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Psychopharmacology of COVID-19

Melanie Bilbul, Patricia Paparone, Anna M. Kim, Shruti Mutalik, Carrie L. Ernst

PII: S0033-3182(20)30144-4
DOI: https://doi.org/10.1016/j.psym.2020.05.006
Reference: PSYM 1107

To appear in: Psychosomatics

Received Date: 24 April 2020

Revised Date: 11 May 2020
Accepted Date: 12 May 2020

Please cite this article as: Bilbul M, Paparone P, Kim AM, Mutalik S, Ernst CL, Psychopharmacology of
COVID-19, Psychosomatics (2020), doi: https://doi.org/10.1016/j.psym.2020.05.006.

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© 2020 Published by Elsevier Inc. on behalf of Academy of Consultation-Liaison Psychiatry.

Title: Psychopharmacology of COVID-19

Melanie Bilbul1, Patricia Paparone1, Anna M. Kim1, Shruti Mutalik1 and Carrie L. Ernst1,2

1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY

2. Department of Medical Education, Icahn School of Medicine at Mount Sinai, New York,
NY

Corresponding Author: Carrie L. Ernst

Corresponding Author Address: One Gustave L. Levy Place, Box 1230, New York, NY 10029
Corresponding Author Email: carrie.ernst@mssm.edu
Corresponding Author Phone: 212-659-8856

Declarations of Interest: Dr. Ernst receives royalties from American Psychiatric Publishing, Inc;
the other authors have no interests to declare
Abstract

BACKGROUND: With the rapid, global spread of SARS-CoV-2, hospitals have become
inundated with patients suffering from COVID-19. Consultation-liaison psychiatrists are actively
involved in managing these patients and should familiarize themselves with how the virus and its
proposed treatments can affect psychotropic management. The only FDA approved drug to treat
COVID-19 is remdesivir, and other off-label medications used include chloroquine and
hydroxychloroquine, tocilizumab, lopinavir/ritonavir, favipiravir, convalescent plasma therapy,
azithromycin, vitamin C, corticosteroids, interferon and colchicine.

PURPOSE: To provide an overview of the major safety considerations relevant to clinicians who
prescribe psychotropics to patients with COVID-19, both related to the illness and its proposed
treatments.

METHODS: In this targeted review we performed structured literature searches in PubMed to

identify articles describing the impacts of COVID-19 on different organ systems, the
neuropsychiatric adverse effects of treatments, and any potential drug interactions with
psychotropics. The articles most relevant to this manuscript were included.

RESULTS: COVID-19 impacts multiple organ systems, including gastrointestinal, renal,

cardiovascular, pulmonary, immunological, and hematological systems. This may lead to
pharmacokinetic changes that impact psychotropic medications and increase sensitivity to
psychotropic-related adverse effects. Additionally, several proposed treatments for COVID-19
have neuropsychiatric effects and potential interactions with commonly used psychotropics.

CONCLUSION: Clinicians should be aware of the need to adjust existing psychotropics or avoid
using certain medications in some COVID-19 patients. They should also be familiar with
neuropsychiatric effects of medications being used to treat this disease. Further research is
needed to identify strategies to manage psychiatric issues in this population.

Keywords: COVID-19, psychotropic, psychopharmacology, side effects

Introduction

With the rapid, global spread of SARS-CoV-2, hospitals have become inundated with patients
suffering from COVID-19 infection. Remdesivir was recently approved by the US Food and
Drug Administration (FDA) to treat severe COVID-19 (1), and many other medications are
either being studied in clinical trials or being used off-label and/or for compassionate use (2).

As the pandemic spreads, Consultation Liaison (CL) psychiatrists are being called upon to help
manage the psychiatric conditions of individuals with COVID-19 and are encountering
challenging clinical scenarios of multiple medical comorbidities and unfamiliar drugs.
Psychiatrists should familiarize themselves with the mechanism of action of these treatments,
neuropsychiatric side effects and possible interactions with psychotropics. Additionally, since
COVID-19 affects multiple organ systems, psychiatrists will need to be aware of safety concerns
inherent in prescribing psychotropics to these patients.

This article is divided into 2 main sections. The first provides an update on the organ systems
that may be negatively impacted by COVID-19 and recommendations for safer use of
psychotropics in these patients. The second section reviews potential neuropsychiatric side
effects of the early approved and investigational treatments for COVID-19 as well as
pharmacokinetic and pharmacodynamic drug-interactions when used concurrently with
psychotropics. COVID-19 therapies reviewed include remdesivir, chloroquine,
hydroxychloroquine, azithromycin, tocilizumab, lopinavir/ritonavir, favipiravir, convalescent
plasma therapy, corticosteroids, interferon, vitamin C, and colchicine.

Given the limited literature in this area, we undertook a non-systematic narrative review that was
focused on practical clinical concerns. We utilized a structured PubMed search using the
following search terms in combination with the names of the medications mentioned above:
“COVID-19,” “coronavirus,” “Psychotropic medications,” “QT prolongation,” “Psychiatric side
effects,” “Neuropsychiatric side effects,” “drug interactions,” and pertinent organ systems, e.g.
“hepatic,” “renal,” “hematological,” “pulmonary,” and “cardiac.” This was followed by a search
of manufacturer’s package inserts for pertinent facts about specific medications, including drug
interactions.

We selected the above medications as they were the ones most commonly being used in
healthcare settings and clinical trials at the time of preparation of this manuscript, although we
are aware that this is a rapidly evolving field and thus this list is not meant to be comprehensive.

Impact of COVID-19 on Psychotropic Drug Safety

COVID-19 is believed to impact multiple organs, including the liver, kidneys, lungs and heart, as
well as the immune and hematological systems (3). Damage to these organs or systems may lead
to pharmacokinetic changes that impact absorption, distribution, metabolism and/or excretion of
psychotropic medications as well as increased sensitivity to certain psychotropic-related adverse
effects. As such, clinicians should be aware of the potential need to make adjustments to existing
psychotropic regimens or avoid using certain psychotropic agents if such safety concerns arise
(Tables 1 and 2).
Hematological Effects
An early report noted the presence of lymphopenia (lymphocyte count less than 1.0 x 109/L) in
63% and leukopenia (white blood cell count less than 4 x109/L) in 25% of COVID-19 patients
(4). It has been proposed that lymphopenia is a feature of severe COVID-19 cases and may
serve as a poor prognostic factor. Contributing factors likely include direct infection of
lymphocytes and cytokine storm (5) It therefore seems prudent to utilize caution and consider
avoiding medications which have the potential to further impact white blood cell production,
particularly lymphocytes. By contrast, clinicians might determine that it is acceptable from a
safety standpoint to continue psychotropics which have only been associated with
agranulocytosis and neutropenia, assuming the patient does not have a secondary bacterial
infection. Several psychotropics have been implicated in hematological adverse effects,
including leukopenia, neutropenia, and agranulocytosis. The most commonly implicated
psychotropics include carbamazepine and clozapine, but there is a class effect FDA warning on
all first and secondary generation antipsychotics for the potential association with leukopenia,
neutropenia and agranulocytosis as well as a number of published case reports. Carbamazepine is
more likely to be associated with an early transient leukopenia, but has also been associated with
agranulocytosis and aplastic anemia (6).

While the leukopenia and lymphopenia observed in COVID-19 patients may be less of a concern
for clozapine prescribers in the setting of a normal neutrophil count, clozapine deserves unique
mention given several potential challenges associated with its use during the COVID-19
pandemic. These challenges have been recently reviewed along with recommendations for
management in a consensus statement by Siskind and colleagues (7). Patients on clozapine may
have difficulty accessing routine absolute neutrophil count (ANC) monitoring and the Food and
Drug Administration (FDA) has released guidance allowing healthcare providers to use medical
judgment to delay laboratory testing for drugs subject to Risk Evaluation and Mitigation Strategy
(REMS) (8). While there is no data yet available on COVID-19 in patients on clozapine, it has
been suggested that clozapine is associated with a higher risk of pneumonia and its
complications. Explanations include aspiration, sialorrhea, sedation, and poorly understood
effects on the immune system (7,9). Patients should be educated on symptoms of pneumonia and
urgently evaluated by a clinician if symptoms of infection emerge. Complicating the picture
further, elevation of clozapine levels has been observed with multiple acute viral and bacterial
infections. This may in part be related to effects of systemic infection and inflammation on
CYP450 enzymes (10). Clinicians should closely monitor clozapine levels and consider reducing
the dose by up to a half in patients with fever and other signs of infection.

Coagulation abnormalities such as PT and aPTT prolongation, thrombocytopenia and

disseminated intravascular coagulation (DIC) are also frequently observed in COVID-19
patients. At the same time, many COVID-19 patients experience increased thrombotic risk and
may be prescribed prophylactic anti-coagulants(5). These factors may impact the decision to
prescribe psychotropics that have been associated with platelet dysfunction and increased
bleeding risk (e.g. selective serotonin reuptake inhibitors and valproic acid). Clinicians should be
especially mindful of using these medications in patients who have other risk factors for
bleeding, such as concomitant anti-coagulation therapy and history of significant bleeding event.
Cardiac Effects
There is limited available information regarding cardiovascular involvement due to COVID-19
infection, although tachyarrhythmias and heart failure have been described with other severe
acute respiratory syndrome (SARS) beta-coronavirus infections (11). A recent report described
acute myopericarditis in a patient with COVID-19 (12) and a meta-analysis found acute cardiac
injury in at least 8% of patients with COVID-19 (13). It has been suggested that COVID-19 most
likely has an arrhythmogenic effect (14). Proposed mechanisms of myocardial injury include
derangement of Angiotensin Converting Enzyme 2 (ACE2) signal pathways, cytokine storm and
myocarditis. Additionally, several medications being utilized off-label in the management of
COVID-19 (azithromycin, hydroxychloroquine, chloroquine, and lopinavir/ritonavir) have been
reported to prolong the QT interval. QT prolongation, particularly in those with underlying
medical risk factors, has been linked to lethal ventricular arrhythmias, such as Torsades de
Pointes (TdP).

A complete discussion of the cardiac side effects of psychotropics is beyond the scope of this
paper, except to note that it has been well described in the literature that a number of
psychotropic medications can prolong the QT interval. Although the data are often difficult to
interpret due to confounding factors, antipsychotics, tricyclic antidepressants and the SSRI
citalopram, appear to be the agents of most concern. It is difficult to stratify antipsychotic
medications by QT prolongation risk. Of the typical antipsychotics, thioridazine causes the
greatest QT prolongation, although IV haloperidol has also been implicated. The greatest risk
among the atypicals appears to be related to ziprasidone and possibly iloperidone. Aripiprazole
and possibly lurasidone have been associated with the lowest risk based on available data (15).

Health care providers should be aware of the baseline corrected QT interval (QTc) and all
concomitant medications, labs, medical comorbidities and family history prior to prescribing
psychotropics in COVID-19 patients. Caution should be used in patients with a baseline
prolonged QTc and/or other risk factors for drug-induced QT prolongation and TdP: use of QT
prolonging medications, cardiac comorbidities, age >65, female sex, family history of sudden
cardiac death, hypokalemia/hypomagnesemia, and illicit substance use. If QT-prolonging
medications are used in a patient with a QTc>500ms or other significant risk factors, ECGs
should be monitored frequently (daily in high risk cases), potassium and magnesium should be
repleted, cardiology involvement should be considered, and every attempt made to reduce risk
factors (15). In patients who test positive for COVID-19 but are already taking a psychotropic
drug that has inherent potential for QTc prolongation, risk-benefit decisions must be made on a
case-by-case basis regarding continuation versus switching to an alternative medication.

Hepatic Effects
Several studies have reported acute liver injury, particularly in severe COVID-19 cases
(4,16,17). The etiology of the liver injury is not known and hypotheses include viral infection,
drug-induced liver injury, and systemic inflammation due to cytokine storm or hypoxia (16). Lab
abnormalities observed include elevated AST, ALT and bilirubin (17). Liver function tests
should be monitored and, if abnormal, consideration given to avoiding psychotropics that can
also cause hepatic injury or making dose adjustments if heavily dependent on hepatic
metabolism. Since most psychotropics are lipid soluble and require hepatic metabolism prior to
clearance, clinicians should review the package insert to determine if a dose adjustment is
needed. Additionally, many psychotropics (valproate, carbamazepine, tricyclic antidepressants,
serotonin norepinephrine reuptake inhibitors and second-generation antipsychotics) have been
associated with mild hepatoxicity that manifests with modest, transient increases in liver
enzymes. Only a few, are thought to have a high risk of causing serious drug-induced liver injury
(DILI), including chlorpromazine, carbamazepine, valproate, duloxetine and nefazodone (18,19).
Such high risk psychotropics should be preferentially avoided in patients with COVID-19
associated liver disease.

Renal Effects
Acute kidney injury has been observed, particularly in patients with COVID-19-associated acute
respiratory distress syndrome (ARDS) and pre-existing chronic kidney disease. Several causes
have been proposed, including impaired gas exchange, hemodynamic alterations, sepsis, and an
inflammatory/immune reaction involving release of circulating mediators that cause injury to
kidney cells (20). In such patients, avoiding potentially nephrotoxic drugs, such as lithium, may
be required. Additionally, psychiatrists should be aware of any renal impairment and make
necessary dose adjustments as per the manufacturer’s prescribing information. Psychotropics
highly dependent on renal excretion include lithium, gabapentin, topiramate, pregabalin and
paliperidone. Many other psychotropics have renally excreted active metabolites. Levels of these
medications or their metabolites can increase in the setting of impaired renal clearance such that
reduced dosing or avoiding the medication may be required. For example, administration of
duloxetine is not recommended for patients with severe renal impairment (CrCL of <30 mL/min)
(18).

Neurological Effects
Based on similarities between SARS-CoV2 and other coronaviruses, it is thought likely that
SARS-CoV2 has neuroinvasive potential (21) but there remain many unanswered questions
about neurological manifestations of COVID-19. Initial observations note a variety of
neurological syndromes in COVID-19 patients, particularly the more severely affected. These
include stroke, delirium, seizures, and an encephalitis-type presentation. A recent paper from
Wuhan (22) reports neurologic symptoms in 36.4% of COVID-19 patients, falling into 3
categories: 1) Central nervous system symptoms or diseases (headache, dizziness, impaired
consciousness, ataxia, acute cerebrovascular disease, and seizure); 2) Peripheral nervous system
symptoms (impairment in taste, vision and smell, neuropathic pain) and 3) Skeletal muscular
injury. It is not known whether these neurologic syndromes are a direct effect of the virus
entering the central nervous system or an indirect response to the cytokine storm that patients are
experiencing. A specific prevalence rate of delirium was not reported but is presumed to be very
high and to contribute to poor adherence with care and other safety concerns. Certainly, for
patients with severe COVID-19 infections, there are many other potential etiologies of delirium,
including organ failure, hypoxia, sepsis, medication effects, and electrolyte/metabolic
abnormalities. Observational studies have in fact reported high rates of benzodiazepine use for
sedation in ventilator-dependent COVID-19 patients (23). Environmental factors such as
isolation from family members and difficulty mobilizing patients also contribute (24).

In COVID-19 patients with delirium, clinicians should be mindful about prescribing

benzodiazepines, opioids and drugs with strong anticholinergic properties (tertiary amine
tricyclic antidepressants, low potency antipsychotics, benztropine and diphenhydramine) as these
medications have the potential to cause or exacerbate confusion, sedation and/or falls. Clinicians
should also be cautious about prescribing psychotropics that can lower the seizure threshold in
patients with seizures or structural brain lesions. Such medications include most antipsychotics
(especially clozapine, quetiapine, olanzapine and first generation antipsychotics) (25) and certain
antidepressants (bupropion, tricyclics) (26).

Pulmonary Effects
As the lung is considered the primary organ that is affected by COVID-19, most patients present
with respiratory symptoms, such as cough and shortness of breath. Affected individuals may
develop pneumonia and acute respiratory distress syndrome leading to high supplemental oxygen
requirements and in the most severe cases, invasive ventilation (4). Psychiatric consultants may
be asked to evaluate and manage COVID-19 patients with anxiety or panic symptoms in addition
to respiratory distress. While there may be circumstances in which the use of small doses of a
benzodiazepine is appropriate, it is important to be aware of the potential for benzodiazepines to
suppress respiratory drive, particularly at higher doses. Clinicians therefore need to consider
risks versus benefits in using benzodiazepines in patients with prominent respiratory symptoms.

Psychiatric considerations of proposed COVID-19 Treatments

Many of the proposed COVID-19 treatments have the potential for neuropsychiatric side effects
as well as drug-drug interactions. These are reviewed in the section below and summarized in
Table 3.

Remdesivir

Remdesivir is an antiviral medication that interacts with RNA polymerase and evades
proofreading by viral exonuclease leading to a decrease in viral RNA (27). On May 1, 2020, the
U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) to
use remdesivir for treatment of suspected or confirmed severe COVID-19 infection (1), with
severe defined as “patients with an oxygen saturation ≤ 94% on room air or requiring
supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane
oxygenation (ECMO)”. The EUA was based on early promising data from a randomized double-
blinded, placebo-controlled (28) and an open-label trial (29). Remdesivir is administered by
infusion, with a treatment course of 5 or 10 days, depending on severity of disease.
Neuropsychiatric effects
No information is available regarding neuropsychiatric side effects, but administration has been
associated with infusion-related reactions that can present with hypotension, diaphoresis and
shivering (1). Such symptoms might be misconstrued as a panic attack.
Psychotropic Considerations
Remdesivir carries a risk of transaminase elevations (30), specifically but not limited to alanine
aminotransferase (ALT) elevations up to 20 times the upper limit of normal (1). This may impact
the decision to use hepatically metabolized psychotropics, such as valproic acid.
Chloroquine and Hydroxychloroquine
Chloroquine, a synthetic form of quinine used for the treatment and prophylaxis of malaria, and
hydroxychloroquine a derivative compound used in the treatment of inflammatory disorders such
as rheumatic arthritis and systemic lupus erythematosus, are being considered as a possible
treatment for COVID-19 infection. Interest in these medications is in part due to their potential
for interference with virus-receptor binding and immune-modulating effects (31). The most
promising study is a small open-label trial from France (32), although a recent large
observational study showed that the risk of intubation or death was not significantly higher or
lower among patients who received the drug than among those who did not (33). The authors
suggest that their findings do not support continued use of the drug in COVID-19 patients
outside of clinical trials. Neuropsychiatric effects

Neuropsychiatric side effects of chloroquine and hydroxychloroquine include psychosis,

delirium, agitation, suicidality, personality changes, depression, and sleep disturbances (34,35).
Risk factors for hydroxychloroquine-induced neuropsychiatric effects may be concurrent use of
CYP3A4 inhibitors or low-dose glucocorticoids, alcohol intake, family history of psychiatric
disease, female gender, low body weight and supratherapeutic dosing (36).

A number of mechanisms have been postulated for the pathogenesis of hydroxychloroquine-

induced neuropsychiatric effects, such as cholinergic imbalance due to acetylcholinesterase
inhibition, inhibition of the serotonin transporter protein, and NMDA and GABA antagonism
(34).

Psychotropic Considerations

Hydroxychloroquine and chloroquine can cause heart conduction disorders, including QT

interval prolongation, bundle branch block, AV block, and torsades de pointes (37). On April
24, 2020, the FDA issued a safety announcement against use of hydroxychloroquine or
chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart
rhythm problems (38). Caution should be used when combining them with QT prolonging
psychotropics. These agents can also be hepatotoxic (39) and epileptogenic (40), so caution
should be exercised in patients with hepatic disease, or in conjunction with psychotropics that
may be hepatotoxic or may lower the seizure threshold.

Both chloroquine and hydroxychloroquine are metabolized by CYP3A4 (41), so CYP3A4

inhibitors (e.g. fluvoxamine), could raise plasma levels and increase the potential for adverse
effects. By contrast, CYP3A4 inducers, such as carbamazepine, oxcarbazepine and modafinil
could decrease levels of chloroquine or hydroxychloroquine, potentially rendering them less
effective. Given hydroxychloroquine’s long half-life (40 hours), the potential for continued
adverse effects and drug-interactions may continue for days after the drug has been discontinued
(35).

Tocilizumab
Tocilizumab is a recombinant humanized monoclonal antibody that acts as an interleukin-6 (IL-
6) receptor inhibitor (42) and is FDA approved to treat several types of arthritis (43).
Tocilizumab is being trialed in severe COVID-19 patients with elevated IL-6 because IL-6
appears to be involved in cytokine storms that have been observed in critically ill patients with
COVID-19 (44).

Neuropsychiatric effects

Data from rheumatic arthritis patients suggest that Tocilizumab may have some positive effects
on depressive symptoms in rheumatoid arthritis (45,46), however unpublished data from a small
study surprisingly suggests that patients who received tocilizumab following allogeneic
hematopoietic cell transplantation experienced worse symptoms of depression, anxiety, pain, and
sleep (47).

Psychotropic Considerations

No major interactions have been reported.

Favipiravir

Favipiravir is an antiviral thought to act as an RNA dependent RNA polymerase inhibitor (48).
It was approved in China in February 2020 for treatment of influenza (48) and there are current
trials evaluating its efficacy on SARS-Cov-2. It is not currently approved for use in the United
States.
Neuropsychiatric effects
No published information is available.
Psychotropic Considerations
There is no published information available. One published case report suggested a mild QT
prolongation in an Ebola virus patient who received favipiravir (49).

Lopinavir/Ritonavir (Kaletra)

Lopinavir/Ritonavir is an antiviral medication used to treat HIV-1 infection (50) The two
medications work synergistically: lopinavir is a protease inhibitor and ritonavir helps to boost
plasma levels of lopinavir by inhibiting its metabolism(50). Unfortunately, a recently published
randomized, controlled, open-label trial found no additional benefit with lopinavir-ritonavir
treatment in hospitalized patients with SARS-CoV-2 as compared with standard care (51).

Neuropsychiatric effects
The manufacturer’s prescribing information lists possible psychiatric side effects, including
abnormal dreams, agitation, anxiety, confusion and emotional lability although there is limited
information in published case reports or trials regarding the incidence of such effects (50).
Protease inhibitors as a class have been associated with neurological adverse events, such as
paresthesias, taste alterations, and neurotoxicity (52).

Psychotropic Considerations

Protease inhibitors are extensively metabolized by the cytochrome P450 system and have been
shown to interact with many drugs, including psychotropics (53). Use of Ritonavir may lead to
increased concentrations of co-administered drugs that are CYP3A4 or CYP2D6 substrates or
decreased concentrations of CYP1A2 or CYP2B6 substrates, many of which are psychotropics.

Use of Lopinavir/Ritonavir is contraindicated with medications that include pimozide,

midazolam, and triazolam due to increased drug levels and potentiation of adverse effects. Use of
benzodiazepines not dependent on CYP metabolism (lorazepam, temazepam or oxazepam) is
recommended. Due to CYP450 enzyme or glucuronidation inducing effects, Ritonavir-boosted
protease inhibitors also have been shown to lower concentrations of some psychotropics (e.g.
bupropion, methadone, lamotrigine and olanzapine), thus leading to increased dose requirements
for these medications (53).

Since most psychotropics are substrates for CYP isoenzymes, there are many additional
theoretical interactions, but the clinical significance varies by agent. Clinicians should assess
each potential interaction individually by reviewing available literature and manufacturer
prescribing information.

Other potential non-psychiatric side effects that may have implications for psychiatrists include
the following: Stevens Johnson syndrome, diabetes mellitus, QTc prolongation, pancreatitis,
neutropenia, hepatotoxicity and chronic kidney disease (50).

Convalescent plasma therapy

Antibody containing convalescent plasma from recovered patients has been used with some
success as a last resort to treat severe viral respiratory infections such as SARS-CoV, MERS-
CoV, and Ebola although large clinical trials are absent (54). Trials are currently underway to
study the effectiveness of convalescent plasma therapy in the treatment of individuals with
severe respiratory failure associated with COVID-19.

Neuropsychiatric effects

When used for the treatment of other severe acute viral respiratory infections, convalescent
plasma therapy was not associated with serious adverse events (55), although in general, plasma
transfusions can cause a range of adverse events from mild fever and allergic reactions to life
threatening bronchospasm/anaphylaxis, transfusion-related acute lung injury and transfusion
associated circulatory overload (56).
Specific neuropsychiatric effects have not been reported, although allergic reactions,
cardiovascular complications and bronchospasm can produce symptoms such as shortness of
breath and palpitations that mimic panic attacks.

A potential psychological adverse effect of convalescent plasma therapy relates to ethical

concerns about coercion, confidentiality, and privacy for the prospective donors that were
initially raised during the Ebola outbreak (57) and led to a World Health Organization document
providing guidance on the ethical use of convalescent plasma (58).

Psychotropic Considerations

There are no specific interactions between psychotropics and plasma transfusions, but patients
who develop transfusion reactions might receive steroids or diphenhydramine which can have
negative synergistic effects with existing psychotropics.

Azithromycin

Azithromycin is an antibacterial agent which may have antiviral and anti-inflammatory activity
(32). It is under investigational use for treatment of COVID-19 when given in conjunction with
chloroquine or hydroxychloroquine. In one small French study (n=20), azithromycin added to
hydroxychloroquine was significantly more efficient for virus elimination as compared to
hydroxychloroquine alone (32).

Neuropsychiatric effects

Side effects that have been reported include psychotic depression, catatonia, delirium, aggressive
reaction, anxiety, dizziness, headache, vertigo and somnolence (59,60).

Psychotropic Considerations

Azithromycin has not been implicated in pharmacokinetic interactions with psychotropics but
has been associated with QTc prolongation and life-threatening TdP arrhythmias. It has also
been associated with hepatotoxicity (61).

Vitamin C

High dose intravenous vitamin C (ascorbic acid), an antioxidant and reducing agent, has been
investigated in the treatment of sepsis due to its enhancement of the immune response (62). In
the intensive care setting, vitamin C administration has been correlated with preventing
progressive organ dysfunction and reducing mortality in sepsis and acute respiratory distress
syndrome (ARDS) (63), and is being investigated in critically ill patients with COVID-19.

Neuropsychiatric effects
There are no known adverse neuropsychiatric consequences of high-dose IV vitamin C
administration, but some studies have associated lower levels of vitamin C with depression,
confusion and anger (64). Vitamin C deficiency has also been identified as a possible risk factor
for delirium (65).

Psychotropic Considerations

Coadministration with barbiturates may decrease the effects of vitamin C (62).

Corticosteroids

Corticosteroids are involved in immune function, inflammation, and carbohydrate metabolism

and are used in the treatment of endocrinopathies, autoimmune disorders, and asthma/allergies
(66). In previous pandemics, such as SARS and MERS, corticosteroids were not recommended
due to concern that they may exacerbate lung injury (67). Given evidence suggesting that severe
COVID-19 may be associated with a cytokine storm and hyperinflammation syndrome (67),
corticosteroids may have a role in treatment.

Neuropsychiatric effects

The neuropsychiatric side effects of corticosteroids have been well described in the literature and
include depression, mania, agitation, mood lability, anxiety, insomnia, catatonia,
depersonalization, delirium, and psychosis (66). The majority of neuropsychiatric side effects
occur early in treatment course, usually within days, and dosing is the most significant risk factor
(i.e. at prednisone equivalents of >40mg/day) (66).

Psychotropic considerations

Corticosteroids have been inconsistently reported to be weak CYP 3A4 and CYP2C19 inducers
(68), which could lead to decreased effects of CYP3A4 or CYP2C19 substrate psychotropics
(69). Additionally, phenytoin has been shown to increase hepatic metabolism of systemic
corticosteroids (70).

Interferon

Interferons (IFNs) are glycoproteins that have immunomodulatory, antiproliferative, and

hormone-like activities (71). IFN alpha and beta have anti-SARS-CoV-1 activity in vitro and
IFN beta reduces the replication of MERS-CoV (72,73) in vitro. Based on this information, IFN
has been considered as a potential treatment for COVID-19, including in combination with
Ribavirin, a guanosine analogue with broad spectrum antiviral potency (74).

Neuropsychiatric effects

IFN alpha has a boxed warning for “life threatening or fatal neuropsychiatric disorders” (75).
Specific effects include fatigue, mood disorders, suicidality, anxiety disorders, irritability,
lability, apathy, sleep disturbance, and cognitive deficits (76). Side effects of IFN beta can
include fatigue, weight loss, myalgia and arthralgia (77), but not generally depression. Given the
potential for significant psychiatric side effects of IFN alpha, it is important for clinicians to
screen for baseline psychiatric history and monitor closely for emergence of any symptoms.

Psychotropic Considerations

There are no known pharmacokinetic interactions with psychotropics but clinicians should be
mindful of the potential for bone marrow suppression which may raise safety concerns with
concurrent use of psychotropics, such as carbamazepine, valproate and clozapine. Additionally,
seizures in conjunction with bupropion use have been reported (78).

Colchicine

Colchicine is a plant-derived alkaloid with anti-inflammatory properties that is used for a variety
of rheumatological and cardiac conditions (79). It is hypothesized that colchicine could treat
COVID-19 through targeting the overactive IL-6 pathway (80).

Neuropsychiatric effects

Colchicine does not typically produce any neuropsychiatric effects, but at toxic doses, can cause
delirium, seizures and muscle weakness.. (81).

Psychotropic Considerations

Colchicine has a narrow therapeutic index and attention must be paid to potential drug
interactions that might increase cause toxicity. Colchicine is metabolized by CYP3A4 and
excreted via the P-glycoprotein (P-gp) transport system as well as cleared by the kidneys through
glomerular filtration. Dose adjustment is recommended with concurrent use of CYP 3A4 or P-gp
inhibitors as well as in patients with hepatic or renal impairment (82). CYP3A4 inducers can
lead to increased metabolism, and theoretically decreased effectiveness of colchicine.

Discussion
COVID-19 and its treatments can impact many organ systems and contribute to a host of drug
interactions and neuropsychiatric effects. This can have safety implications for use of
psychotropics, which are highly metabolized by the hepatic cytochrome p450 system and carry
their own potential for drug-interactions and end-organ adverse effects.

While there are no absolute contraindications to use of psychotropics in COVID-19 patients,

psychiatrists must be mindful of potential adverse effects and conduct a thoughtful risk-benefit
analysis as part of their clinical decision-making process. For example, chloroquine,
hydroxychloroquine, and azithromycin have the potential for QT prolongation, which can be
problematic in patients with tenuous cardiac status. Generally, psychiatrists might avoid
antipsychotic medications in the setting of a prolonged QT interval. However, in our experience,
hyperactive delirium in COVID-19 patients is highly prevalent and manifests with severe
agitation that can be difficult to treat and leads to dangerous behaviors such as removing oxygen
or assaulting staff. While there is limited evidence to support the use of any interventions in the
management of agitation in COVID-19 associated delirium, most CL psychiatrists consider
antipsychotics such as haloperidol the gold standard for managing agitation in delirious patients.
In these situations, the CL psychiatrist should assist the medical team in reasoning through the
cardiac risks of using an antipsychotic balanced against effective management of the agitation.
Use of an antipsychotic with cardiology involvement and frequent EKG monitoring or telemetry
may be deemed acceptable. Alternatives such as alpha-2 agonists (dexmedetomidine and
clonidine) or anti-epileptics (valproic acid) should be considered if the individual patient’s
cardiac risk is determined to be high and/or if the antipsychotic is clinically ineffective.
Melatonin has been proposed for addressing consciousness and sleep-wake cycle disturbances in
delirious COVID-19 patients, especially given its potential for anti-oxidative, anti-inflammatory
and immune-enhancing effects (83). With the exception of patients who chronically use alcohol
or benzodiazepines and may be at risk for withdrawal, benzodiazepines should be avoided if
possible and considered only as a last resort for highly agitated delirious patients for whom other
treatments are unavailable or ineffective. Early delirium screening and non-pharmacological
strategies to prevent or treat delirium such as frequent orientation and early mobilization should
be employed if practically feasible (24).

As another example, we have observed many non-delirious COVID-19 patients with significant
anxiety in the setting of respiratory distress. In some cases, the anxiety leads to requests to leave
against medical advice or refusal to remain isolated. For these patients, psychiatrists should
consider whether the benefit of a low dose benzodiazepine outweighs the potential risk of
respiratory depression. Use of benzodiazepines may be reasonable in patients with adequate
oxygen saturation and absence of confusion or a depressed sensorium. Depending on the
individual patient’s circumstances and symptoms, alternative medications such as gabapentin,
buspirone, hydroxyzine, a low dose atypical antipsychotic, or a selective serotonin reuptake
inhibitor (SSRI) may be appropriate. Non pharmacological/psychosocial interventions (eg,
behaviorally oriented therapies) should also be utilized.

Other important tasks for the psychiatrist treating a COVID-19 patient include review of all
medications, monitoring for neuropsychiatric side effects of medications such as
hydroxychloroquine or corticosteroids and differentiating between primary psychiatric symptoms
versus those that are secondary to COVID-19 or other medications.

Interestingly, several psychotropics, including haloperidol and valproic acid were recently named
on a list of FDA approved medications with potential for in vitro action against SARS-CoV-2
(84) Fluvoxamine is also under investigation for its potential to reduce the inflammatory
response during sepsis by inhibiting cytokine production(85), and melatonin for its anti-oxidative
and anti-inflammatory properties (86). If more data becomes available, psychiatrists might
consider preferentially using these agents if clinically appropriate.
In summary, psychiatrists must be aware of the likelihood of encountering patients with COVID-
19 infection and must remain cognizant of the neuropsychiatric effects and drug-drug
interactions of COVID-19 treatments as well as the end-organ effects of COVID-19.

Disclosures
Dr. Ernst receives royalty payments from American Psychiatric Publishing, Inc. The other
authors report no proprietary or commercial interest in any product mentioned or concept
discussed in this article.

This research did not receive any specific grant from funding agencies in the public, commercial,
or not-for-profit sectors.

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 Table 1. Potential Psychotropic Safety Concerns in COVID-19 Organized by Drug Class

Drug Class Specific Drugs Problem Solution

Antipsychotics Clozapine Patients with difficulty accessing Reduce frequency of ANC monitoring
ANC monitoring at discretion of provider

May be associated with increased risk Education of patients and urgent

of pneumonia and its complications clinical assessment including ANC for
those with symptoms of infection

Levels can increase with acute Consider halving clozapine dose in

infection leading to clozapine toxicity patients with fever, pneumonia and/or
flu-like symptoms; temporarily
discontinue clozapine if toxicity
emerges

COVID-19 associated with leukopenia Monitor complete blood count (CBC);

and lymphopenia; unclear impact on if persistent white blood cell
neutrophils; clozapine associated with abnormalities, weigh risks vs benefits
neutropenia and agranulocytosis and of continuing clozapine; when total
more rarely lymphopenia or aplastic white blood cell count is decreased but
anemia neutrophil count is normal, consider
continuing clozapine

COVID-19 associated with seizures; Recognize potential for lowered seizure

clozapine can lower seizure threshold threshold; assure non-toxic clozapine
level; consider holding clozapine,
decreasing dose, or adding anti-
epileptic

Other COVID-19 associated with decreased Monitor CBC; if persistent hematologic

Antipsychotics white blood cell and lymphocyte abnormalities (eg, lymphopenia,
counts; rare reports of antipsychotic- neutropenia, thrombocytopenia) weigh
associated aplastic anemia or risks vs benefits of continuing
lymphopenia, especially with antipsychotic agent
phenothiazines (chlorpromazine,
fluphenazine, thioridazine)

Coagulation abnormalities (PT and

aPTT prolongation,
thrombocytopenia) are observed in
COVID-19 patients; rare reports of
thrombocytopenia associated with
multiple antipsychotics

Concern for COVID-19 associated Baseline EKG for QTc; caution in

tachyarrhythmias and cardiac injury patients with baseline prolonged QTc
and potential for several medications and/or other risk factors for drug-
being used to treat COVID-19 to induced QT prolongation and TdP;
cause QT prolongation; all daily EKG and electrolyte monitoring,
antipsychotics with potential for QT reduce other risk factors, and
prolongation cardiology consult in high risk cases if
opt to use antipsychotic; case-by-case
 risk-benefit discussion

Monitor liver function tests and avoid

Acute liver injury in COVID-19 chlorpromazine in patients with liver
patients; antipsychotics (especially injury; risk vs benefit assessment for
chlorpromazine) with potential for other antipsychotic use
drug-induced liver injury
Consider avoiding antipsychotics
COVID-19 associated with seizures; (especially clozapine, quetiapine,
all anti-psychotics can lower seizure olanzapine and first generation drugs)
threshold or adding anti-epileptic drug in patients
who have seizures

Anti-Epileptic Carbamazepine COVID-19 associated with leukopenia Monitor CBC; if persistent white blood
Drugs (AED) and lymphopenia; leukopenia and rare cell abnormalities or aplastic anemia,
reports of aplastic anemia associated use alternative AED
with carbamazepine use;

Acute liver injury in COVID-19 Monitor liver function tests and avoid
patients; carbamazepine with carbamazepine in patients with liver
potential for drug-induced liver injury injury

Valproic Acid Coagulation abnormalities (PT and Monitor platelet count; avoid valproic
aPTT prolongation, acid if thrombocytopenia
thrombocytopenia) observed in
COVID-19 patients; valproic acid
associated with thrombocytopenia

Acute liver injury in COVID-19 Monitor liver function tests and avoid
patients; valproic acid with potential valproic acid in patients with liver
for drug-induced liver injury injury

Gabapentin COVID-19 with potential for acute Adjust gabapentin dose based on renal
kidney injury; gabapentin clearance function
dependent on intact renal function

Selective (all) Coagulation abnormalities observed in Monitor coagulation factors and

Serotonin COVID-19 patients and many platelet count; weigh risks and benefits
Reuptake COVID-19 patients receiving for individual patient but consider
Inhibitors anticoagulation; SSRIs and SNRIs avoiding SSRIs and SNRIs in patients
(SSRIs) and associated with impaired platelet with recent bleeding or high risk for
Serotonin aggregation and abnormal bleeding bleeding (eg, thrombocytopenia,
Norepinephrine concurrent anticoagulation therapy,
Reuptake history of hemorrhage); can instead use
Inhibitors non serotonin reuptake inhibitor
(SNRIs) antidepressant such as bupropion

Concern for COVID-19 associated Baseline EKG for QTc; caution in

tachyarrhythmias and cardiac injury patients with baseline prolonged QTc
and potential for several medications and/or other risk factors for drug-
being used to treat COVID-19 to induced QT prolongation and TdP;
cause QT prolongation; citalopram consider using SSRI other than
with potential for QT prolongation citalopram in high risk cases
 Acute liver injury in COVID-19 Monitor liver function tests avoid
patients; duloxetine with potential for duloxetine in patients with liver injury
drug-induced liver injury

Bupropion COVID-19 associated with seizures; Avoid bupropion in patients with

bupropion can lower seizure threshold seizures or lowered seizure threshold

Lithium COVID-19 with potential for acute Adjust lithium dose based on renal
kidney injury; lithium clearance function; consider temporarily holding
dependent on intact renal function; lithium until acute kidney injury
lithium with nephrotoxic potential resolves

Benzodiazepines (all) COVID-19 associated with delirium; Avoid or taper existing

benzodiazepines can exacerbate benzodiazepines in patients with
delirium delirium if possible

COVID-19 associated with prominent Weigh risks vs benefits in using

respiratory symptoms; benzodiazepines in patients with
benzodiazepines can suppress prominent respiratory symptoms; a low
respiratory drive dose may be able to be used safely in
non-delirious patients

Lopinavir/Ritonavir contraindicated Avoid midazolam and triazolam and

with midazolam and triazolam (and consider using lorazepam, temazepam
can raise levels of some other or oxazepam in patients taking
benzodiazepines) due to CYP450 Lopinavir/Ritonavir
inhibition
 Table 2. Potential Psychotropic Safety Concerns in COVID-19 Organized by Organ System

Organ System affected by COVID- Systemic Effects and Symptoms Potential Psychotropic Safety Concerns
19
Hematologic Lymphopenia Consider avoiding medications that can negatively
impact white blood cell (WBC) production
Coagulopathy (increased PT, aPTT; decreased
platelets) Highest risk: carbamazepine, clozapine, olanzapine
Moderate risk: all 1st and 2nd generation antipsychotics
(especially low potency conventionals)
Rare reports: TCAs, benzodiazepines
(chlordiazepoxide), gabapentin, and valproate

Consider avoiding medications that can increase

bleeding risk (via thrombocytopenia or impaired
platelet aggregation): valproic acid, SSRIs, SNRIs
Cardiac Concern for tachyarrhythmias, heart failure, Caution with psychotropics known to prolong QTc and
myopericarditis, acute cardiac injury in patients with other underlying risk factors for QT
prolongation
Several medications being utilized for COVID-
19 (azithromycin, hydroxychloroquine, Highest risk: antipsychotics, citalopram, tricyclic
chloroquine, lopinavir/ritonavir) reported to antidepressants
prolong QT interval

Hepatic Risk of acute liver injury, especially in severe In patients with hepatic injury or failure:
cases
Consider avoiding psychotropics that can also cause
serious drug-induced liver injury (DILI):
chlorpromazine, carbamazepine, valproate, duloxetine
and nefazodone.

Refer to prescribing information to determine if dose

adjustments are needed

Renal Acute kidney injury has been observed, Consider dose adjustment with some psychotropics
particularly in patients with COVID-19- (e.g. lithium, gabapentin, topiramate, pregabalin,
associated acute respiratory distress syndrome paliperidone, and duloxetine)
(ARDS) and pre-existing chronic kidney disease
Consider avoiding potentially nephrotoxic drugs
Nervous system Central Nervous System: headache, dizziness, In patients with delirium, caution with deliriogenic
impaired consciousness, ataxia, stroke, delirium, medications: benzodiazepines, opioids, sedative-
seizures hypnotics, and those drugs with strong anticholinergic
effects (tertiary amine tricyclic antidepressants, low
Peripheral nervous system: impaired potency first generation antipsychotics, some second-
taste/smell/vision, neuropathic pain generation antipsychotics, benztropine and
diphenhydramine

Caution with medications that can lower seizure

threshold: antipsychotics and certain antidepressants
(bupropion, tricyclics)
Pulmonary Cough, shortness of breath, pneumonia and acute In COVID-19 patients with anxiety or panic symptoms,
respiratory distress syndrome weigh risks vs benefits in using benzodiazepines in
patients with prominent respiratory symptoms, given
potential to suppress respiratory drive
 Table 2. Psychiatric Side Effects and Drug Interactions with Proposed COVID-19 Treatments

Proposed COVID Mechanism of Action Psychiatric side effects Drug-drug Interactions

19 treatment
Azithromycin Used with hydroxychloroquine. Psychotic depression, catatonia, • Risk of QTc prolongation – caution with
delirium, aggressive reaction, psychotropics known to prolong QTc
Antibacterial (primarily) anxiety, dizziness, headache, • Risk of hepatotoxicity- caution with hepatotoxic
vertigo and somnolence drugs
Antiviral and anti-inflammatory
(potential)
Chloroquine and Anti-inflammatory Psychosis, delirium, suicidality, • Risk of QTc prolongation – caution with QT
hydroxychloroquine personality changes, depression, prolonging drugs. Do not use outside of the
Antiviral: interference with nervousness, irritability, hospital setting or a clinical trial due to risk of
virus-receptor binding compulsive impulses, heart rhythm problems (FDA)
preoccupations, and • Metabolized by CYP3A4 – potential drug
aggressiveness interactions with CYP3A4 inhibitors (eg,
Immune modulating effects fluvoxamine) and inducers (eg, carbamazepine,
oxcarbazepine, modafinil)
• Risk of hepatotoxicity- caution with hepatotoxic
drugs
• Risk of seizures- caution with psychotropics that
can lower the seizure threshold
• Higher risk of neuropsychiatric side effects
when combined with CYP3A4 inhibitors, low-
dose glucocorticoids, alcohol intake, family
history of psychiatric disease, female gender,
low body weight and supratherapeutic dosing

• Long half-life (40 hours) - adverse effects and

drug-interactions may continue for days after
the drug has been discontinued

Colchicine Anti-inflammatory At toxic doses: delirium, • Narrow therapeutic index – potential for toxicity
seizures, muscle weakness, • Caution in renal and hepatic failure
Immune modulator: targets IL- depressed reflexes • Caution with P-gp and CYP 3A4 inhibitors (eg,
6 pathway, inhibition of fluvoxamine)
NLRP3 inflammasome. May • CYP3A4 inducers may decrease levels
attenuate cytokine storm.

Convalescent Antibody containing No specific psychiatric effects • There are no specific interactions
plasma therapy convalescent plasma from
patients who have recovered (N.B. allergic reactions can (N.B. patients who develop transfusion reactions
from viral infections produce shortness of breath and might receive steroids or diphenhydramine which can
palpitations that mimic panic have negative synergistic effects with existing
attacks) psychotropics).

Potential psychological effects

for donors
Corticosteroids Immune modulators and anti- Depression, mania, agitation, • Inconsistently reported to be weak CYP 3A4
inflammatory: may lessen mood lability, anxiety, insomnia, and CYP2C19 inducers
cytokine storm and catatonia, depersonalization, • Phenytoin – increases hepatic metabolism of
hyperinflammation syndrome delirium, dementia, and systemic corticosteroids
psychosis • Caution with bupropion- lowers seizure
threshold
• Majority of neuropsychiatric side effects occur
early in treatment course, usually within days,
and dosing is the most significant risk factor
 (i.e. at prednisone equivalents of >40mg/day)

Favipiravir Anti-viral: RNA dependent No information • Possible QT prolongation

RNA polymerase inhibitor

Interferon Immune modulator, IFN alpha: boxed warning for • No known pharmacokinetic interactions with
antiproliferative, and hormone- “life threatening or fatal psychotropics
like activities neuropsychiatric disorders.” • Potential for bone marrow suppression - safety
Specific effects include fatigue, concerns with some psychotropics (eg,
Anti-viral mood disorders, suicidality, carbamazepine, valproate and clozapine)
anxiety disorders, irritability, • May lower seizure threshold: caution with
lability, apathy, sleep psychotropics that also lower seizure threshold
disturbance, and cognitive
deficits

IFN beta: fatigue, weight loss,

myalgia, arthralgia
Lopinavir/Ritonavir Anti-viral Possible abnormal dreams, • Extensively metabolized by cytochrome P450 –
agitation, anxiety, confusion and risk of multiple possible interactions
Lopinavir: protease inhibitor emotional lability • May get increased concentrations of co-
administered CYP3A4 or CYP2D6 substrates
All protease inhibitors associated • May get decreased concentrations of CYP1A2
Ritonavir: boosts plasma levels
with paresthesias, taste or CYP2B6 substrates
of lopinavir
alterations, and neurotoxicity • Contraindicated with pimozide, midazolam, and
triazolam due to increased drug levels and
potentiation of adverse effects
• Lowers concentrations of some psychotropics
(e.g., bupropion, methadone, lamotrigine and
olanzapine)
•
• Other potential side effects that may impact
psychotropic use: Stevens Johnson syndrome,
diabetes mellitus, QTc prolongation,
pancreatitis, neutropenia, hepatotoxicity and
chronic kidney disease

Remdesivir *Only FDA-approved No information • No information is available about

medication for severe COVID- pharmacokinetic drug-drug interactions
19 • Risk of elevated aminotransferase levels (e.g.
ALT up to 20x upper limit of normal)– caution
Interacts with RNA with potentially hepatotoxic psychotropics
polymerase, leads to decrease
in viral RNA
Tocilizumab Immune modulator: Possible positive effects on • No major interactions reported
recombinant humanized depressive symptoms
monoclonal antibody that acts
as an IL-6 inhibitor; may lessen
cytokine storm
Vitamin C Enhances immune response, No evidence for • Coadministration with barbiturates may
antioxidant and reducing agent neuropsychiatric adverse effects; decrease the effects of vitamin C

Of note, lower levels associated

with depression, confusion,
anger, delirium