Review Article Psychopharmacology of COVID-19

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19. The COVID-19 resource centre is hosted on Elsevier Connect, the company’s public news and information website.

Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre – including this research content – immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Psychosomatics 2020:-:-–- a 2020 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.

Melanie Bilbul, M.D., C.M., F.R.C.P.(C), Patricia Paparone, M.D., Anna M. Kim, M.D., Shruti Mutalik, M.D., Carrie L. Ernst, M.D.

  

Background: With the rapid, global spread of severe acute respiratory syndrome coronavirus 2, hospitals have become inundated with patients suffering from corona- virus disease 2019. 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 Food and Drug Administration– 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. Objective: To provide an overview of the major safety considerations relevant to clinicians who prescribe psy- chotropics 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 one 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 psycho- tropic medications and increase sensitivity to psychotropic-related adverse effects. In addition, several proposed treatments for COVID-19 have neuropsychiatric effects and potential interactions with commonly used psychotropics. Conclusions: Clinicians should be aware of the need to adjust existing psycho- tropics or avoid using certain medications in some pa- tients with COVID-19. 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.

Key words: COVID-19, psychotropic, psychopharmacology, side effects.

(Psychosomatics 2020; -:-–-)

INTRODUCTION

With the rapid, global spread of severe acute respira- tory syndrome coronavirus 2 (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 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

Received April 24, 2020; revised May 11, 2020; accepted May 12, 2020. From the Department of Psychiatry (M.B., P.P., A.M.K., S.M., C.L.E.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Medical Education (C.L.E.), Icahn School of Medicine at Mount Sinai, New York, NY. Send correspondence and reprint requests to Carrie L. Ernst, MD, One Gustave L. Levy Place, Box 1230, New York, NY 10029; e-mail: carrie.ernst@mssm.edu

a 2020 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.

  

Psychosomatics -:-, – 2020

http://www.psychosomaticsjournal.org 1

Psychopharmacology of COVID-19

with the mechanism of action of these treatments, neuropsychiatric side effects, and possible interactions with psychotropics. In addition, as COVID-19 affects multiple organ systems, psychiatrists will need to be aware of safety concerns inherent in prescribing psy- chotropics 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 recommenda- tions 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, hydroxy- chloroquine, azithromycin, tocilizumab, lopinavir/ ritonavir, favipiravir, convalescent plasma therapy, cor- ticosteroids, interferon (IFN), vitamin C, and colchicine.

Given the limited literature in this area, we un- dertook a nonsystematic narrative review that was focused on practical clinical concerns. We used a structured PubMed search using the following search terms in combination with the names of the medica- tions mentioned previously: “COVID-19”, “coronavi- rus”, “Psychotropic medications”, “QT prolongation”, “Psychiatric side effects”, “Neuropsychiatric side ef- fects”, “drug interactions”, and pertinent organ sys- tems, for example, “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 aforementioned medications as they were the ones most commonly being used in health care settings and clinical trials at the time of prepara- tion of this article, 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 medica- tions as well as increased sensitivity to certain psycho- tropic 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 3 109/L) in 63% and leukopenia (white blood cell count less than 4 3 109/L) in 25% of patients with COVID-19.4 It has been pro- posed 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 use caution and consider avoiding medica- tions that 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 agranulocy- tosis. 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. Carba- mazepine 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 patients with COVID-19 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 moni- toring, and the FDA has released guidance allowing health care providers to use medical judgment to delay

  

2 http://www.psychosomaticsjournal.org

Psychosomatics -:-, – 2020

Bilbul et al.

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

Drug class

Antipsychotics

Specific drugs

Clozapine

Problem

Patients with difficulty accessing ANC monitoring May be associated with increased risk of

pneumonia and its complications
Levels can increase with acute infection leading to

clozapine toxicity
COVID-19 associated with leukopenia and

lymphopenia; unclear impact on neutrophils; clozapine associated with neutropenia and agranulocytosis and more rarely lymphopenia or aplastic anemia

COVID-19 associated with seizures; clozapine can lower seizure threshold

COVID-19 associated with decreased white blood cell and lymphocyte counts; rare reports of antipsychotic-associated aplastic anemia or lymphopenia, especially with phenothiazines (chlorpromazine, fluphenazine, thioridazine)

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

Concern for COVID-19 associated tachyarrhythmias and cardiac injury and potential for several medications being used to treat COVID-19 to cause QT prolongation; all antipsychotics with potential for QT prolongation

Acute liver injury in patients with COVID-19; antipsychotics (especially chlorpromazine) with potential for drug-induced liver injury

COVID-19 associated with seizures; all antipsychotics can lower seizure threshold

COVID-19 associated with leukopenia and lymphopenia; leukopenia and rare reports of aplastic anemia associated with carbamazepine use;

Acute liver injury in patients with COVID-19; carbamazepine with potential for drug-induced liver injury

Coagulation abnormalities (PT and aPTT prolongation, thrombocytopenia) observed in patients with COVID-19; valproic acid associated with thrombocytopenia

Acute liver injury in patients with COVID-19; valproic acid with potential for drug-induced liver injury

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

Solution

Reduce frequency of ANC monitoring at discretion of provider

Education of patients and urgent clinical assessment including ANC for those with symptoms of infection

Consider halving clozapine dose in patients with fever, pneumonia, and/or flu-like symptoms; temporarily discontinue clozapine if toxicity emerges

Monitor complete blood count (CBC); if persistent white blood cell abnormalities, weigh risks versus benefits of continuing clozapine; when total white blood cell count is decreased but neutrophil count is normal, consider continuing clozapine

Recognize potential for lowered seizure threshold; assure nontoxic clozapine level; consider holding clozapine, decreasing dose, or adding antiepileptic

Monitor CBC; if persistent hematologic abnormalities (e.g., lymphopenia, neutropenia, thrombocytopenia) weigh risks versus benefits of continuing antipsychotic agent

Baseline EKG for QTc; caution in patients with baseline prolonged QTc and/or other risk factors for drug-induced QT prolongation and TdP; daily EKG and electrolyte monitoring, reduce other risk factors, and cardiology consult in high-risk cases if opt to use antipsychotic; case-by-case risk-benefit discussion

Monitor liver function tests and avoid chlorpromazine in patients with liver injury; risk versus benefit assessment for other antipsychotic use

Consider avoiding antipsychotics (especially clozapine, quetiapine, olanzapine, and first- generation drugs) or adding antiepileptic drug (AED) in patients who have seizures

Monitor CBC; if persistent white blood cell abnormalities or aplastic anemia, use alternative AED

Monitor liver function tests and avoid carbamazepine in patients with liver injury

Monitor platelet count; avoid valproic acid if thrombocytopenia

Monitor liver function tests and avoid valproic acid in patients with liver injury

Adjust gabapentin dose based on renal function

Antiepileptics

Carbamazepine

Valproic acid

Gabapentin

Other antipsychotics

Psychosomatics -:-, – 2020 http://www.psychosomaticsjournal.org 3

Psychopharmacology of COVID-19

TABLE 1. (Continued)

Drug class

Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)

Bupropion Lithium

Benzodiazepines

Specific drugs

All

Problem

Coagulation abnormalities observed in patients with COVID-19 and many patients with COVID-19 receiving anticoagulation; SSRIs and SNRIs associated with impaired platelet aggregation and abnormal bleeding

Concern for COVID-19–associated tachyarrhythmias and cardiac injury and potential for several medications being used to treat COVID-19 to cause QT prolongation; citalopram with potential for QT prolongation

Acute liver injury in patients with COVID-19; duloxetine with a potential for drug-induced liver injury

COVID-19 associated with seizures; bupropion can lower seizure threshold

COVID-19 with potential for acute kidney injury; lithium clearance dependent on intact renal function; lithium with nephrotoxic potential

COVID-19 associated with delirium; benzodiazepines can exacerbate delirium

COVID-19 associated with prominent respiratory symptoms; benzodiazepines can suppress respiratory drive

Lopinavir/Ritonavir contraindicated with midazolam and triazolam (and can raise levels of some other benzodiazepines) due to CYP450 inhibition

Solution

Monitor coagulation factors and platelet count; weigh risks and benefits for individual patient but consider avoiding SSRIs and SNRIs in patients with recent bleeding or high risk for bleeding (e.g., thrombocytopenia, concurrent anticoagulation therapy, history of hemorrhage); can instead use nonserotonin reuptake inhibitor antidepressant such as bupropion

Baseline EKG for QTc; caution in patients with baseline prolonged QTc and/or other risk factors for drug-induced QT prolongation and TdP; consider using SSRI other than citalopram in high-risk cases

Monitor liver function tests, avoid duloxetine in patients with liver injury

Avoid bupropion in patients with seizures or lowered seizure threshold

Adjust lithium dose based on renal function; consider temporarily holding lithium until acute kidney injury resolves

Avoid or taper existing benzodiazepines in patients with delirium if possible

Weigh risks versus benefits in using benzodiazepines in patients with prominent respiratory symptoms; a low dose may be able to be used safely in nondelirious patients

Avoid midazolam and triazolam and consider using lorazepam, temazepam, or oxazepam in patients taking lopinavir/ritonavir

All

ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; COVID-19 = coronavirus disease 2019; EKG = electrocardiogram; PT = prothrombin time; TdP = torsades de pointes.

laboratory testing for drugs subject to Risk Evaluation and Mitigation Strategy.8 While there are 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. Ex- planations include aspiration, sialorrhea, sedation, and poorly understood effects on the immune system.7,9 Patients should be educated on symptoms of pneu- monia and urgently evaluated by a clinician if symp- toms 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 prothrombin time and activated partial thromboplastin time

prolongation, thrombocytopenia, and disseminated intravascular coagulation are also frequently observed in patients with COVID-19. At the same time, many patients with COVID-19 experience increased throm- botic risk and may be prescribed prophylactic antico- agulants.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 [SSRIs] 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 a history of significant bleeding event.

Cardiac Effects

There is limited available information regarding car- diovascular involvement in COVID-19 infection,

 

4 http://www.psychosomaticsjournal.org

Psychosomatics -:-, – 2020

although tachyarrhythmias and heart failure have been described with other SARS beta-coronavirus in- fections.11 A recent report described acute myoper- icarditis 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 signal pathways, cytokine storm, and myocarditis. In addi- tion, several medications being used off-label in the

management of COVID-19 (azithromycin, hydroxy- chloroquine, chloroquine, and lopinavir/ritonavir) have been reported to prolong the QT interval. QT prolon- gation, particularly in those with underlying medical risk factors, has been linked to lethal ventricular ar- rhythmias, such as torsades de pointes.

A complete discussion of the cardiac side effects of psychotropics is beyond the scope of this article, 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

Bilbul et al.

TABLE 2. Potential Psychotropic Safety Concerns in COVID-19 Organized by Organ System

Organ system affected by COVID-19

Hematologic

Cardiac

Hepatic

Renal

Nervous system

Pulmonary

Systemic effects and symptoms

Lymphopenia
Coagulopathy (increased PT, aPTT; decreased

platelets)

Concern for tachyarrhythmias, heart failure, myopericarditis, acute cardiac injury

Several medications being used for COVID-19 (azithromycin, hydroxychloroquine, chloroquine, lopinavir/ritonavir) reported to prolong QT interval

Risk of acute liver injury, especially in severe cases

Acute kidney injury has been observed, particularly in patients with COVID-19–associated acute respiratory distress syndrome (ARDS) and preexisting chronic kidney disease

Central nervous system: headache, dizziness, impaired consciousness, ataxia, stroke, delirium, seizures

Peripheral nervous system: impaired taste/smell/ vision, neuropathic pain

Cough, shortness of breath, pneumonia and ARDS

Potential psychotropic safety concerns

Consider avoiding medications that can negatively impact white blood cell production

Highest risk: carbamazepine, clozapine, olanzapine Moderate risk: all first and second 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
Caution with psychotropics known to prolong QTc and in patients

with other underlying risk factors for QT prolongation Highest risk: antipsychotics, citalopram, tricyclic antidepressants

In patients with hepatic injury or failure:
Consider avoiding psychotropics that can also cause serious drug-

induced liver injury: chlorpromazine, carbamazepine, valproate,

duloxetine, and nefazodone.
Refer to prescribing information to determine if dose adjustments

are needed
Consider dose adjustment with some psychotropics (e.g., lithium,

gabapentin, topiramate, pregabalin, paliperidone, and duloxetine) Consider avoiding potentially nephrotoxic drugs

In patients with delirium, caution with deliriogenic medications: benzodiazepines, opioids, sedative-hypnotics, and those drugs with strong anticholinergic effects (tertiary amine tricyclic antidepressants, low-potency first-generation antipsychotics, some second-generation antipsychotics, benztropine, and diphenhydramine)

Caution with medications that can lower seizure threshold: antipsychotics and certain antidepressants (bupropion, tricyclics) In COVID-19 patients with anxiety or panic symptoms, weigh risks

versus benefits in using benzodiazepines in patients with prominent respiratory symptoms, given potential to suppress respiratory drive

 

aPTT = activated partial thromboplastin time; COVID-19 = coronavirus disease 2019; PT = prothrombin time; QTc = corrected QT interval; SNRI = serotonin norepinephrine reuptake inhibitors; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclics antidepressant.

Psychosomatics -:-, – 2020

http://www.psychosomaticsjournal.org 5

Psychopharmacology of COVID-19

interpret because of confounding factors, antipsy- chotics, tricyclic antidepressants, and the SSRI cit- alopram appear to be the agents of most concern. It is difficult to stratify antipsychotic medications by QT prolongation risk. Of the typical antipsychotics, thio- ridazine causes the greatest QT prolongation, although intravenous 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 concomi- tant medications, laboratory test results, medical comorbidities, and family history before prescribing psychotropics in patients with COVID-19. Caution should be used in patients with a baseline prolonged QTc and/or other risk factors for drug-induced QT prolongation and torsades de pointes: the use of QT- prolonging medications, cardiac comorbidities, age .65, female sex, family history of sudden cardiac death, hypokalemia/hypomagnesemia, and illicit sub- stance use. If QT-prolonging medications are used in a patient with a QTc .500 ms or other significant risk factors, electrocardiograms 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 alterna- tive 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 hy- potheses include viral infection, drug-induced liver injury, and systemic inflammation due to cytokine storm or hypoxia.16 Laboratory abnormalities observed include elevated aspartate aminotransferase, alanine aminotransferase, and bilirubin.17 Liver function tests should be monitored, and if abnormal, consideration should be given to avoiding psycho- tropics that can also cause hepatic injury or making dose adjustments if heavily dependent on hepatic

metabolism. As most psychotropics are lipid soluble and require hepatic metabolism before clearance, clinicians should review the package insert to deter- mine if a dose adjustment is needed. In addition, many psychotropics (valproate, carbamazepine, tri- cyclic antidepressants, serotonin norepinephrine re- uptake inhibitors, and second-generation antipsychotics) have been associated with mild hep- atoxicity that manifests with modest, transient in- creases in liver enzymes. Only a few are thought to have a high risk of causing serious drug-induced liver injury, 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 and preexisting chronic kidney dis- ease. 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. In addition, psychiatrists should be aware of any renal impairment and make necessary dose adjustments as per the manufacturer’s prescribing information. Psy- chotropics highly dependent on renal excretion include lithium, gabapentin, topiramate, pregabalin, and pal- iperidone. Many other psychotropics have caused renal excretion of active metabolites. Levels of these medi- cations 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 a neuroinvasive potential,21 but there remain many unanswered questions about neurological manifesta- tions of COVID-19. Initial observations note a variety of neurological syndromes in patients with COVID-19,

   

6 http://www.psychosomaticsjournal.org

Psychosomatics -:-, – 2020

particularly the more severely affected ones. These include stroke, delirium, seizures, and an encephalitis- type presentation. A recent article from Wuhan22 re- ports neurologic symptoms in 36.4% of patients with COVID-19, 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 po- tential 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 patients with COVID- 19.23 Environmental factors such as isolation from family members and difficulty mobilizing patients also contribute.24

In patients with COVID-19 and delirium, clinicians should be mindful about prescribing benzodiazepines, opioids, and drugs with strong anticholinergic proper- ties (tertiary amine tricyclic antidepressants, low- potency antipsychotics, benztropine, and diphenhy- dramine) 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 (bupro- pion, 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

Bilbul et al. severe cases, invasive ventilation.4 Psychiatric consul-

tants may be asked to evaluate and manage patients with COVID-19 and 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 of benzodiazepines to suppress respiratory drive, particularly at higher doses. Clini- cians therefore need to consider risks versus benefits in using benzodiazepines in patients with prominent res- piratory 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 following section 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 US FDA issued an Emergency Use Authorization 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 supple- mental oxygen, mechanical ventilation, or extracorpo- real membrane oxygenation.” The Emergency Use Authorization was based on early promising data from a randomized double-blinded, placebo-controlled28 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 hypo- tension, diaphoresis, and shivering.1 Such symptoms might be misconstrued as a panic attack.

Psychotropic Considerations

Remdesivir carries a risk of transaminase eleva- tions,30 specifically but not limited to alanine

   

Psychosomatics -:-, – 2020

http://www.psychosomaticsjournal.org 7

Psychopharmacology of COVID-19

TABLE 3. Psychiatric Side Effects and Drug Interactions with Proposed COVID-19 Treatments

Proposed COVID-19 treatment

Azithromycin

Chloroquine and hydroxychloroquine

Mechanism of action

Used with hydroxychloroquine.

Antibacterial (primarily) Antiviral and anti-

inflammatory (potential) Anti-inflammatory Antiviral: interference with

virus-receptor binding Immune-modulating effects

Psychiatric side effects

Psychotic depression, catatonia, delirium, aggressive reaction, anxiety, dizziness, headache, vertigo, and somnolence

Psychosis, delirium, suicidality, personality changes, depression, nervousness, irritability, compulsive impulses, preoccupations, and aggressiveness

Drug-drug interactions

Risk of QTc prolongation—caution with psy- chotropics known to prolong QTc

Risk of hepatotoxicity—caution with hepato- toxic drugs

Risk of QTc prolongation—caution with QT prolonging drugs. Do not use outside of the hospital setting or a clinical trial due to risk of heart rhythm problems (FDA)

Metabolized by CYP3A4—potential drug in- teractions with CYP3A4 inhibitors (e.g., flu- voxamine) and inducers (e.g., carbamazepine, oxcarbazepine, modafinil)

Risk of hepatotoxicity—caution with hepato- toxic 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 h)—adverse effects and drug- interactions may continue for days after the drug has been discontinued

Narrow therapeutic index—potential for toxicity

Caution in renal and hepatic failure
Caution with P-gp and CYP3A4 inhibitors

(e.g., fluvoxamine)
CYP3A4 inducers may decrease levels
There are no specific interactions (Note:

patients who develop transfusion reactions might receive steroids or diphenhydramine which can have negative synergistic effects with existing psychotropics.)

Inconsistently reported to be weak CYP3A4 and CYP2C19 inducers

Phenytoin—increases hepatic metabolism of systemic corticosteroids

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 .40 mg/d)

Possible QT prolongation

Colchicine

Convalescent plasma therapy

Corticosteroids

Favipiravir

Anti-inflammatory Immune modulator: targets

IL-6 pathway, inhibition of NLRP3 inflammasome. May attenuate cytokine storm.

Antibody containing convalescent plasma from patients who have recovered from viral infections

Immune modulators and anti-inflammatory: may lessen cytokine storm and hyperinflammation syndrome

Antiviral: RNA-dependent RNA polymerase inhibitor

At toxic doses: delirium, seizures, muscle weakness, depressed reflexes

No specific psychiatric effects (Note: allergic reactions can produce shortness of breath and palpitations that mimic panic attacks)

Potential psychological effects for donors

Depression, mania, agitation, mood lability, anxiety, insomnia, catatonia, depersonalization, delirium, dementia, and psychosis

No information

aminotransferase 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.

8 http://www.psychosomaticsjournal.org

Chloroquine and Hydroxychloroquine Chloroquine, a synthetic form of quinine used for the

treatment and

prophylaxis of malaria, and Psychosomatics -:-, – 2020

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 because of their potential for interference with

virus-receptor binding and immune-modulating ef- fects.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 intuba- tion or death was not significantly higher or lower among patients who received the drug than among

Bilbul et al.

TABLE 3. (Continued) Proposed COVID-19

treatment

Interferon

Lopinavir/Ritonavir

Mechanism of action

Immune modulator, antiproliferative, and hormone-like activities

Antiviral

Antiviral Lopinavir: protease

inhibitor
Ritonavir: boosts plasma

levels of lopinavir

Psychiatric side effects

IFN alpha: boxed warning for “life-threatening or fatal neuropsychiatric disorders.” Specific effects include fatigue, mood disorders, suicidality, anxiety disorders, irritability, lability, apathy, sleep disturbance, and cognitive deficits

IFN beta: fatigue, weight loss, myalgia, arthralgia

Possible abnormal dreams, agitation, anxiety, confusion, and emotional lability

All protease inhibitors associated with paresthesias, taste alterations, and neurotoxicity

No information

Possible positive effects on depressive symptoms

No evidence for neuropsychiatric adverse effects;

Of note, lower levels associated with depression, confusion, anger, delirium

Drug-drug interactions

No known pharmacokinetic interactions with psychotropics

Potential for bone marrow suppression—safety concerns with some psychotropics (e.g., carba- mazepine, valproate, and clozapine)

May lower seizure threshold: caution with psychotropics that also lower seizure threshold

Extensively metabolized by cytochrome P450– risk of multiple possible interactions

May get increased concentrations of coad- ministered CYP3A4 or CYP2D6 substrates

May get decreased concentrations of CYP1A2 or CYP2B6 substrates

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, pancrea- titis, neutropenia, hepatotoxicity, and chronic kidney disease

No information is available about pharmaco- kinetic drug-drug interactions

Risk of elevated aminotransferase levels (e.g. ALT up to 203 upper limit of normal)— caution with potentially hepatotoxic psychotropics

No major interactions reported

Coadministration with barbiturates may decrease the effects of vitamin C

 

Remdesivir

Tocilizumab

Vitamin C

Only FDA-approved medication for severe COVID-19

Interacts with RNA polymerase, leads to decrease in viral RNA

Immune modulator: recombinant humanized monoclonal antibody that acts as an IL-6 inhibitor; may lessen cytokine storm

Enhances immune response, antioxidant and reducing agent

ALT = alanine aminotransferase; COVID-19 = coronavirus disease 2019; FDA = Food and Drug Administration; IFN = interferon; IL = interleukin; P-gp = P-glycoprotein.

Psychosomatics -:-, – 2020

http://www.psychosomaticsjournal.org 9

Psychopharmacology of COVID-19

those who did not.33 The authors suggest that their findings do not support continued use of the drug in patients with COVID-19 outside of clinical trials.

Neuropsychiatric Effects

Neuropsychiatric side effects of chloroquine and hydroxychloroquine include psychosis, delirium, agita- tion, 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 imbal- ance due to acetylcholinesterase inhibition, inhibition of the serotonin transporter protein, and N-methyl-D- aspartate and gamma aminobutyric acid antagonism.34

Psychotropic Considerations

Hydroxychloroquine and chloroquine can cause heart conduction disorders, including QT interval prolon- gation, bundle branch block, atrioventricular block, and torsades de pointes.37 On April 24, 2020, the FDA issued a safety announcement against the use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial because of risk of heart rhythm problems.38 Caution should be used when combining them with QT- prolonging psychotropics. These agents can also be hepatotoxic39 and epileptogenic,40 so caution should be exercised in patients with hepatic disease, or in conjunction with psychotropics that may be hepato- toxic 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 in- ducers, 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 h), 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 receptor inhibi- tor42 and is FDA approved to treat several types of arthritis.43 Tocilizumab is being trialed in patients with severe COVID-19 and elevated interleukin-6 because interleukin-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 depres- sive symptoms in rheumatoid arthritis45,46; however, unpublished data from a small study surprisingly sug- gest that patients who received tocilizumab after allo- geneic 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 prolonga- tion in a patient with Ebola virus who received favipiravir.49

Lopinavir/Ritonavir (Kaletra)

Lopinavir/Ritonavir is an antiviral medication used to treat HIV-1 infection.50 The 2 medications work syn- ergistically: Lopinavir is a protease inhibitor, and ri- tonavir helps to boost plasma levels of lopinavir by

   

10 http://www.psychosomaticsjournal.org

Psychosomatics -:-, – 2020

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 pub- lished 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 The use of ritonavir may lead to increased concentra- tions of coadministered drugs that are CYP3A4 or CYP2D6 substrates or decreased concentrations of CYP1A2 or CYP2B6 substrates, many of which are psychotropics.

The use of lopinavir/ritonavir is contraindicated with medications that include pimozide, midazolam, and triazolam because of increased drug levels and potentiation of adverse effects. The use of benzodiaze- pines not dependent on CYP metabolism (lorazepam, temazepam, or oxazepam) is recommended. Owing 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 olanza- pine), thus leading to increased dose requirements for these medications.53

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

Other potential nonpsychiatric side effects that may have implications for psychiatrists include Stevens Johnson syndrome, diabetes mellitus, QTc prolonga- tion, pancreatitis, neutropenia, hepatotoxicity, and chronic kidney disease.50

Bilbul et al. Convalescent Plasma Therapy

Antibody containing convalescent plasma from recov- ered patients has been used with some success as a last resort to treat severe viral respiratory infections such as SARS-CoV, Middle Eastern respiratory syndrome- CoV, and Ebola, although large clinical trials are ab- sent.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 ther- apy 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 re- ported, although allergic reactions, cardiovascular complications, and bronchospasm can produce symp- toms such as shortness of breath and palpitations that mimic panic attacks.

A potential psychological adverse effect of conva- lescent plasma therapy relates to ethical concerns about coercion, confidentiality, and privacy of the prospective donors that were initially raised during the Ebola outbreak57 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 psychotro- pics and plasma transfusions, but patients who develop transfusion reactions might receive steroids or diphen- hydramine which can have negative synergistic effects with existing psychotropics.

Azithromycin

Azithromycin is an antibacterial agent which may have antiviral and anti-inflammatory activities.32 It is under investigational use for treatment of COVID-19 when given in conjunction with chloroquine or hydroxy- chloroquine. In one small French study (n = 20), azi- thromycin added to hydroxychloroquine was

  

Psychosomatics -:-, – 2020

http://www.psychosomaticsjournal.org 11

Psychopharmacology of COVID-19 significantly more efficient for virus elimination than

hydroxychloroquine alone.32

Neuropsychiatric Effects

Side effects that have been reported include psychotic depression, catatonia, delirium, aggressive reaction,

because of the 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 Most neuropsychiatric side effects occur early in the treatment course, usually within days, and dosing is the most significant risk factor (i.e., at pred- nisone equivalents of .40 mg/d).66

Psychotropic Considerations

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

Interferon

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 Middle Eastern respiratory syndrome-coronavirus in vitro.72,73 Based on this information, IFN has been considered as a potential treatment for COVID-19, including in com- bination with ribavirin, a guanosine analogue with a 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 distur- bance, 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 base- line psychiatric history and monitor closely for emer- gence of any symptoms.

anxiety, dizziness, headache, somnolence.59,60

Psychotropic Considerations

vertigo, and

Azithromycin has not been implicated in pharmacoki- netic interactions with psychotropics but has been associated with QTc prolongation and life-threatening torsades de pointes 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 because of 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 syn- drome63 and is being investigated in critically ill pa- tients with COVID-19.

Neuropsychiatric Effects

There are no known adverse neuropsychiatric conse- quences of high-dose intravenous vitamin C adminis- tration, 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 pan- demics, such as SARS and Middle Eastern respiratory syndrome, corticosteroids were not recommended

   

12 http://www.psychosomaticsjournal.org

Psychosomatics -:-, – 2020

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. In addition, 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 hy- pothesized that colchicine could treat COVID-19 through targeting the overactive interleukin-6 pathway.80

Neuropsychiatric Effects

Colchicine does not typically produce any neuropsy- chiatric effects, but at toxic doses, it can cause delirium, seizures, and muscle weakness.81

Psychotropic Considerations

Colchicine has a narrow therapeutic index, and atten- tion must be paid to potential drug interactions that might increase toxicity. Colchicine is metabolized by CYP3A4 and excreted via the P-glycoprotein transport system as well as cleared by the kidneys through glomerular filtration. Dose adjustment is recommended with concurrent use of CYP3A4 or P-glycoprotein in- hibitors 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 im- plications 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 the use of psychotropics in patients with COVID-19, 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 azi- thromycin 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 patients with COVID-19 is highly prevalent, 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 consultation-liaison psychia- trists consider antipsychotics such as haloperidol the gold standard for managing agitation in delirious pa- tients. In these situations, the consultation-liaison psy- chiatrist should assist the medical team in reasoning through the cardiac risks of using an antipsychotic balanced against effective management of the agitation. The use of an antipsychotic with cardiology involve- ment and frequent electrocardiogram monitoring or telemetry may be deemed acceptable. Alternatives such as alpha-2 agonists (dexmedetomidine and clonidine) or antiepileptics (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 con- sciousness and sleep-wake cycle disturbances in delir- ious patients with COVID-19, especially given its potential for antioxidative, anti-inflammatory, and immune-enhancing effects.83 With the exception of patients who chronically use alcohol or benzodiaze- pines and may be at risk for withdrawal, benzodiaze- pines 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 nonpharmacological strategies to prevent or treat delirium such as frequent orientation and early mobilization should be used if practically feasible.24

As another example, we have observed many nondelirious patients with COVID-19 and 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

Bilbul et al.

  

Psychosomatics -:-, – 2020

http://www.psychosomaticsjournal.org 13

Psychopharmacology of COVID-19

potential risk of respiratory depression. The use of benzodiazepines may be reasonable in patients with adequate oxygen saturation and in the 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 SSRI may be appropriate. Nonpharmacological/psy- chosocial interventions (e.g., behaviorally oriented therapies) should also be used.

Other important tasks for the psychiatrist treating a patient with COVID-19 include review of all medica- tions, monitoring for neuropsychiatric side effects of medications such as hydroxychloroquine or corticoste- roids, 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

References

1. Fact Sheet for Healthcare Providers – Emergency Use Authorization (EUA) of Remdesivir (GS-5734TM) [Internet]. U.S. Food and Drug Administration (FDA). 2020. Available from: https://www.fda.gov/media/137566/download. [Accessed 24 May 2020]

2. Kalil AC: Treating COVID-19—off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA 2020. https://doi.org/10.1001/jama.2020. 4742

3. Wang T, Du Z, Zhu F, et al: Comorbidities and multi- organ injuries in the treatment of COVID-19. Lancet 2020; 395:e52

4. Huang C, Wang Y, Li X, et al: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497–506

5. Terpos E, Ntanasis-Stathopoulos I, Elalamy I, et al: Hema- tological findings and complications of COVID-19. Am J Hematol 2020; 95:834–847

6. Oyesanmi O, Kunkel EJS, Monti DA, Field HL: Hemato- logic side effects of psychotropics. Psychosomatics 1999; 40:414–421

7. Siskind D, Honer WG, Clark S, et al: Consensus statement on the use of clozapine during the COVID-19 pandemic. J Psychiatry Neurosci 2020; 45:200061

8. Policy for Certain REMS Requirements During the COVID19 Public Health Emergency [Internet]. FDA. Available from: https://www.fda.gov/media/136317/download. [Accessed 24 May 2020]

inflammatory response during sepsis by inhibiting cytokine production,85 and melatonin for its anti- oxidative and anti-inflammatory properties.86 If more data become 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 neuropsy- chiatric effects and drug-drug interactions of COVID- 19 treatments as well as the end-organ effects of COVID-19.

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

Disclosure: C.L.E. receives royalty payments from American Psychiatric Publishing, Inc. The other au- thors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

9. de Leon J, Sanz EJ, Norén GN, De las Cuevas C: Pneumonia may be more frequent and have more fatal outcomes with clozapine than with other second-generation antipsychotics. World Psychiatry 2020; 19:120

10. Clark SR, Warren NS, Kim G, et al: Elevated clozapine levels associated with infection: a systematic review. Schiz- ophr Res 2018; 192:50–56

11. Yu C-M, Wong RS-M, Wu EB, et al: Cardiovascular com- plications of severe acute respiratory syndrome. Postgrad Med J 2006; 82:140–144

12. Inciardi RM, Lupi L, Zaccone G, et al: Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020. https://doi.org/10.1001/jamacardio. 2020.1096

13. Li B, Yang J, Zhao F, et al: Prevalence and impact of car- diovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol 2020; 109:531–538

14. Wu C-I, Postema PG, Arbelo E, et al: SARS-CoV-2, COVID-19 and inherited arrhythmia syndromes. Hear Rhythm 2020. https://doi.org/10.1016/j.hrthm.2020.03. 024

15. Beach SR, Celano CM, Sugrue AM, et al: QT prolongation, torsades de Pointes, and psychotropic medications: a 5-year update. Psychosomatics 2018; 59:105–122

16. Lee I-C, Huo T-I, Huang Y-H: Gastrointestinal and liver manifestations in patients with COVID-19. J Chin Med Assoc 2020; 83:521–523

17. Xie H, Zhao J, Lian N, Lin S, Xie Q, Zhuo H: Clinical characteristics of non-ICU hospitalized patients with

 

14 http://www.psychosomaticsjournal.org

Psychosomatics -:-, – 2020

coronavirus disease 2019 and liver injury: a retrospective

study. Liver Int 2020; 40:1321–1326

18. Goldberg J, Ernst C: Managing the side effects of psycho-
tropic medications, 2nd ed. Washington DC: American
Psychiatric Association Publishing; 2019

19. Telles-Correia D, Barbosa A, Cortez-Pinto H, Campos C,
Rocha NBF, Machado S: Psychotropic drugs and liver dis- ease: a critical review of pharmacokinetics and liver toxicity. World J Gastrointest Pharmacol Ther 2017; 8:26–38

20. Fanelli V, Fiorentino M, Cantaluppi V, et al: Acute kidney injury in SARS-CoV-2 infected patients. Crit Care 2020; 24:155

21. Li Y-C, Bai W-Z, Hashikawa T: The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol 2020; 92:552–555

22. Mao L, Jin H, Wang M, et al: Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020:e201127

23. Helms J, Kremer S, Merdji H, et al: Neurologic features in severe SARS-CoV-2 infection. N Engl J Med 2020; 382:2268–2270

24. Kotfis K, Roberson SW, Wilson JE, Dabrowski W, Pun BT, Ely EW: COVID-19: ICU delirium management during SARS-CoV-2 pandemic. Crit Care 2020; 24:1–9

25. Wu C-S, Wang S-C, Yeh I-J, Liu S-K: Comparative risk of seizure with use of first- and second-generation antipsychotics in patients with schizophrenia and mood disorders. J Clin Psychiatry 2016; 77:e573–e579

26. Johannessen Landmark C, Henning O, Johannessen SI: Proconvulsant effects of antidepressants — what is the cur- rent evidence? Epilepsy Behav 2016; 61:287–291

27. Al-Tawfiq JA, Al-Homoud AH, Memish ZA: Remdesivir as a possible therapeutic option for the COVID-19. Trav Med Infect Dis 2020; 34:101615

28. A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults Adaptive COVID-19 Treatment Trial (ACTT) [Internet]. 2020. Available from: https://ichgcp.net/de/clinical-trials-registry/NCT04280705. [Accessed 20 May 2020]

29. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734TM) in Participants With Severe Coronavirus Disease (COVID-19) [Internet]. 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT042 92899. [Accessed 24 May 2020].

30. COVID-19 Investigation Team. Clinical and virologic charac- teristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States. Nat Med 2020. https://doi. org/10.1038/s41591-020-0877-5

31. Sahraei Z, Shabani M, Shokouhi S, Saffaei A: Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine. Int J Antimicrob Agents 2020; 55

32. Gautret P, Lagier J-C, Parola P, et al: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020:105949

33. Geleris J, Sun Y, Platt J, et al: Observational study of hydroxy- chloroquine in hospitalized patients with Covid-19. N Engl J Med 2020. https://doi.org/10.1056/NEJMoa2012410

34. Good MI, Shader RI: Behavioral toxicity and equivocal suicide associated with chloroquine and its derivatives. Am J Psychiatry 1977; 134:798–801

35. Manufacter’s Package Insert, Hydroxychloroquine [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_ docs/label/2017/009768s037s045s047lbl.pdf. [Accessed 20 May 2020]

36. Mascolo A, Berrino PM, Gareri P, et al: Neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: a review article. Inflammopharmacol- ogy 2018; 26:1141–1149

37. McGhie TK, Harvey P, Su J, Anderson N, Tomlinson G, Touma Z: Electrocardiogram abnormalities related to anti- malarials in systemic lupus erythematosus. Clin Exp Rheu- matol 2018; 36:545–551

38. FDA cautions against use of hydroxychloroquine or chlo- roquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems [Internet]. FDA. 2020. Available from: https://www.fda.gov/media/ 137250/download. [Accessed 24 May 2020]

39. Makin AJ, Wendon J, Fitt S, Portmann BC, Williams R: Fulminant hepatic failure secondary to hydroxychloroquine. Gut 1994; 35:569–570

40. Krzeminski P, Lesiak A, Narbutt J: Seizures as a rare adverse effect of chloroquine therapy in systemic lupus erythematosus patients: a case report and literature survey. Postepy Der- matol Alergol 2018; 35:429–430

41. Browning DJ. In: Browning DJ, (ed) Pharmacology of chloroquine and hydroxychloroquine BT – hydroxy- chloroquine and chloroquine retinopathy. New York, NY: Springer New York; 2014. p. 35–63. Available from: https://doi.org/10.1007/978-1-4939-0597-3_2. [Accessed 24 May 2020]

42. Sheppard M, Laskou F, Stapleton PP, Hadavi S, Dasgupta B: Tocilizumab (actemra). Hum Vaccin Immun- other 2017; 13:1972–1988

43. Manufacterer’s Packge Insert, Actemra (tocilizumab) [Internet]. Available from: https://www.actemrahcp.com/. [Accessed 20 May 2020]

44. Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J: Tocilizumab treatment in COVID-19: a single center experience. J Med Virol 2020; 92:814–818

45. Singh JA, Beg S, Lopez-Olivo MA: Tocilizumab for rheu- matoid arthritis: a Cochrane systematic review. J Rheumatol 2011; 38:10–20

46. Harrold LR, John A, Reed GW, et al: Impact of tocilizumab monotherapy on clinical and patient-reported quality-of-life outcomes in patients with rheumatoid arthritis. Rheumatol Ther 2017; 4:405–417

47. Knight JM, Costanzo ES, Singh S, et al: Inflammation and the brain: tocilizumab may redefine our understanding of depression and related symptoms in the medically ill. Orlando, FL: ACLP; 2018

Bilbul et al.

Psychosomatics -:-, – 2020

http://www.psychosomaticsjournal.org 15

Psychopharmacology of COVID-19

48. Dong L, Hu S, Gao J: Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther 2020; 14:58–60

49. Chinello P, Petrosillo N, Pittalis S, et al: QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient. PLoS Negl Trop Dis 2017; 11:e0006034

50. Kaletra (lopinavir and ritonavir): Manufacturer’s Prescribing Information [Internet]. Available from: https://www. accessdata.fda.gov/drugsatfda_docs/label/2016/021251s052_ 021906s046lbl.pdf. [Accessed 23 April 2020]

51. Cao B, Wang Y, Wen D, et al: A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020; 382:1787–1799

52. Abers MS, Shandera WX, Kass JS: Neurological and psy- chiatric adverse effects of antiretroviral drugs. CNS Drugs 2014; 28:131–145

53. Goodlet KJ, Zmarlicka MT, Peckham AM: Drug–drug in- teractions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs. CNS Spectr 2019; 24:287–312

54. Chen L, Xiong J, Bao L, Shi Y: Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis 2020; 20:398–400

55. Cunningham AC, Goh HP, Koh D: Treatment of COVID-19: old tricks for new challenges. Crit Care 2020; 24:91

56. Pandey S, Vyas GN: Adverse effects of plasma transfusion. Transfus 2012; 52:65S–79S

57. Van Griensven J, De Weiggheleire A, Delamou A, et al: The use of Ebola convalescent plasma to treat Ebola virus disease in resource-constrained settings: a perspective from the field. Clin Infect Dis 2016; 62:69–74

58. World Health Organization (2015). Ethics of using convalescent whole blood and convalescent plasma during the Ebola epidemic: interim guidance for ethics review committees, researchers, na- tional health authorities and blood transfusion services. World Health Organization 2015. Available from: https://apps.who.int/ iris/handle/10665/161912

59. ZITHROMAX® (azithromycin tablets) and (azithromycin for oral suspension) [Internet]. FDA. Available from: https:// http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/05071 0s039,050711s036,050784s023lbl.pdf. [Accessed 22 April 2020]

60. Ginsberg DL: Azithromycin-induced psychotic depression and catatonia. Prim Psychiatry 2006; 13:22–26

61. Leitner JM, Graninger W, Thalhammer F: Hepatotoxicity of antibacterials: pathomechanisms and clinical data. Infection 2010; 38:3–11

62. Linster CL, Van Schaftingen E: Vitamin C. FEBS J 2007; 274:1–22

63. Truwit JD, Hite RD, Morris PE, et al: Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA 2019; 322:1261–1270

64. Pullar JM, Carr AC, Bozonet SM, Vissers M: High vitamin C status is associated with elevated mood in male tertiary students. Antioxidants 2018; 7:91

65. Torbergsen AC, Watne LO, Frihagen F, Wyller TB, Brugaard A, Mowe M: Vitamin deficiency as a risk factor for delirium. Eur Geriatr Med 2015; 6:314–318

66. Dubovsky AN, Arvikar S, Stern TA, Axelrod L: The neuropsychiatric complications of glucocorticoid use: steroid psychosis revisited. Psychosomatics 2012; 53:103–115

67. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ: COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395:1033–1034

68. Flockhart DA, Oesterheld JR: Cytochrome P450-mediated drug interactions. Child Adolesc Psychiatr Clin N Am 2000; 9:43–76

69. Villikka K, Varis T, Backman J, Neuvonen P, Kivistö K: Effect of methylprednisolone on CYP3A4-mediated drug metabolism in vivo. Eur J Clin Pharmacol 2001; 57:457–460

70. McLelland J, Jack W: Phenytoin/dexamethasone interaction: a clinical problem. Lancet 1978; 311:1096–1097

71. Jacobs L, Johnson KP: A brief history of the use of in- terferons as treatment of multiple sclerosis. Arch Neurol 1994; 51:1245–1252

72. Hensley LE, Fritz EA, Jahrling PB, Karp C, Huggins JW, Geisbert TW: Interferon-b 1a and SARS coronavirus repli- cation. Emerg Infect Dis 2004; 10:317

73. Ströher U, DiCaro A, Li Y, et al: Severe acute respiratory syndrome-related coronavirus is inhibited by interferon-a. J Infect Dis 2004; 189:1164–1167

74. Lu C-C, Chen M-Y, Chang Y-L: Potential therapeutic agents against COVID-19: what we know so far. J Chin Med Assoc 2020; 83:534–536

75. PEGASYS (peginterferon alfa-2a) injection – Highlights of Prescribing Information [Internet]. FDA. 2020. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/ label/2017/103964s5270lbl.pdf. [Accessed 20 April 2020].

76. Davoodi L, Masoum B, Moosazadeh M, Jafarpour H, Haghshenas MR, Mousavi T: Psychiatric side effects of pegylated interferon-a and ribavirin therapy in Iranian patients with chronic hepatitis C: a meta-analysis. Exp Ther Med 2018; 16:971–978

77. Reder AT, Feng X: How type I interferons work in multiple sclerosis and other diseases: some unexpected mechanisms. J Interferon Cytokine Res 2014; 34:589–599

78. Ahmed F, Jacobson IM, Herrera JL, et al: Seizures during pegylated interferon and ribavirin therapy for chronic Hep- atitis C: observations from the WIN-R trial. J Clin Gastro- enterol 2011; 45:286–292

79. Slobodnick A, Shah B, Krasnokutsky S, Pillinger MH: Up- date on colchicine, 2017. Rheumatology (Oxford) 2017; 57(suppl_l):i4–i11

80. Tardif J-C, Bassevitch Z: Colchicine Coronavirus SARS- CoV2 Trial (COLCORONA) (COVID-19) [Internet]. Avail- able from: https://clinicaltrials.gov/ct2/show/NCT04322682. [Accessed 24 May 2020]

81. Finkelstein Y, Aks SE, Hutson JR, et al: Colchicine poisoning: the dark side of an ancient drug. Clin Toxicol 2010; 48:407–414

16 http://www.psychosomaticsjournal.org

Psychosomatics -:-, – 2020

82. Nuki G: Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 2008; 10:218

83. Zambrelli E, Canevini M, Gambini O, D’Agostino A: Delirium and sleep disturbances in COVID–19: a possible role for melatonin in hospitalized patients? Sleep Med 2020; 70:111

84. Gordon DE, Jang GM, Bouhaddou M, et al: A SARS- CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing. bioRxiv

[Internet]. 2020. Available from: http://biorxiv.org/content/ early/2020/03/27/2020.03.22.002386.abstract. [Accessed 24 May 2020].

85. Rosen DA, Seki SM, Fernández-Castañeda A, et al: Modu- lation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med 2019; 11:eaau5266

86. Zhang R, Wang X, Ni L, et al: COVID-19: melatonin as a potential adjuvant treatment. Life Sci 2020; 250: 117583

Bilbul et al.

Psychosomatics -:-, – 2020

http://www.psychosomaticsjournal.org 17

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: