and psychosocial risk factors for anxiety exist in COVID-19-ill individuals. Biological
risk factors include stress, resilience, genetics, gender, age, immune system, direct infection of the
central nervous system (CNS) with SARS-CoV-2, comorbid psychiatric and general medical illnesses,
ARDS and ICU stay. Anosmia and hypogeusia are COVID-19-specific anxiety risk factors. Knowledge of
the anxiety risk factors is essential to focus on timely interventions, because anxiety may be a compli-
cation of and exacerbate the COVID-19 course.
An inverse correlation exists between resilience and anxiety because of COVID-19, and therefore
efforts should be made to increase resilience in COVID-19 patients.
In COVID-19, important anxiety mechanism is neuroinflammation resulting from activation of the
immune system and an ensuing cytokine storm.
The general approach to management of anxiety in COVID-19 should be compassionate, similar to
that during trauma or disaster, with efforts focussed on instilling a sense of hope and resilience.
In selecting pharmacological treatment of anxiety, the stress response and immune system effects
should be key. Medications with cardio-respiratory adverse effects should be avoided in patients with
respiratory problems.
Anxiety is a disorder that will require for long-term follow up at least one month after COVID-19.
ARTICLE HISTORY
Received 5 November 2020
Revised 26 January 2021
Accepted 3 February 2021
KEYWORDS
Anxiety; COVID-19; immune-
inflammatory; acute
respiratory distress
syndrome; resilience; anti-
anxiety therapy
Introduction
Coronavirus disease 2019 (COVID-19) is a new serious viral upper
respiratory infectious disease, caused by the severe acute respira-
tory disease coronavirus-2 (SARS-CoV-2), which developed into a
pandemic in March 2020, and has a wide spectrum of clinical
manifestations, including neurologic and neuropsychiatric
(Steardo et al. 2020; Troyer et al. 2020; Jansen van Vuren et al.
2021). Similarly to previous coronavirus infections, Severe Acute
Respiratory Syndrome (SARS) and Middle East Respiratory
Syndrome (MERS) (Ahmed et al. 2020), COVID-19 may give rise to
anxiety but the magnitude of the complication is of greater
proportions, likely due to the nature of the SARS-CoV-2 infection
and the magnitude of the COVID-19 pandemic. There are abun-
dant reports in the biomedical literature of anxiety developing in
patients in the course of acute COVID-19 infection and in the
post-COVID-19 recovery period, which may worsen the disease
course and diminishes the quality of life of patients recovered
from COVID-19 (Kelly 2020; Nalleballe et al. 2020). While occa-
sional anxiety symptoms may be a normal reaction to external
and internal stimuli, persistent symptoms of anxiety will become
pathological and develop into an anxiety disorder when they
interfere with the functioning of the individual and cause distress
CONTACT Genoveva Uzunova Genoveva_uzunova@msn.com Psychiatric Research Institute at Montefiore-Einstein, Albert Einstein College of Medicine, Bronx,
NY, USA
ß2021 Informa UK Limited, trading as Taylor & Francis Group
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE
https://doi.org/10.1080/13651501.2021.1887264
(APA 2013). Given the seriousness and proportions of the compli-
cation of anxiety in COVID-19 patients, we review the presenta-
tion of anxiety in patients with acute symptomatic or
asymptomatic COVID-19 and in the recovery phase after viral
clearance. We included peer-reviewed original research papers
and reviews from the National Centre for Biotechnology
Information (NCBI) PubMed. Notably, in COVID-19, anxiety is often
co-morbid with psychiatric conditions, including depression, post-
traumatic stress disorder (PTSD), obsessive-compulsive disorder
(OCD), insomnia and delirium (Nalleballe et al. 2020; Rogers et al.
2020; Varatharaj, Thomas et al. 2020). Therefore, although we dis-
cuss anxiety, it is important to consider and manage these serious
co-morbid neuropsychiatric COVID-19 complications. Strikingly,
recent retrospective analyses of 62,354 COVID-19 patients in the
US reveal a bidirectional relationship between COVID-19 and psy-
chiatric illness, including anxiety: in COVID-19 patients without
prior psychiatric history there is a higher risk for a first psychiatric
diagnosis of anxiety, insomnia or dementia in the 14–90 days fol-
lowing infection, and individuals with prior psychiatric illness are
more likely to develop COVID-19 (Taquet et al. 2020). There is sig-
nificant anxiety during the COVID-19 pandemic, reflected in the
great number of scientific papers published within the last year.
Anxiety may affect the general population and individuals
infected with SARS-CoV-2. The focus of our narrative review is
only on anxiety in individuals with ascertained COVID-19 infection,
symptomatic or asymptomatic, and in the post-COVID-19 recovery
phase. The papers in PubMed on anxiety in COVID-19 are increas-
ing in number almost daily. Until 28 September 2020, we per-
formed a literature search with the terms ‘COVID-19’,‘patient’,
and ‘anxiety’, which retrieved 233 articles, 5 of which are clinical
trials, 2 –meta analyses, and 11 –reviews. All of the results, of
course, are within the last year. We also performed a PubMed
search with the terms ‘coronavirus’,‘patient’and ‘anxiety’which
retrieved references mostly within the last one year and five refer-
ences within the last 10 years. We searched for the terms ‘Acute
Respiratory Distress Syndrome (ARDS)’and ‘anxiety’and ‘COVID-
19’. The reason is that anxiety is often a sequela of ARDS even in
the absence of COVID-19 due to several factors, including lack of
sufficient oxygenation of the lungs (Hopkins et al. 2010). We per-
formed additional literature searches in the course of the review
for rating scales used to assess anxiety in COVID-19 patients,
including ‘Hospital Anxiety and Depression Scale (HADS)’,‘COVID-
19’and ‘anxiety’, and ‘HADS’and ‘coronavirus’. From the retrieved
articles, we selected for the review, based on the abstracts, those
articles that discuss only patients and individuals with COVID-19
in a hospital or community setting, mainly at home.
In this review, we also include papers from our observations of
neuropsychiatric issues in patients with COVID-19 (Fineberg, Van
Ameringen et al. 2020; Pallanti et al. 2020; Pallanti et al. 2020). We
focus mainly on anxiety in adults since at the time of this review,
is the largest population affected by COVID-19 (Boehmer et al.
2020). We discuss the causes, presentation, screening, diagnosis
and treatments for anxiety, and suggest guidelines for the man-
agement of anxiety in patients with acute symptomatic and
asymptomatic COVID-19, and in the recovery phase. At the time
of our review, most of the papers discuss the causes, presentation
and diagnosis of anxiety and less weight was given to treatments.
We present the treatments based on the literature and our own
experience with treatment of anxiety. Early screening and multi-
disciplinary interventions will be key to prevention of anxiety and
the associated neuropsychiatric complications in COVID-
19 patients.
The review focuses on anxiety in patients mostly with symp-
tomatic COVID-19 infection (hospitalised and at home isolation),
and in the recovery phase. Question remains whether there is a
greater risk for anxiety in symptomatic COVID-19 infection,
because of COVID-19 infection (respiratory failure, difficulty
breathing, anosmia and other infection symptoms that may cause
distress) and immunological factors (such as the cytokine storm
that may result in psychiatric disorders), as compared to the gen-
eral population. At present, the few published studies indicate
that anxiety is present both in asymptomatic and symptomatic
COVID-19 patients (Iqbal et al. 2020). This can be a subject of
future studies.
Overview of COVID-19 pandemic
The SARS-CoV-2 that is in the coronavirus family with the Severe
Acute Respiratory Syndrome coronavirus (SARS-CoV) and the
Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV),
caused in 2019 in Wuhan, China a novel respiratory infectious dis-
ease, COVID-19, which reached pandemic proportions in 2020 and
is associated with very high morbidity and mortality (Esakandari
et al. 2020; Garc
ıa2020). Currently according to the Centre for
Disease Control in the US COVID-19 is the likely the third leading
cause of death, after heart disease and cancer (Ellis 2021). We are
still learning about the SARS-CoV-2 and COVID-19, and there are
no definitive treatments. About nine vaccines against the SARS-
CoV-2 are being developed worldwide (Corum and Carl 2021),
two vaccines, the mRNA vaccines from Pfizer-BioNTech SE and
Moderna Inc are authorised for emergency use in the US by the
Food and Drug Administration (FDA 2021), and vaccinations of
groups at highest risk are underway in the US and other coun-
tries. However, vaccination for the two approved vaccines requires
two vaccinations spaced by several weeks, it will take time until
immunity develops in the individuals and the population as a
whole, and the vaccines are not of sufficient supply yet for all
individuals. On 6 January 2021, the daily hospitalisations from
COVID-19 in the USA were the highest during the pandemic
(Caspani and Szekely 2021). Recently several new SARS-CoV-2
virus variants emerged worldwide, a UK B.1.1.7 variant, detected
also in the USA, that is highly infectious, a South African variant
and a Brazil variant (CDC 2021). The disease course caused by
these the new virus strains, however, is believed to be similar to
that caused by the strain that caused the initial pandemic, and
the UK strain is believed to be susceptible to the approved cor-
onavirus vaccines by Pfizer-BioNTech SE and Moderna Inc. The
demographics of the affected populations are changing since the
beginning of the pandemic when older adults were mainly
affected. At present, the population affected by COVID-19 is
younger, including a lot of young adults and children (Boehmer
et al. 2020). In adults, symptomatic COVID-19 is characterised with
fever, cough, sore throat, dyspnoea, conjunctivitis, fatigue, and
gastrointestinal symptoms (diarrhea, nausea and vomiting), in
mild cases. More severe cases have pneumonia and cardiovascular
abnormalities. Severe cases have sepsis, ARDS, multiorgan failure,
and shock (Esakandari et al. 2020). The immune system is very
important in the severity and course of COVID-19, and in the
development of complications such as long COVID-19 (Brodin
2021). Frequently there are neurological and neuropsychiatric
abnormalities, including headache, confusion, memory loss, hypo-
geusia, anosmia, anxiety, seizures, Guillain-Barre syndrome,
encephalitis, and cerebrovascular stroke (Al-Sarraj et al. 2020;
Guadarrama-Ortiz et al. 2020; Speth et al. 2020). Children more
2 G. UZUNOVA ET AL.
frequently have asymptomatic infection and can have atypical
manifestations (Su et al. 2020; Brodin 2021).
Overview of the mechanisms of anxiety (Central
nervous system, CNS and non-CNS), neuroanatomy,
neurocircuitry and neurochemistry of anxiety, and the
roles of the immune system and neuroinflammation
Whereas the neurocircuitry and neuroanatomy of anxiety are
extensively studied in animal models and humans without COVID-
19 (Tovote et al. 2015; Robinson et al. 2019), there is not much
evidence from humans with COVID-19. Human studies of the anx-
iety neurocircuitry using neuroimaging reveal that the amygdala
are activated in response to disorder-relevant stimuli in PTSD and
phobias, and the insular cortex shows heightened activation in
many anxiety disorders (Shin and Liberzon 2010). Overall, the
brain regions involved in anxiety are subcortical regions, including
the bed nucleus of the stria terminalis (BNST), the amygdala and
the hippocampus, and their connectivity to cortical regions,
including the dorsal medial and lateral prefrontal/cingulate cortex,
and the insula (Robinson et al. 2019). Some of these regions over-
lap with the stress neurocircuitry, highlighting the role of stress in
anxiety (Awasthi et al. 2020). The cerebellum is implicated in the
anxiety neurocircuitry (Moreno-Rius 2018). The neurocircuitry of
anxiety in COVID-19 is expected to be similar to that identified to
date; however, we cannot exclude SARS-CoV-2 infection-specific
factors. In one recent study, quantitative diffusion tensor imaging
(DTI) of brain from six COVID-19 patients with ARDS in the
Intensive care unit (ICU), shows abnormalities in frontal, temporal,
parietal and occipital cortices and hippocampi, and inflammation
in several white matter tracts (Newcombe et al. 2021). These find-
ings suggest that there is vasogenic edoema in cortical white and
grey matter tracts, consistent with sepsis-associated encephalop-
athy (Newcombe et al. 2021). The widespread cortical and hippo-
campal abnormalities observed by DTI may explain the mental
status alterations in many COVID-19 patients. In these patients,
the mesencephalic and pontine reticular formation show quantita-
tive DTI signs of cytotoxic edoema, which may reflect inflamma-
tion resulting from direct SARS-CoV-2 infection (Newcombe et al.
2021). The involvement of brainstem arousal nuclei may provide
neuroanatomical substrates for anxiety and PTSD (Venkatraman
et al. 2017; Garcia-Rill 2019).
Different neurochemical substrates, neurotransmitters, including
GABA, monoamines (serotonin, dopamine, and norepinephrine),
glutamate, endocannabinoids and neuropeptides within the iden-
tified anxiety and fear circuits in brain are involved in anxiety,
which have been the basis for development of anti-anxiety medi-
cations (Adell 2010; Gonda et al. 2019). In addition, immunological
mechanisms and neuroinflammation contribute to anxiety (Felger
2018). Neuroimaging studies in humans suggest that cytokines
may exert effects in brain regions involved in anxiety, including
amygdala, insula and anterior cingulate cortex (Mehta et al. 2018).
The immune system and neuroinflammation are involved in
anxiety and depression, as shown in many studies (Felger 2018).
In patients with rheumatoid arthritis (RA), the levels of proinflam-
matory cytokines Interleukin-17 (IL-17), Tumour necrosis factor-
alpha (TNF-a) and Interleukin-6 (IL-6) are significantly elevated in
comparison with healthy controls (p¼0.016, p<0.001 and
p¼0.012 respectively) (Liu et al. 2012). Within the RA arthritis
group, IL-17 is significantly elevated only in the patients with anx-
iety, and there is a positive correlation between the severity of
anxiety and IL-17 levels, even after adjustment for the level of
pain and disease activity. The anxiety is measured using the
Hospital Anxiety and Depression Scale (HADS). Another study
finds that pregnant women with severe anxiety have higher levels
of IL-17A, and pregnant women with severe anxiety and severe
depression have higher levels of IL-17A, IL-17F and IL-2 (Leff
Gelman et al. 2019). The severity of anxiety is measured using the
Hamilton Anxiety Rating Scale, HARS, and the severity of depres-
sion –using the Hamilton Depression Rating Scale, HDRS.
Cultures of activated T cells from patients with generalised anxiety
disorder (GAD) produced a higher amount of Th17-derived pro-
inflammatory cytokines IL-17A and TNF-athan controls, and there
is deficiency in Th1 cytokines (Vieira et al. 2010). The authors
interpret these findings as evidence in support of the higher inci-
dence of infections in persons with GAD. Therefore, they have sig-
nificance for understanding the higher occurrence of anxiety in
COVID-19 patients, which may exacerbate the infection course.
However, in another study with adolescents, the serum levels of
IL-17 correlate negatively with anxiety (Pallavi et al. 2015). The
strong negative correlation of IL-17 with anxiety is an interesting
finding, which the authors attribute to the adolescent age group
studied, and the presence of both anxiety and depression. Further
studies are necessary to investigate the role of IL-17 in different
age groups and types of anxiety (Pallavi et al. 2015). It remains to
be shown that COVID-19 patients with anxiety have higher IL-17/
IL-17A, and if there is correlation between the levels of IL-17A
and the severity of anxiety. Given what is already known about
the role of IL-17 in anxiety in humans and mice, and the presence
of cytokine storm in COVID-19 with increased levels of IL-17 (Luo
et al. 2020; Shibabaw 2020), it can be hypothesised that IL-17
plays a pathogenetic role in anxiety in COVID-19 infection. The
mechanisms through which the immune system is involved in
COVID-19 in anxiety are investigated, and this will have signifi-
cance for development of treatments. Recent studies in mice find
a link between anxiety and IL-17a, produced by meningeal cdT
cells (Alves de Lima et al. 2020). These cells express the chemo-
kine receptor CXCR6 and produce IL-17a physiologically after
engaging of the T-cell receptor and commensal-derived signals.
Cortical glutamatergic neurons have IL-17a receptor, which when
genetically deleted, is associated with reduced anxiety.
In COVID-19, there are several mechanisms through which the
viral infection may induce neuroinflammation and release of
proinflammatory cytokines in brain (Jarrahi et al. 2020; Kempuraj
et al. 2020), which in turn may alter brain neurochemistry, neuro-
receptors and neurotransmitters that are involved in anxiety
(Steardo, Steardo et al. 2020;Ed
en et al. 2021). At present, there
are mainly hypotheses based on the presence of neuroinflamma-
tion and inflammatory markers in the cerebrospinal fluid
(CSF)(Farhadian et al. 2020). Future studies will have to investigate
this.
Factors contributing to anxiety in COVID-19 patients
The factors contributing to anxiety in COVID-19 patients can be
divided into biological and psychosocial (Figure 1). Both categories
of factors are specific for each individual patient. Among the bio-
logical factors,genetics,gender (female), stress and resilience are
key. Stress, through cortisol increases the levels of pro-inflamma-
tory cytokines and susceptibility to infection (Cohen et al. 2012).
Therefore, stress may weaken the resistance of the organism to
infection with SARS-CoV-2 and lead to more serious illness with
complications. Second, stress triggers anxiety (Jordan et al. 2020).
Anxiety may be due to direct CNS infection with SARS-CoV-2 since
coronaviruses can use the trans-olfactory route to enter the CNS
(Steardo, Steardo et al. 2020). It remains to be determined;
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 3
however, to what extent anxiety is a result of direct presence of
the virus in the CNS. So far, neuropathological findings in human
brain in COVID-19 are equivocal and may be due to direct infec-
tion and replication of SARS-CoV-2 in brain, or indirectly due to a
systemic toxic reaction, and/or a harmful immune response and
cytokine secretion because of viral infection (Al-Sarraj et al. 2020).
Patients with COVID-19 report anosmia (lack of smell) and
hypogeusia (lack of taste), which may cause anxiety for several
reasons. First, the patients report that they feel disconnected and
distant from the surrounding world, which may cause anxiety
(Pallanti et al. 2020). Second, this may be result of direct infection
of the CNS with SARS-CoV-2 and localisation in brain regions
within the anxiety neurocircuitry (Speth et al. 2020). In COVID-19
patients, Patient Health Questionnaire-2 (PHQ-2) and Generalised
Anxiety Disorder 2-item (GAD-2) showed that only severity of
taste or smell loss, and not other infection-associated symptoms
such as shortness of breath (SOB) were associated with anxiety
and depressed mood (Speth et al. 2020). Therefore, the emotional
disturbances may be viewed because of the trans-olfactory pene-
tration of the coronavirus. Anosmia and hypogeusia may be used
as early diagnostic markers for anxiety in COVID-19 patients.
Acute respiratory distress syndrome (ARDS) that develops as a
complication during the course of COVID-19 may cause anxiety in
the absence of coronavirus infection due to oxygen insufficiency
and other factors (Hopkins et al. 2010; Bienvenu et al. 2018;
Worsham et al. 2020). In one study, patients with ARDS are eval-
uated for anxiety, and associated depression and post-traumatic
stress disorder (PTSD) at 3, 6, 12, 24, 36, 48 and 50 months, using
the HADS (for anxiety and depression), and the Impact of Event
Scale –Revised (IES-R, for PTSD) (Bienvenu et al. 2018). A propor-
tion of the patients have prior psychiatric disorder, including
depression, nicotine, alcohol and drug use. From 186 participants,
96 (52%) showed continuous prolonged symptoms, namely 71
(38%) –prolonged anxiety (56 with recurring, and 15 –with con-
tinuous symptoms), 59 (32%) –prolonged depression, and 43
(23%) –prolonged PTSD. The median duration of these conditions
was 33–39 months. Female gender, Caucasian race and lower edu-
cational level were associated with greater anxiety. Presence of
mental illness and stress prior to the ARDS also increased the like-
lihood for anxiety as a complication of ARDS. The three domains
(anxiety, depression and PTSD) tended to co-occur.
In COVID-19, pathological activation of monocytes/macro-
phages and lymphocytes may cause a cytokine storm, which may
result in lung injury, ARDS, and further release of pro-inflamma-
tory cytokines (Hojyo et al. 2020; Mulchandani et al. 2020). They
may cause anxiety through an IL-17 mechanism and additionally
through ARDS and oxygen insufficiency (Bienvenu et al. 2018;
Shibabaw 2020). The SARS-CoV-2 infection may have four differ-
ent stages ranging from mild, common, severe and critical, which
are characterised with different cytokine profiles (Huang et al.
2020; Yi et al. 2021). Many pro-inflammatory cytokines, including
IL-6, TNF, IL-17, Il-1, IL-2, IFN-c, G-CSF and MCP-1 (macrophage
inflammatory protein 1) are elevated in mild and especially in
severely ill COVID-19 patients (De Biasi, Meschiari et al. 2020;
Ghazavi et al. 2021; Wang et al. 2020a). However, the precise cyto-
kine changes in every disease stage are not well defined yet, and
the cytokine storm cannot likely account for all cases of anxiety in
mild or asymptomatic cases. It is known that IL-6 is probably
responsible for the cytokine storm that causes organ damage in
severe and critical COVID-19 (Yi et al. 2021). Most likely, the
pathogenesis of anxiety will be result of several factors, acting in
combination. Other biological factors are pre-existing health con-
ditions such as mental illness or another general medical condi-
tion such as diabetes, uncertainty due to a novel infectious
disease with high morbidity for which there are not effective
treatments, and reduction in physical activity. The presence of
psychiatric conditions, including anxiety (Plunkett et al. 2020),
depression, bipolar disorder, substance abuse, eating disorders
(Termorshuizen et al. 2020), or schizophrenia (Liu et al. 2020), may
predispose to greater anxiety associated with COVID-19.
It is important to have in mind possible iatrogenic causes of
anxiety in patients with COVID-19. Certain medications for man-
agement of COVID-19, and psychotropic medications particularly,
may cause anxiety, as an undesirable adverse effect. Therefore,
they will have to be used with caution in patients with COVID-19.
Long-term use of benzodiazepines for treatment of anxiety may
cause anxiety after discontinuation (rebound), indirectly, by
impairing sleep, and may cause delirium (Chouinard 2004).
Therefore, in such instances, non-benzodiazepine anxiolytics
should be substituted as a treatment (Nuss et al. 2019). In add-
ition, corticosteroid treatments are reported to correlate with anx-
iety in COVID-19 patients (Liu et al. 2020), which is expected due
to the effects of corticosteroids on the hypothalamic-pituitary-
adrenal (HPA) axis.
Psychosocial factors include uncertainty of the course of a viral
disease, stigma, fear of infecting others, isolation, lack of access to
Figure 1. Factors contributing to anxiety in patients with COVID-19.
4 G. UZUNOVA ET AL.
healthcare, income and job loss because of the coronavirus pan-
demic (Guo et al. 2020).
Presentation of anxiety in COVID-19 patients
Anxiety disorders have common features of excessive anxiety and
fear and related behavioural disturbances (APA 2013). Anxiety dis-
orders may include somatic symptoms, including dizziness, dys-
pnoea, chest pain, hyperventilation, confusion, fatigue, muscle
tension, gastrointenstinal problems, insomnia and agitation. These
may overlap with symptoms of COVID-19 and are difficult to dis-
tinguish. In this respect, using appropriate anxiety rating scales,
such as the Hospital Anxiety and Depression Scale –Anxiety
(HADS-A), Generalised Anxiety Disorder-2 or 7 scale (GAD-2 or
GAD-7)(Sapra et al. 2020), and anti-inflammatory treatments that
have effects on both anxiety and COVID-19, discussed below will
be very useful, given the role of the immune system in both con-
ditions. Very useful will be application of anxiety peripheral blood
biomarkers (Vismara et al. 2020). It is notable that some patients
with COVID-19 display a correlation between anxiety and inflam-
matory markers (Hu et al. 2020; Parker et al. 2020). It is possible
for anxiety to be comorbid with, or often specifically precede
delirium, which is a complication of acute COVID-19 infection
(Han et al. 2020; Iqbal et al. 2020; Parker et al. 2020). While physi-
cians and psychiatrists should have this in mind as a differential
diagnosis of anxiety in COVID-19 infection, delirium is not the
focus of this review. The patients in the published papers
reviewed have completed questionnaires for anxiety and studies
are cross-sectional, and the presence of delirium is excluded.
Papers from different countries, including United States, China,
Qatar, Italy, Ecuador, report on anxiety in COVID-19, and the diag-
nosis of an anxiety disorder may differ among the different coun-
tries. The published papers diagnose anxiety based on rating
scales for anxiety, and in some instances, on additional psychiatric
interview. Therefore, as noted in the Introduction, it is not speci-
fied whether there are symptoms of anxiety only or an anxiety
disorder. In all instances of reported anxiety, the score using a rat-
ing scale is higher than the normal values. We summarised key
papers in Table 1 and specified the means of establishing the
presence of anxiety, including the type of rating scale adminis-
tered. The anxiety rating scales are discussed in more detail in the
section on Screening for and diagnosis of anxiety. In one refer-
ence, 8 (16%) of 50 patients (mostly male, median age 39.5 years),
seen by a psychiatry consultation-liaison (CL) team in Qatar, posi-
tive for SARS-CoV-2 by PCR, have anxiety at the initial evaluation
by performing complete psychiatric history. From these 50
patients, 19 (38%) are asymptomatic (Iqbal et al. 2020). The sever-
ity of SARS-CoV-2 infection varied from asymptomatic, mild with
upper respiratory symptoms, pneumonia and serious with ARDS,
sepsis and shock. Subsequently, during the CL assessment, 32
(64%) of all patients had anxiety. Other psychiatric symptoms
were insomnia (70%), agitation (50%), depressed mood (42%), and
irritability (32%). Higher psychiatric morbidity was associated with
more social media use. The authors highlight the necessity for
long-term follow up of COVID-19 patients due to anxiety that
may be a long-term consequence of critical illness and ICU stay
(Nikayin et al. 2016).
In one cross-sectional study in Fangcang shelter hospital in
Wuhan, China, 307 patients admitted for COVID-19, are evaluated
from 23 to 26 February 2020 for mental health complications of
anxiety, depression and poor sleep by administering mobile
phone anonymous questionnaires (Dai et al. 2020). In addition to
socio-demographics and COVID-19 symptoms, the following
questionnaires are administered –Self-Rating Anxiety Scale
(SRAS), Self-Rating Depression Scale (SRDS), and Pittsburgh Sleep
Quality Index (PSQI). Patients with prior serious psychiatric dis-
order are not included but some patients report nicotine or alco-
hol use. The prevalence of anxiety was 57 patients (18.6%) and
poor sleep –260 patients (84, 7%). Having two or more physical
symptoms of COVID-19 and poor sleep were predictors of anxiety.
This study indicates that severity of COVID-19 correlates with
development of anxiety.
In individuals infected with SARS-CoV-2, de novo neuropsychi-
atric symptoms are observed in a very high fraction of the popu-
lation (Theoharides and Conti 2020; Varatharaj, Thomas et al.
2020). At present, few published studies examine the neuro-
psychiatric effects, including anxiety, of COVID-19 on patients
with prior mental illness in comparison with patients without
prior mental illness (Sergeant et al. 2020) (Parker et al. 2020). One
prospective study reports that more patients with previous psy-
chiatric diagnosis screened positive for mood symptoms using
HADS than those without psychiatric diagnosis, but the differen-
ces were not statistically significant (Parker et al. 2020). This is an
area of further investigation as more becomes known about the
COVID-19 infection and its course. Generally, the COVID-19 infec-
tion is expected to worsen pre-existing neuropsychiatric condi-
tions, and or to be associated with more neuropsychiatric
complications, including anxiety (Hao et al. 2020). However, given
the induction of cytokines and presence of inflammation, it is not
known what effects this may have on the CNS. For example, it
has been found that fever improves the symptoms of autism in
children (Grzadzinski et al. 2018). The mechanisms underlying this
effect are not precisely known although there are speculations
that this may be due to the locus coeruleus-noradrenergic system
(Mehler and Purpura 2009) and IL-17 based on studies in a mouse
model (Reed et al. 2020). Studies in mouse models of neurodeve-
lopmental disorders show that IL-17 produced during inflamma-
tion may promote sociability (Reed et al. 2020).
In one study, 402 adults (265 male and 137 female, mean age
59 and 56 years, respectively) recovered from COVID-19, were
examined one month later using detailed history, a battery of rat-
ing scales for psychiatric disorders, including anxiety, depression,
PTSD, OCD, and insomnia (Mazza et al. 2020). Sociodemographic
factors, clinical data, baseline inflammatory markers and follow up
oxygen levels were collected. The aims were to examine the men-
tal health complications of COVID-19 in these patients, and to
evaluate the immune-inflammatory nature of any observed psy-
chiatric disorders, in order to identify biomarkers, given the role
inflammation plays in many psychiatric disorders, including anx-
iety, depression and PTSD. A fraction of the studied population
had prior mental illness. Fifty six percent of the patients had at
least one psychiatric complication of COVID-19, 42% self-rated for
anxiety (using the State-Trait Anxiety Inventory form Y, STAI-Y) ,
31% –for depression (using Zung Self-Rating Depression Scale,
ZSDS, and Beck Depression Inventory, BDI), 28% –for PTSD (using
Impact of Events Scale-Revised, IES-R, and PTSD Checklist for
DSM-5, PCL-5), 20% for OC symptoms (using Obsessive-
Compulsive Inventory, OCI), and 40% –for insomnia (using
Medical Outcomes Study Sleep Scale, MOS-SS, and Women’s
Health Initiative Insomnia Rating Scale, WHIIRS). Females had
lower baseline levels of inflammatory markers than males, but suf-
fered from anxiety or depression to a greater proportion. Patients
that had a prior mental illness showed increased scores on most
measures at the same levels of inflammatory markers. The base-
line levels of immune-inflammatory markers correlated positively
with anxiety and depression at follow up. This study underscores
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 5
Table 1. Anxiety characteristics in subjects with COVID-19 infection.
Age
Number of
patients;
gender
Anxiety evaluation specifics
(place, time period)
Symptomatic
COVID-19?
Comorbid
psychiatric or general
medical conditions
Anxiety prevalence;
diagnostic means (incl.
rating scales)
Treatment
of anxiety Reference Notes
18–86 yrs;
mean –43.9
yrs;
median –39.5 yrs
50 patients;
male –48
female –2
Psychiatry consultation-
liaison evaluation upon
referral from hospital
ward (40) or emergency
department
(10)(retrospective study)
asymptomatic –19/
50;
mild –8/50;
pneumonia to critical
illness –23/50
prior psychiatric disorder
–17 (34%)
comorbid medical illness
–30 (60%)
anxiety in 32 (64%) by
complete
psychiatric history
NR Iqbal et al. (2020) Evidence for anxiety and
psychiatric complications
of COVID-19 in
asymptomatic SARS-CoV-
2 positive individuals
without prior
psychiatric history.
45–59 yrs 307 patients;
male –174
female –133
Between 23 and 26
February 2020 (mobile
phone-administered
questionnaires)
asymptomatic –20;
symptomatic –287
patients with serious
prior psychiatric
disorder, including
anxiety are excluded
male –28 anxiety
female –29 anxiety;
total anxiety –18.6% per
Self-Rating Anxiety Scale;
Self-Rating Depression
Scale;
Pittsburgh Sleep
Quality Index
NR Dai et al. (2020) Anxiety correlated positively
with two or more
physical symptoms of
COVID-19 and poor
sleep quality.
18 yrs and older 296 patients
male –173 (58.4%);
female –123 (41.6%)
Patients from FangCang
Hospital in Wuhan,
China, between 3 March
2020 and 5 March 2020
all patients have mild
COVID-
19 symptoms
patients with serious
prior psychiatric
disorder, including
anxiety are excluded;
only patients with mild
COVID-19 included
20.9% anxiety
HADS; Connor-Davidson
Resilience Scale
NR Zhang et al. (2020) Resilience and anxiety are
inversely correlated;
Gender and having
colleagues with COVID-19
influence anxiety.
Mean age 58 yrs 78 patients
male –33 (42.3%)
female –45 (57.7%)
Patients admitted with
COVID-19 to infectious
ward in hospital in
Wuhan, China between
14 February 2020 and 18
March 2020
all patients are
symptomatic with
variable COVID-
19 severity
35.9% –hypertension
11.5% –
diabetes mellitus
30 patients (38.5%)
–anxiety per
Zung Self Rating Anxiety
Scale
22 (20.5%) –mild;
5 (12.8%) –moderate;
3 (2.6% –severe
anxiety);
19 (24.3%) –depression
and anxiety
NR Nie et al. (2020) Patients with COVID-19,
especially those with
family members with or
died from COVID-19 are
more susceptible
to anxiety.
Mean age 48.8 þ/
14.3 yrs
85 patients; 50.6% –
male; 49.9%
–female
Inpatients in two isolation
wards in Tongji hospital,
Wuhan, China, from 7 to
24 March 2020. Cross-
sectional study using
questionnaires
administered online (48)
or in paper form (37).
All patients are
diagnosed with
COVID-19, unstable
patients and those
with dementia or
psychotic disorders
are excluded
Anxiety is comobrbid
with depression or
insomnia in
some patients
38.8% –anxiety as
measured using the
Chinese version of
Generalised Anxiety
Disorder –7 Item
questionnaire (GAD-7);
22.4% –mild; 11.8%
–moderate; 4.7%
–severe
NR Hu et al. (2020) Female sex, higher levels of
Interleukin 1-beta (IL-1b)
and self-perceived illness
severity correlate
positively with higher
GAD-7 scores and anxiety
(also with depression
and insomnia).
Mean age 57.8 yrs:
18–18 yrs
402 patients; 265 –
male; 137 –female
Patients evaluated in the ED
of IRCCS San Rafaelle
Hospital, Milan from 6
April 2020 to 9 June
2020; 300 –admitted for
severe pneumonia; 102 –
managed at home;
Evaluation performed
about one month after
hospital discharge or ED
visit (home managed)
All are COVID-19
symptomatic
106 patients have prior
positive
psychiatric history
42% patients –anxiety
per State-Trait Anxiety
Inventory form Y,
STAI-Y
NR Mazza et al. (2020) Patients with prior
psychiatric disorder and
females suffer more
from anxiety.
(continued)
6 G. UZUNOVA ET AL.
Table 1. Continued.
Age
Number of
patients;
gender
Anxiety evaluation specifics
(place, time period)
Symptomatic
COVID-19?
Comorbid
psychiatric or general
medical conditions
Anxiety prevalence;
diagnostic means (incl.
rating scales)
Treatment
of anxiety Reference Notes
Mean age 55 yrs;
43–65 yrs
105 patients; 77 –
male; 28 –female
Patients evaluated
1–3 months after clinical
recovery and virological
clearance following
hospitalisation for COVID-
19 in S. Paolo and S.
Carlo Hospitals in Milan
from April to June, 2020
55/105 (52.4%)
patients report
persistence of
physical symptoms
after virological
clearance. 31.4% –
asthenia; 27.6% –
dyspnoea.
Persistent physical
symptoms are
more common in
patients with
pathological HADS-
A/D
6 of 105 (5.7%) and 3 of
105 (2.8%) –treated
with antidepressant
and anxiolytic
therapies, respectively
before hospitalisation
for COVID-19; 17.1% –
cognitive disorders
after virological
clearance as assed
using the Mini Mental
Status Exam (MMSE)
29 of 100 (29%) –
anxiety per Hospital
Anxiety and
Depression Scale,
HADS-A; 11 of 100
(11%) have depression
per HADS-D; 30 of
100 score positive on
HADS-A/D: 33% –
both anxiety and
depression; 63% –
only anxiety and 4% –
only depression
NR Tomasoni
et al. (2021)
Patients show anxiety after
virological clearance.
Presence of anxiety
correlates with
persistence of physical
COVID-19 symptoms.
Anxiety is observed with
depression and
cognitive disorders.
Median age 55 yrs 675 patients; 358
(53%) –female;
317(47%) –male
Cross-sectional survey in
patients discharged from
hospital in Wuhan, China
between 27 January 2020
and 21 April 2020; survey
about 36.75 days
after discharge
Patients had COVID-
19 of varying
severity and at
least one symptom
persisted after
hospital discharge,
the most common
being chest
distress, cough
and fatigue
There is substantial
comorbidity of PTSD,
depression and
anxiety, as assessed in
this study
Anxiety is determined
using the GAD-7
scale;
605/675 patients –mild;
70/675 –moderate to
severe anxiety
NR Liu et al. (2020) The anxiety in patients
discharged due to
COVID-19 increases with
increase of disease
severity, living with
children, death of a
family member from
COVID-19, and treatment
of COVID-19 with
corticosteroids
Mean age 59
yrs (25–95)
58 patients; 21 (36%)
–female; 37 (64%)
–male
Patients with acute COVID-
19 admitted to non-
surgical inpatient units at
a large academic centre
in New York City (a
tertiary care centre and a
community hospital).
Screening tests are
administered at
admission and two
weeks later by phone.
All patients have
acute COVID-19 of
different
illness severity
15 (26%) of patients
have past psychiatric
history, including
anxiety disorder in 5
(8.6%) patients
Brief psychiatric history is
taken at admission
screening. The anxiety
is measured using
HADS-A. 21 patients
(36%) show anxiety
8 at screening and 4
(9%) –two
weeks later.
NR Parker et al. (2020) Anxiety is positively
correlated with
peripheral blood levels of
Interleukin-6 (IL-6)
measured before
study entry.
NR: not reported; ED: emergency department; yrs: years.
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 7
the high proportion of anxiety after recovery from symptomatic
COVID-19, and the necessity for long-term follow up of these
patients for psychiatric complications.
Psychological morbidity in patients in the Intensive Care Unit
(ICU) is an important and overlooked issue. It affects both the
patient and the family members. It is necessary to prevent neuro-
psychiatric complications in ICU survivors (including anxiety) and
HADS is a useful screening tool (Dijkstra-Kersten et al. 2020). A
high percentage (one-third) of ICU survivors experience anxiety
during their first year of post-ICU recovery, and psychiatric symp-
toms during admission and memories of an in-ICU delusional
event are associated with post-ICU anxiety (Nikayin et al. 2016). It
is important that a multispecialty team of physicians, including a
psychiatrist, evaluate and treat the critically ill COVID-19 patient,
in order to prevent the mental health complications, including
anxiety, depression and PTSD (Hosey and Needham 2020).
Screening for and diagnosis of anxiety
For diagnosis of anxiety, primary is performing a thorough patient
history, as much as possible, given the seriousness of the COVID-
19 illness, including taking the psychiatric and medical history,
and administering psychiatric rating scales for anxiety, depression
and PTSD. In the US, the diagnosis of anxiety should be made
according to the DSM-5 criteria for anxiety (APA 2013). In other
countries, for example in Italy, the adopted international diagnos-
tic criteria for anxiety are very similar to DSM-5 (Professor Stefano
Pallanti). Given the role of inflammation in anxiety and COVID-19,
peripheral blood markers of immunity and inflammation are use-
ful measures and biomarkers. If the patients are in home quaran-
tine, diagnosis will be completed by phone and video
consultation with a psychiatrist.
Previous coronavirus illness outbreaks, including Severe Acute
Respiratory Syndrome (SARS) and Middle Eastern Respiratory
Syndrome (MERS), have been associated with psychiatric problems
in survivors, including anxiety, depression and PTSD (Almqvist
et al. 2020; Rogers et al. 2020). Considering the experience from
previous coronavirus outbreaks, researchers have proposed a set
of outcome measures and rating scales, based on the World
Health Organisation (WHO) International Classification of
Functioning, Disability and Health (ICF) framework (Patel et al.
2020). Among the selected measures are the Hospital Anxiety
and Depression Scale (HADS) and the Impact of Event Scale
(IES-R). Based on the PubMed literature for COVID-19, we found
that the following screening questionnaires to be very useful in
screening for anxiety and depression in patients: HADS,Patient
Health Questionnaire, PHQ-2, Generalised Anxiety Disorder
Questionnaire, GAD-2, GAD-7 (Paz et al. 2020), and the State-
Trait Anxiety Inventory form Y, STAI-Y (Mazza, De Lorenzo
et al. 2020). These questionnaires can used as basis for timely
identifying of anxiety and depression in patients by physicians
from different specialties without need for much special-
ised training.
HADS is very useful in a hospital setting (Stern 2014). The
patients have to be hemodynamically stable in order to complete
the questionnaire. It is simple and easy to use. Its advantage is
that it detects both anxiety and depression. It is created to detect
anxiety and depression in patients with medical diseases, and
therefore it is particularly suitable for patients with COVID-19.
HADS consists of two subscales –HADS-A for anxiety detection
and HADS-D, for depression detection. For anxiety, the HADS-A
score gives a specificity of 0.78 and sensitivity of 0.9, and for
depression the HADS-D score gives a specificity of 0.79 and
sensitivity of 0.83 (Bjelland et al. 2002). Moreover, there is good
correspondence between the diagnosis of anxiety with HADS and
other rating scales for anxiety. HADS is useful for detection of
anxiety disorders for somatic (general medical), psychiatric, pri-
mary care patients and in the general population (Bjelland et al.
2002). Therefore, it will be useful also for detection of anxiety in
the post-COVID-19 recovery phase and in asymptomatic COVID-19
patients. It is validated and is used in many languages and coun-
tries and in various hospital and community settings (Stern 2014).
Its limitation is that it does not detect all symptoms of anxiety
and depression such as shortness of breath, chest tightness and
sleep disturbances. The latter three symptoms are frequent in
COVID-19 and may also be due to the viral infection of the
respiratory tract.
One study reports that patients with mild to moderate COVID-
19, who had fatal outcomes, had higher cortisol levels and HADS
scores. Furthermore, HADS scores were positively correlated with
serum cortisol levels (Ramezani et al. 2020). Therefore, timely psy-
chological interventions can improve the health outcomes in vul-
nerable populations.
Some publications in PubMed discuss anxiety in patients with
medical conditions such as epilepsy (Fonseca et al. 2020; Van
Hees et al. 2020), Parkinson’s disease (Del Prete et al. 2020; Salari
et al. 2020), diabetes (Merzon et al. 2020) or cancer (Musche et al.
2020), that also have COVID-19. In these groups of patients, HADS
is a useful screening tool for anxiety. In patients with epilepsy
and COVID-19, female gender and financial problems were associ-
ated with greater anxiety, which reflects the risk factors for anx-
iety in the general population (Van Hees et al. 2020). More
knowledge on the risk factors for anxiety in different patient
groups will help psychiatrists and other physicians provide timely
interventions.
PHQ-2 and GAD-2 are useful as initial screening tools for acute
anxiety. Therefore, these screening tools will have to be used with
other more broad psychiatric questionnaires for long-term follow
up of patients with anxiety, including the Anxiety Symptoms
Questionnaire, ASQ (Baker et al. 2019). ASQ may be used in clin-
ical and college settings to detect anxiety and depression. An
essential screening tool for obsessive-compulsive disorder is the
Yale Brown Obsessive Compulsive Scale, Y-BOCS, which can be
part of the evaluation of patients with pre-existing obsessive-com-
pulsive disorder, or for long-term follow up of anxiety resulting
from COVID-19 infection (Davide et al. 2020; Ji et al. 2020).
During the COVID-19 pandemic, rating scales are developed
specifically to evaluate anxiety resulting from COVID-19. The
Coronavirus Anxiety Scale (CAS) is a brief mental health
screener, consisting of five items (Chandu et al. 2020; Lee 2020;
Lee et al. 2020). Elevated CAS scores are associated with COVID-
19 diagnosis, impairment, alcohol and drug use, negative religious
coping, extreme hopelessness, and suicidal ideation. The psycho-
logical distress resulting from the COVID-19 pandemic, which
expressed as heightened generalised anxiety, depression and
death anxiety is described with the term coronaphobia (Lee
et al. 2020).
It is imperative to administer timely screenings for anxiety and
associated depression in COVID-19 patients, both in quarantine in
the community, and in the hospital. In one study (Guo et al.
2020), hospitalised patients with COVID-19 had a higher incidence
of anxiety (p<0.001), depression (p<0.001) and PTSD (p<0.001)
as compared to the COVID-19 negative controls. Furthermore,
C-reactive protein (CRP) levels in peripheral blood, an inflamma-
tory biomarker, correlated positively with PHQ-9 score (R ¼0.31,
P¼0.003, Spearman’s correlation) of patients with depression.
8 G. UZUNOVA ET AL.
In one study with 296 patients with mild COVID-19 in a hos-
pital setting in Wuhan, China, resilience and anxiety were eval-
uated using the Connor Davidson Resilience Scale and HADS. The
mean total resilience score of the participants was slightly below
the score of the general Chinese population. Resilience was
inversely correlated with and was a protective factor for anxiety
and depression. Higher anxiety was associated with female gen-
der and having a colleague with COVID-19; depression was associ-
ated with having family members with COVID-19 (Zhang et al.
2020). In this study, patients with prior mental illness were
excluded. From all patients, about 20.9% had anxiety and 18.6%
had depression. Therefore, promoting resilience among patients
with COVID-19 in order to prevent negative psychological conse-
quences is key. In another study in China with 78 COVID-19
patients, 38.5% had anxiety and 35.9% had depression. Higher
depression and anxiety scores were associated with having a fam-
ily member with COVID-19 or died from COVID-19 (Nie et al.
2020). Therefore, special attention should be paid to these
patients to promote resilience.
Management of anxiety
It is important to manage anxiety during the acute asymptomatic,
symptomatic infection, and in the post-COVID-19 recovery phase.
The general approach to anxiety management in patients with
COVID-19 can follow guidelines adopted for management of psy-
chiatric disorders associated with disaster and/or trauma
(Fineberg, Van Ameringen et al. 2020). Of course, in cases of acute
COVID-19 infection, treatment of the infection and associated
complications should be primary. It is crucial to exclude poten-
tially lethal causes of anxiety such as hypoxia or tachycardia.
Efforts should focus on instilling a sense of hope and strengthen-
ing resilience. The general approach in management of patients
with anxiety may be as follows:
1. Adopt a compassionate approach, having in mind the bio-
logical, sociodemographic, and cultural specifics for each
patient. It is suitable to use telemedicine including telephone
and video calls.
2. Perform thorough and careful patient history and administer
rating scales specific for detection of anxiety, which are dis-
cussed above. Evaluate if there are pre-existing psychiatric
and general medical conditions that may contribute to a
greater risk of anxiety, including neuropsychiatric disorder
(anxiety, depression, substance use disorder, and eating dis-
order), neurological, cardiac, pulmonary disease,
and diabetes.
3. Assess suicidal risk.
4. Provide psychoeducation about the risks associated with the
SARS-CoV-2, how to avoid infecting others within the social
circles. Highlight the possibility that anxiety is a condition
that will require long-term management including techniques
for relaxation such as mindfulness, exercise, proper nutrition
and daily schedule. In patients with challenging social situa-
tions, such as loss of income, job, place to live, refer to social
services for long-term assistance, to help mitigate anxiety.
5. Inquire about internet usage and social media consumption.
Patients quarantined at home may spend a lot of time on
social media and reading news that may heighten anxiety.
Recommend no more than an hour daily for social media
and internet use and that patients to refer only to trusted
sources of health and COVID-19 information, besides their
treating physicians and psychiatrists, including the World
Health Organisation (WHO), Centre for Disease Control (CDC),
The US Food and Drug Administration (FDA) (section on
COVID-19), The National Institutes of Health (NIH), and the
Centre for Health Security at Johns Hopkins University.
Treatments for anxiety are very important, in order to reduce
the morbidity and improve the COVID-19 infection outcomes.
Important are awareness of and treatment of anxiety as a long-
term sequela of COVID-19. Anxiety and other neuropsychiatric dis-
orders worsen because of stress present during the pandemic.
Notably, anxiety is associated with higher incidence of COVID-19
infection (Taquet et al. 2020) and may worsen the COVID-19 infec-
tion outcomes. All of the above points should be considered by
psychiatrists and physicians from other specialties, to adopt a
multispecialty approach and monitor for anxiety (and associated
depression, OCD and PTSD). The experience with COVID-19 is rap-
idly evolving and we are presenting the current situation, and
offering appropriate recommendations for timely diagnosis and
management of anxiety. Efforts have to be made to increase the
resilience of COVID-19 patients. Some ways are to reduce stress,
provide adequate nutrition and physical therapy, and timely
examination by a psychiatrist and screening for anxiety. An out-
standing example is a specialised centre for promoting resilience
and management of stress, adopted by Mount Sinai Hospital in
New York City (DePierro et al. 2020).
In management of anxiety as a complication of COVID-19, we
recommend the following pharmacological and non-pharmaco-
logical interventions that will depend on the condition of the
patient and the stage and seriousness of COVID-19 infection
(acute or recovery):
1. Medications for treatment of anxiety:
1.1. First-line anti-anxiety medications. These medications are
approved for treatment of anxiety. They act primarily on neu-
rotransmitters and neuromodulators within in the anxiety
neurocircuitry. Since they have different adverse effects, it is
necessary to make a careful choice, taking into account the
COVID-19 illness and other factors, discussed below.
A) Selective serotonin reuptake inhibitors (SSRI) –citalopram,
escitalopram, fluoxetine, paroxetine sertraline. The SSRI flu-
voxamine, which is effective in OCD and certain types of
anxiety, including separation and general anxiety disorders,
may be effective in treatment of COVID-19 due to a poten-
tial ‘cytokine storm suppressing’mechanism (Dryden 2020).
This is due to the ability of fluovoxamine to bind to endo-
plasmic reticulum resident protein sigma-1 receptor on
immune cells, and suppress the pathologic release of cyto-
kines (Rosen et al. 2019). Based on this mechanism, a clin-
ical trial is initiated by investigators from Washington
University School of Medicine, to determine if administered
early in the course of COVID-19 infection, fluvoxamine will
prevent more serious complications resulting from a cyto-
kine storm (NCT04342663). Earlier it has been shown that
fluvoxamine may dampen the immune response in mice
during sepsis and protect from septic shock (Rosen et al.
2019). Therefore, treating anxiety with a psychiatric drug
may improve the COVID-19 infection through several mech-
anisms. It is important to have in mind that SSRIs have a
latency in their therapeutic effects.
B) Serotonin norepinephrine reuptake inhibitors (SNRI) –ven-
lafaxine, desvenlafaxine, duloxetine.
C) Tricyclic antidepressants (TCA) –amitriptyline, imipra-
mine, nortriptyline. TCA’s are anticholinergic, their use in
older individuals may precipitate delirium and therefore
they have to be used with caution (Kassie et al. 2019).
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 9
D) Benzodiazepines –alprazolam, clonazepam, diazepam,
lorazepam. It is important to emphasise that non-selective
benzodiazepines such as alprazolam, diazepam, clonazepam
and lorazepam may cause respiratory adverse effects, par-
ticularly in certain patients with respiratory problems,
including COPD and sleep apnoea (Vozoris 2014; Vozoris
et al. 2014; Vozoris and Stephenson 2015; Wang et al.
2018), and therefore for safety reasons have to be avoided
in COVID-19 patients with ARDS and respiratory problems.
In addition, they may precipitate delirium and are not the
medications of choice in COVID-19 critically ill patients and
post critical illness (Pun et al. 2021).
E) Gabapentinoids are similar to the inhibitory neurotrans-
mitter GABA but have different mechanisms of action and
bind to calcium channels. Pregabalin is a medication used
to treat generalised anxiety disorder. It is a gabapentinoid
that acts by inhibiting voltage-dependent calcium channels.
Because of its actions, the levels of the GABA-synthesising
enzyme L-glutamic acid decarboxylase (GAD) may change.
It is important to note that this medication is on the
Schedule V controlled substances in the U.S., and is
reported to cause serious cardiac adverse effects, including
heart failure and edoema (Ho et al. 2013) Therefore, its use
for management of anxiety in COVID-19 patients, especially
in those with pre-existing cardiac conditions or more severe
COVID-19, should be avoided. Gabapentin is another gaba-
pentinoid. It can be used for off-label treatment of anxiety
disorder, but its other more common uses are for neuro-
pathic pain and seizures. It is a medication often used to
treat diabetic neuropathy. There is a published report on
the beneficial use of gabapentin for treatment of neuro-
pathic pain in a female patient with COVID-19, asthma and
COPD (Aksan et al. 2020). However, in 2019 the U.S. Food
and Drug Administration (FDA) issued a warning of the risks
of respiratory depression associated with use of pregabalin
and gabapentin, particularly in combination with opioids, or
people with respiratory problems (FDA 2019). Therefore, to
be on the safe side, it would be pertinent to use other anti-
anxiety medications as first-line treatment of anxiety in
COVID-19 patients.
In conclusion, it is key to select anti-anxiety pharmacotherapy
individually for each patient, considering the condition of the
patient, associated neuropsychiatric and general medical disor-
ders, the desired and adverse effects of the drug, any other medi-
cations that the patient is taking, and possible drug–drug
interactions. In COVID-19, in our opinion, it is important to select
an anti-anxiety medication based on several dimensions that are
highly relevant to the disease pathogenesis –clinical efficacy and
tolerability of the drug, but also cortisol response (as stress wor-
sens anxiety)(Ramezani et al. 2020), and importantly –immune
response (that is intimately connected to both the COVID-19 and
anxiety mechanisms)(Hu et al. 2020). Important is to consider the
effects of anti-anxiety medications on sleep because insomnia
may be a symptom of anxiety. In this respect, the hormones oxy-
tocin and melatonin discussed below as adjunctive medications
for anxiety, have excellent tolerability, anti-anxiety, anti-inflamma-
tory and cytokine-modulating effects. Moreover, melatonin is very
efficient in management of insomnia.
1.2. Adjunctive medications. In addition to the approved and used
in the clinic anti-anxiety medications, there is evidence from
mechanistic perspective and use in patients for the effectiveness
of the hormones oxytocin and melatonin as treatments for
anxiety in COVID-19, which also may have anti-inflammatory
properties and benefit as adjuvant treatment for COVID-19.
Therefore, more clinical trials and cases are necessary to ascer-
tain the effectiveness of oxytocin and melatonin for manage-
ment of anxiety in COVID-19 patients.
A. Oxytocin can regulate stress, anxiety and depression
(Uzunova et al. 2019). It has anti-inflammatory and
proimmune properties and may attenuate or mitigate
the cytokine storm arising in COVID-19 infection (Imami
et al. 2020). In humans, intravenous oxytocin reduces
the proinflammatory cytokine response induced by bac-
terial endotoxin lipopolysaccharide (LPS), and causes a
reduction in Tumour necrosis factor-a(TNFa) and
Interleukin-6 (IL-6; Clodi et al. 2008). Therefore, oxytocin
may be beneficial as an adjunctive treatment of the
COVID-19 infection (Buemann et al. 2020), and may aid
in management of the stress and anxiety simultaneously
(Uzunova et al. 2019). There is a phase II clinical trial
reported in Clinicaltrials.gov for use of oxytocin as an
adjunct treatment for COVID-19, in addition to the
standard therapy including oxygen, hydroxycloroquine,
antiretroviral therapy, azithromycin (NCT04386447).
Importantly, therapeutic use of oxytocin in other neuro-
psychiatric and general medical conditions so far has
shown that it has an excellent therapeutic index and
absence of serious adverse effects. Oxytocin is used in
treatment of autism spectrum disorder that is character-
ised with high anxiety, and therefore it may help fight
both anxiety and COVID-19 infection in this
patient group.
B. Melatonin. The pineal hormone melatonin may be par-
ticularly useful because, in addition to anti-anxiety prop-
erties, it has anti-inflammatory, anti-oxidative,
neuroprotective, cardioprotective effects, and may coun-
teract the cytokine storm resulting from SARS-CoV-2
infection (Hollander et al. 2020; Zhang et al. 2020).
Melatonin has shown beneficial effects in viral infections
and pulmonary injury. It has a very good therapeutic
profile, minimal side effects and is safe to use in new-
borns and adults. Accordingly, a case report from The
Cleveland Clinic shows the therapeutic efficacy of
adjunctive melatonin for insomnia, in addition to stand-
ard anti-anxiety therapy, for management of anxiety in a
62-year-old woman with COVID-19, and a history of dia-
betes mellitus and hypertension, who was able to
recover completely and discharged without transfer to
the ICU. Initially, she was admitted to the COVID-19
nursing unit with flu-like symptoms, chest tightness, dif-
ficulty breathing, anxiety attacks, hyperventilation, and
fear. In management of anxiety in this patient, the psy-
chiatrists underscore the need for adhering to the stand-
ard of care, factoring in associated medical
comorbidities, drug–drug interactions, and the patient’s
individual needs (Pozuelo et al. 2020).
Interestingly, at the time of our recommendation for Faculty
Opinions on the beneficial effects of melatonin in anxiety and
COVID-19 in April 2020, there were no clinical trials in
Clinicaltrials.gov evaluating melatonin in COVID-19, whereas there
were clinical trials evaluating melatonin in anxiety. Since then,
seven clinical trials with melatonin in adult patients with COVID-
19, and one –to evaluate the protective effects of melatonin in
healthcare workers exposed to COVID-19, are reported in
Clinicaltrials.gov. This will allow assessing the doses and efficacy
10 G. UZUNOVA ET AL.
of melatonin in patients with COVID-19 (Acu~
na-Castroviejo et al.
2020). In future clinical studies, it will be relevant to include a rat-
ing scale for anxiety, such as HADS, PHQ-2 or CAS, to ascertain if
melatonin is beneficial to simultaneously manage the anxiety and
COVID-19 infection.
C) L-Theanine, (N-ethyl-L-glutamine), is a non-protein amino acid
from tea (Vuong et al. 2011). It has shown initial beneficial
effects in management of different types of anxiety, and
deserves to be mentioned as a possible adjunctive treatment for
anxiety because of COVID-19 infection. Being derived from tea
sources, it is well tolerated. However, its anti-anxiety effects are
still not ascertained (Sarris et al. 2019; Williams et al. 2020), and
it has to be used with caution. Although it is supposed to be
effective in anxiety, it is an excitatory amino acid (Sebih
et al. 2017).
2. Cytokine-blocking biological therapies. Given the proposed
important role pro-inflammatory cytokines play in the pathogen-
esis of COVID-19, ARDS and anxiety, anti-cytokine therapeutics,
such as monoclonal antibodies blocking IL-6, or IL-17 are
expected have therapeutic effects against COVID-19 associated
anxiety. Such antibodies are in clinical development as COVID-
19 treatments. For example, the anti-IL-6 receptor antibody that
reduces the levels of IL-6, sarilumab (Kevzara), produced by
Sanofi Genzyme and Regeneron, approved for use in rheuma-
toid arthritis, is in clinical trials for patients with severe COVID-
19 and pneumonia (Regeneron 2020). The results from the clin-
ical trials with sarilumab and an anti-IL-6 antibody from Roche
have been largely unsuccessful which suggests that other cyto-
kines such as Il-17, or a combination of cytokines have to be tar-
geted (Casillo et al. 2020; Taylor 2020). The cytokine changes in
COVID-19 are very dynamic, cytokines often act in a cascade
(Brodin 2021), and therefore will be difficult to target precisely
at the right stage with antibodies. Alternatively, perhaps, similar
to other immune-inflammatory disorders, such as multiple scler-
osis, other points of the immune-inflammatory pathway need to
be targeted.
3. Non-invasive brain stimulation (NIBS), including transcranial mag-
netic stimulation (TMS) and transcranial direct current stimulation
(tDCS) (Baptista et al. 2020; Shinjo et al. 2020). tDCS is an experi-
mental NIBS technique, which involves placing two electrodes
over the head and running a low intensity current between
them to either stimulate (anodal) or inhibit (cathodal) neuronal
activity. TMS is another NIBS technique, which is FDA-approved
for treatment of depression and involves inducing an electro-
magnetic field within a specific brain region using a coil or a
cap, which can either stimulate or depress neuronal activity
based on the frequency and type of electromagnetic pulses.
4. Physical exercise and aerobic exercise are useful for mitigation
of anxiety. Exercise, in moderate amounts has beneficial effects
on the immune system, the profile of proinflammatory cyto-
kines, the heart and lungs, blood circulation, skeletal muscles,
the brain, and the entire organism (Codella et al. 2020).This
effect can be favourable for increasing the resistance to viral
infections and COVID-19, in adults of different age, including
older adults (Ranasinghe et al. 2020). Physical exercise also
counteracts stress. Owing to these effects, and others, exercise
can improve the resistance to COVID-19, decrease anxiety and
depression, reduce stress, and improve respiratory function
(Kenyon 2020). Therefore, an adequate amount of exercise
should be prescribed to individuals depending on their age and
physical state (Mohamed and Alawna 2020).
5. Physical therapy is very useful in patients with more severe
COVID-19 that have had pulmonary, cardiovascular and
neurological complications, and have been treated in the ICU
(Levy et al. 2020;Lietal.2020; Wang et al. 2020b).
6. Appropriate diet that contains vitamins and probiotics (Kim and
Su 2020).
7. Appropriate daily schedule with regular sleep (Kim and Su 2020).
Sleep is particularly important because often there is a link
between insomnia and anxiety (Buckner et al. 2008), and insom-
nia is a frequent neuropsychiatric complication of COVID-19, fol-
lowing anxiety (Iqbal et al. 2020; Taquet et al. 2020).
8. Psychotherapy –cognitive-behavioural therapy (CBT) is a first line
treatment for anxiety (Bate and Malberg 2020; Fineberg, Van
Ameringen et al. 2020; Khawam et al. 2020; Renjun et al. 2020).
9. Acupuncture (Jia et al. 2020).
10. Meditation and mindfulness (Behan 2020).
11. Yoga through the mechanisms of psychoneuroimmunology
has mitigating effects on anxiety (Rajkumar 2020).
12. Art Therapy which is effective in anxiety management may be
effective in treatment of anxiety as a long-term COVID-19 com-
plication (Zhang et al. 2015). Art therapy is non-verbal therapy
that uses the visual arts such as painting, drawing, sculpting,
and clay modelling. Many clinical studies show the effectiveness
of various types of art therapy in mitigating symptoms of anx-
iety in different age and patient groups. Mindfulness art therapy
has shown particular benefits in reducing anxiety, perceived
stress and salivary cortisol in college students (Beerse et al.
2020). In another study, mindfulness-based art therapy is found
to significantly improve the psychological well-being, reduce the
trait anxiety (measured using trait anxiety inventory), and reduce
depression (measured using the Beck Depression Inventory) of
Korean patients with coronary artery disease, female and male
with mean age 64.81 þ/9.19 years (Jang et al. 2018).
Therefore, our interpretation is that mindfulness-based art ther-
apy may be particularly useful in stable patients with COVID-19,
because it will reduce cortisol, and mitigate anxiety. Moreover,
patients with coronary artery disease may be more prone to
COVID-19 complications (Abrams et al. 2020). In one clinical trial
in the Netherlands, adult women, 18–65 years, with moderate to
severe anxiety (generalised anxiety disorder, social anxiety dis-
order or panic disorder), were assigned arthroscopic art therapy
consisting of drawing, painting of clay modelling based on their
choice for 10–12 sessions over 3 months. Another group were
on waitlist for three months and received their regular medica-
tions, following which they were assigned the same arthroscopic
art therapy for three months, while the art-treated group were
followed up for 3 months. Both groups of women showed a
reduction in their anxiety, quality of life and emotion regulation.
The treatment effects remained after 3 months of follow up. The
Dutch version of the Lehrer Woolfolk Anxiety Symptom
Questionnaire was used to measure the anxiety level (Abbing
et al. 2019). In a study from Latvia, 60 healthcare workers,
women, age 20–69, were administered art therapy for 9 sessions
or 18 hours over 2 months, completed a stress questionnaire,
State Trait Anxiety Inventory Form Y-1 for assessment of anxiety,
and salivary cortisol was measured using HPLC. The results
showed that art therapy is a useful measure to reduce stress,
and for a person to understand stress situations in order to be
able to manage their anxiety (Visnola et al. 2010).
The treatment of anxiety in COVID-19 patients may be more
complex, because the infection has to be treated as a priority,
besides the anxiety. However, the presence of anxiety may wor-
sen the COVID-19 course and outcome and therefore, has to be
treated timely. Importantly, there are no definitive guidelines for
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 11
treatment of anxiety in COVID-19 patients and the approach
should be on a case-by-case basis.
There is a need for long-term follow up of patients with COVID-
19, and especially those that have suffered ARDS, complications
and ICU stay, for anxiety, depression, OCD and PTSD. For example,
in one study, 107 COVID-19 patients in Milan, Italy were adminis-
tered HADS to screen for anxiety and depression after viral clear-
ance (Tomasoni et al. 2021). From these patients, 30% had HADS
results indicative of anxiety and depression. In another study con-
ducted with 675 COVID-19 patients discharged from the hospital
in Wuhan, China, it was found that a very high percentage suf-
fered of mental health complications including anxiety, depression
and PTSD (Liu et al. 2020). From the participants, 90 (13.3%) were
medical staff who were ill. The rates of mental health complica-
tions were the same between all patients, including medical staff
that were ill. We have not discussed two large groups that may
suffer anxiety during the COVID-19 pandemic –healthcare work-
ers and the general population that are not positive for COVID-19.
Therefore, this mental condition needs greater awareness among
all healthcare practitioners.
Discussion
The published studies thus far unequivocally provide evidence for
higher incidence of anxiety in patients with COVID-19 infection,
and in the recovery phase. In fact, the highest percentage of all
COVID-19 neuropsychiatric manifestations/complications can be
attributed to anxiety. The scarce evidence indicates that previous
psychiatric illness is a factor contributing to anxiety (Mazza, De
Lorenzo et al. 2020), and previous psychiatric illness raises the risk
for COVID-19 infection (Taquet et al. 2020). Interestingly, although
anxiety has an immune-inflammatory pathogenesis, patients with
prior mental illness suffered to greater extend from anxiety than
those without prior mental illness, at the same level of inflamma-
tory markers. This may suggest that there is a threshold of activa-
tion of the immune system in anxiety, or may be due to SARS-
CoV-2-specific causes. The latter is likely because at post-COVID-
19 follow up, the levels of inflammatory makers correlated with
the severity of anxiety and depression. To answer these questions,
future investigations of immune-inflammatory markers in patients
with and without COVID-19 and anxiety are necessary. Another
peculiarity is that females have lower values of inflammatory
markers but suffer from anxiety to a greater extent than men,
who have higher levels of inflammatory markers (Mazza, De
Lorenzo et al. 2020). This may be due to the greater susceptibility
of females to stress, and sex-specific immune system factors. For
example, the normal values of inflammatory biomarkers may be
in a lower range in females as compared to males.
Most of the published studies thus far evaluating anxiety and
other neuropsychiatric disorders in patients with COVID-19 are
cross-sectional, and few of the newer studies are prospective
(Parker et al. 2020). In future, it is important to conduct more pro-
spective studies with follow up of the patients after clearance of
COVID-19 symptoms.
Summary and future directions/outstanding questions
In conclusion, COVID-19 is rapidly developing, we are learning
about the disease course and complications every day and there-
fore more is likely to be learned about its neuropsychiatric com-
plications, including anxiety. It will be important in future studies
and published papers to make a clearer distinction between anx-
iety symptoms and anxiety disorder, and which type, if possible.
In the future, given the higher incidence of COVID-19 in young
adults and children, special attention should be given to identify-
ing and treating anxiety in younger age groups. Moreover, the
anxiety in young adults and children may be exacerbated by
school and university closures and social isolation, which are par-
ticularly detrimental in these age groups.
It is necessary to carry out long-term evaluation of anxiety in
subjects that have had COVID-19, and particularly if it was compli-
cated by ARDS or ICU stay, which is trauma, because nothing is
known yet about COVID-19 complications in 2–5 years post recov-
ery from infection. Similarly to survivors of ARDS, trauma, and
other coronavirus respiratory illnesses (SARS, MERS), it is antici-
pated that the incidence of anxiety as a complication, will be
higher. Therefore, it is necessary to adopt approaches for long-
term follow up and management of anxiety (and associated
depression and PTSD) in these groups. Of course, it will be neces-
sary to gather information about these disorders in the psychiatric
history.
At the time of writing this review in October 2020, there are
124 clinical trials evaluating different aspects of anxiety in SARS-
CoV-2 and COVID-19. As the results from these studies emerge
over several years, we will learn more about management of anx-
iety in COVID-19 infection.
Disclosure statement
No potential conflict of interest was reported by the author(s).
ORCID
Genoveva Uzunova http://orcid.org/0000-0002-1922-1925
Stefano Pallanti http://orcid.org/0000-0001-5828-4868
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