Psychopharmacology of COVID-19

Psychopharmacology of COVID-19

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

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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.

(Psychosomatics 2020; 61:411–427)

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

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.

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

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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,

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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

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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 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

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

Other antipsychotics

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

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

Antiepileptics Carbamazepine 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

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