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 coronavirus 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 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 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 psychotropic 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 psychotropics or avoid using certain medications in some patients 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.

Introduction

With the rapid, global spread of severe acute respiratory 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, and many other medications are either being studied in clinical trials or being used off-label and/or for compassionate use.

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 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 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 (IFN), vitamin C, and colchicine.

Given the limited literature in this area, we undertook 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 medications mentioned previously: “COVID-19”, “coronavirus”, “Psychotropic medications”, “QT prolongation”, “Psychiatric side effects”, “Neuropsychiatric side effects”, “drug interactions”, and pertinent organ systems, 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 preparation 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. 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 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 ).

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 monitoringMay be associated with increased risk of pneumonia and its complicationsLevels can increase with acute infection leading to clozapine toxicityCOVID-19 associated with leukopenia and lymphopenia; unclear impact on neutrophils; clozapine associated with neutropenia and agranulocytosis and more rarely lymphopenia or aplastic anemiaCOVID-19 associated with seizures; clozapine can lower seizure threshold	Reduce frequency of ANC monitoring at discretion of providerEducation of patients and urgent clinical assessment including ANC for those with symptoms of infectionConsider halving clozapine dose in patients with fever, pneumonia, and/or flu-like symptoms; temporarily discontinue clozapine if toxicity emergesMonitor 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 clozapineRecognize 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 antipsychoticsConcern 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 prolongationAcute liver injury in patients with COVID-19; antipsychotics (especially chlorpromazine) with potential for drug-induced liver injuryCOVID-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 agentBaseline 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 discussionMonitor liver function tests and avoid chlorpromazine in patients with liver injury; risk versus benefit assessment for other antipsychotic useConsider 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 AEDMonitor liver function tests and avoid carbamazepine in patients with liver injury
	Valproic acid	Coagulation abnormalities (PT and aPTT prolongation, thrombocytopenia) observed in patients with COVID-19; valproic acid associated with thrombocytopeniaAcute liver injury in patients with COVID-19; valproic acid with potential for drug-induced liver injury	Monitor platelet count; avoid valproic acid if thrombocytopeniaMonitor liver function tests and avoid valproic acid in patients with liver injury
	Gabapentin	COVID-19 with potential for acute kidney injury; gabapentin clearance dependent on intact renal function	Adjust gabapentin dose based on renal function
Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)	All	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 bleedingConcern 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 prolongationAcute liver injury in patients with COVID-19; duloxetine with a potential for drug-induced liver injury	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 bupropionBaseline 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 casesMonitor liver function tests, avoid duloxetine in patients with liver injury
Bupropion		COVID-19 associated with seizures; bupropion can lower seizure threshold	Avoid bupropion in patients with seizures or lowered seizure threshold
Lithium		COVID-19 with potential for acute kidney injury; lithium clearance dependent on intact renal function; lithium with nephrotoxic potential	Adjust lithium dose based on renal function; consider temporarily holding lithium until acute kidney injury resolves
Benzodiazepines	All	COVID-19 associated with delirium; benzodiazepines can exacerbate deliriumCOVID-19 associated with prominent respiratory symptoms; benzodiazepines can suppress respiratory driveLopinavir/Ritonavir contraindicated with midazolam and triazolam (and can raise levels of some other benzodiazepines) due to CYP450 inhibition	Avoid or taper existing benzodiazepines in patients with delirium if possibleWeigh risks versus benefits in using benzodiazepines in patients with prominent respiratory symptoms; a low dose may be able to be used safely in nondelirious patientsAvoid midazolam and triazolam and consider using lorazepam, temazepam, or oxazepam in patients taking lopinavir/ritonavir

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

Table 2

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

Organ system affected by COVID-19	Systemic effects and symptoms	Potential psychotropic safety concerns
Hematologic	LymphopeniaCoagulopathy (increased PT, aPTT; decreased platelets)	Consider avoiding medications that can negatively impact white blood cell productionHighest risk: carbamazepine, clozapine, olanzapineModerate risk: all first and second generation antipsychotics (especially low-potency conventionals)Rare reports: TCAs, benzodiazepines (chlordiazepoxide), gabapentin, and valproateConsider avoiding medications that can increase bleeding risk (via thrombocytopenia or impaired platelet aggregation): valproic acid, SSRIs, SNRIs
Cardiac	Concern for tachyarrhythmias, heart failure, myopericarditis, acute cardiac injurySeveral medications being used for COVID-19 (azithromycin, hydroxychloroquine, chloroquine, lopinavir/ritonavir) reported to prolong QT interval	Caution with psychotropics known to prolong QTc and in patients with other underlying risk factors for QT prolongationHighest risk: antipsychotics, citalopram, tricyclic antidepressants
Hepatic	Risk of acute liver injury, especially in severe cases	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
Renal	Acute kidney injury has been observed, particularly in patients with COVID-19–associated acute respiratory distress syndrome (ARDS) and preexisting chronic kidney disease	Consider dose adjustment with some psychotropics (e.g., lithium, gabapentin, topiramate, pregabalin, paliperidone, and duloxetine)Consider avoiding potentially nephrotoxic drugs
Nervous system	Central nervous system: headache, dizziness, impaired consciousness, ataxia, stroke, delirium, seizuresPeripheral nervous system: impaired taste/smell/vision, neuropathic pain	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)
Pulmonary	Cough, shortness of breath, pneumonia and ARDS	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.

Hematological Effects

An early report noted the presence of lymphopenia (lymphocyte count less than 1.0 × 109/L) in 63% and leukopenia (white blood cell count less than 4 × 109/L) in 25% of patients with COVID-19. 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. It therefore seems prudent to use caution and consider avoiding medications 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 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.

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. Patients on clozapine may have difficulty accessing routine absolute neutrophil count monitoring, and the FDA has released guidance allowing health care providers to use medical judgment to delay laboratory testing for drugs subject to Risk Evaluation and Mitigation Strategy. 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. Explanations include aspiration, sialorrhea, sedation, and poorly understood effects on the immune system. , 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. 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 thrombotic risk and may be prescribed prophylactic anticoagulants. 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 anticoagulation therapy and a history of significant bleeding event.

Cardiac Effects

There is limited available information regarding cardiovascular involvement in COVID-19 infection, although tachyarrhythmias and heart failure have been described with other SARS beta-coronavirus infections. A recent report described acute myopericarditis in a patient with COVID-19, and a meta-analysis found acute cardiac injury in at least 8% of patients with COVID-19. It has been suggested that COVID-19 most likely has an arrhythmogenic effect. Proposed mechanisms of myocardial injury include derangement of angiotensin-converting enzyme 2 signal pathways, cytokine storm, and myocarditis. In addition, several medications being used 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.

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 interpret because of 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 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.

Health care providers should be aware of the baseline corrected QT interval (QTc) and all concomitant 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 substance 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. 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. , , 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. Laboratory abnormalities observed include elevated aspartate aminotransferase, alanine aminotransferase, and bilirubin. Liver function tests should be monitored, and if abnormal, consideration should be given to avoiding psychotropics 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 determine if a dose adjustment is needed. In addition, 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, including chlorpromazine, carbamazepine, valproate, duloxetine, and nefazodone. , 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 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. 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. Psychotropics highly dependent on renal excretion include lithium, gabapentin, topiramate, pregabalin, and paliperidone. Many other psychotropics have caused renal excretion of 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).

Neurological Effects

Based on similarities between SARS-CoV2 and other coronaviruses, it is thought likely that SARS-CoV2 has a neuroinvasive potential, but there remain many unanswered questions about neurological manifestations of COVID-19. Initial observations note a variety of neurological syndromes in patients with COVID-19, particularly the more severely affected ones. These include stroke, delirium, seizures, and an encephalitis-type presentation. A recent article from Wuhan reports 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 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 patients with COVID-19. Environmental factors such as isolation from family members and difficulty mobilizing patients also contribute.

In patients with COVID-19 and 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) and certain antidepressants (bupropion, tricyclics).

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. Psychiatric consultants 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. 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 following section and summarized in Table 3 .

Table 3

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

Proposed COVID-19 treatment	Mechanism of action	Psychiatric side effects	Drug-drug interactions
Azithromycin	Used with hydroxychloroquine.Antibacterial (primarily)Antiviral and anti-inflammatory (potential)	Psychotic depression, catatonia, delirium, aggressive reaction, anxiety, dizziness, headache, vertigo, and somnolence	• Risk of QTc prolongation—caution with psychotropics known to prolong QTc • Risk of hepatotoxicity—caution with hepatotoxic drugs
Chloroquine and hydroxychloroquine	Anti-inflammatoryAntiviral: interference with virus-receptor bindingImmune-modulating effects	Psychosis, delirium, suicidality, personality changes, depression, nervousness, irritability, compulsive impulses, preoccupations, and aggressiveness	• 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 interactions with CYP3A4 inhibitors (e.g., fluvoxamine) and inducers (e.g., 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 h)—adverse effects and drug-interactions may continue for days after the drug has been discontinued
Colchicine	Anti-inflammatoryImmune modulator: targets IL-6 pathway, inhibition of NLRP3 inflammasome. May attenuate cytokine storm.	At toxic doses: delirium, seizures, muscle weakness, depressed reflexes	• 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
Convalescent plasma therapy	Antibody containing convalescent plasma from patients who have recovered from viral infections	No specific psychiatric effects (Note: allergic reactions can produce shortness of breath and palpitations that mimic panic attacks)Potential psychological effects for donors	• 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.)
Corticosteroids	Immune modulators and anti-inflammatory: may lessen cytokine storm and hyperinflammation syndrome	Depression, mania, agitation, mood lability, anxiety, insomnia, catatonia, depersonalization, delirium, dementia, and psychosis	• 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)
Favipiravir	Antiviral: RNA-dependent RNA polymerase inhibitor	No information	• Possible QT prolongation
Interferon	Immune modulator, antiproliferative, and hormone-like activitiesAntiviral	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 deficitsIFN beta: fatigue, weight loss, myalgia, arthralgia	• No known pharmacokinetic interactions with psychotropics • Potential for bone marrow suppression—safety concerns with some psychotropics (e.g., carbamazepine, valproate, and clozapine) • May lower seizure threshold: caution with psychotropics that also lower seizure threshold
Lopinavir/Ritonavir	AntiviralLopinavir: protease inhibitorRitonavir: boosts plasma levels of lopinavir	Possible abnormal dreams, agitation, anxiety, confusion, and emotional labilityAll protease inhibitors associated with paresthesias, taste alterations, and neurotoxicity	• Extensively metabolized by cytochrome P450–risk of multiple possible interactions • May get increased concentrations of coadministered 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, pancreatitis, neutropenia, hepatotoxicity, and chronic kidney disease
Remdesivir	Only FDA-approved medication for severe COVID-19Interacts with RNA polymerase, leads to decrease in viral RNA	No information	• No information is available about pharmacokinetic drug-drug interactions • Risk of elevated aminotransferase levels (e.g. ALT up to 20× upper limit of normal)—caution with potentially hepatotoxic psychotropics
Tocilizumab	Immune modulator: recombinant humanized monoclonal antibody that acts as an IL-6 inhibitor; may lessen cytokine storm	Possible positive effects on depressive symptoms	• No major interactions reported
Vitamin C	Enhances immune response, antioxidant and reducing agent	No evidence for neuropsychiatric adverse effects;Of note, lower levels associated with depression, confusion, anger, delirium	• Coadministration with barbiturates may decrease the effects of vitamin C

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

Remdesivir

Remdesivir is an antiviral medication that interacts with RNA polymerase and evades proofreading by viral exonuclease leading to a decrease in viral RNA. 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, with severe defined as “patients with an oxygen saturation ≤94% on room air or requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation.” The Emergency Use Authorization was based on early promising data from a randomized double-blinded, placebo-controlled and an open-label trial. 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. Such symptoms might be misconstrued as a panic attack.

Psychotropic Considerations

Remdesivir carries a risk of transaminase elevations, specifically but not limited to alanine aminotransferase elevations up to 20 times the upper limit of normal. 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 because of their potential for interference with virus-receptor binding and immune-modulating effects. The most promising study is a small open-label trial from France, 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. The authors suggest that their findings do not support continued use of the drug in patients with COVID-19 outside of clinical trials.

Neuropsychiatric side effects of chloroquine and hydroxychloroquine include psychosis, delirium, agitation, suicidality, personality changes, depression, and sleep disturbances. , 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.

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 N-methyl-D-aspartate and gamma aminobutyric acid antagonism.

Hydroxychloroquine and chloroquine can cause heart conduction disorders, including QT interval prolongation, bundle branch block, atrioventricular block, and torsades de pointes. 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. Caution should be used when combining them with QT-prolonging psychotropics. These agents can also be hepatotoxic and epileptogenic, 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, 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 h), the potential for continued adverse effects and drug interactions may continue for days after the drug has been discontinued.

Tocilizumab

Tocilizumab is a recombinant humanized monoclonal antibody that acts as an interleukin-6 receptor inhibitor and is FDA approved to treat several types of arthritis. 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.

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

No major interactions have been reported.

Favipiravir

Favipiravir is an antiviral thought to act as an RNA-dependent RNA polymerase inhibitor. It was approved in China in February 2020 for treatment of influenza, and there are current trials evaluating its efficacy on SARS-Cov-2. It is not currently approved for use in the United States.

No published information is available.

There is no published information available. One published case report suggested a mild QT prolongation in a patient with Ebola virus who received favipiravir.

Lopinavir/Ritonavir (Kaletra)

Lopinavir/Ritonavir is an antiviral medication used to treat HIV-1 infection. The 2 medications work synergistically: Lopinavir is a protease inhibitor, and ritonavir helps to boost plasma levels of lopinavir by inhibiting its metabolism. 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.

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. Protease inhibitors as a class have been associated with neurological adverse events, such as paresthesias, taste alterations, and neurotoxicity.

Protease inhibitors are extensively metabolized by the cytochrome P450 system and have been shown to interact with many drugs, including psychotropics. The use of ritonavir may lead to increased concentrations 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 benzodiazepines 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 olanzapine), thus leading to increased dose requirements for these medications.

As 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's prescribing information.

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

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, Middle Eastern respiratory syndrome-CoV, and Ebola, although large clinical trials are absent. 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.

When used for the treatment of other severe acute viral respiratory infections, convalescent plasma therapy was not associated with serious adverse events, 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.

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 of the prospective donors that were initially raised during the Ebola outbreak and led to a World Health Organization document providing guidance on the ethical use of convalescent plasma.

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 activities. 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 than hydroxychloroquine alone.

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

Azithromycin has not been implicated in pharmacokinetic interactions with psychotropics but has been associated with QTc prolongation and life-threatening torsades de pointes arrhythmias. It has also been associated with hepatotoxicity.

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. 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 and is being investigated in critically ill patients with COVID-19.

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

Corticosteroids

Corticosteroids are involved in immune function, inflammation, and carbohydrate metabolism and are used in the treatment of endocrinopathies, autoimmune disorders, and asthma/allergies. In previous pandemics, such as SARS and Middle Eastern respiratory syndrome, corticosteroids were not recommended because of the concern that they may exacerbate lung injury. Given evidence suggesting that severe COVID-19 may be associated with a cytokine storm and hyperinflammation syndrome, corticosteroids may have a role in treatment.

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

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

Interferon

IFNs are glycoproteins that have immunomodulatory, antiproliferative, and hormone-like activities. 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. , Based on this information, IFN has been considered as a potential treatment for COVID-19, including in combination with ribavirin, a guanosine analogue with a broad-spectrum antiviral potency.

IFN alpha has a 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. Side effects of IFN beta can include fatigue, weight loss, myalgia, and arthralgia, 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.

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.

Colchicine

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

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

Colchicine has a narrow therapeutic index, and attention 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 inhibitors as well as in patients with hepatic or renal impairment. 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 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 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 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 psychiatrists consider antipsychotics such as haloperidol the gold standard for managing agitation in delirious patients. In these situations, the consultation-liaison psychiatrist 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 involvement 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 consciousness and sleep-wake cycle disturbances in delirious patients with COVID-19, especially given its potential for antioxidative, anti-inflammatory, and immune-enhancing effects. 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 nonpharmacological strategies to prevent or treat delirium such as frequent orientation and early mobilization should be used if practically feasible.

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 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/psychosocial 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 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. Fluvoxamine is also under investigation for its potential to reduce the inflammatory response during sepsis by inhibiting cytokine production, and melatonin for its antioxidative and anti-inflammatory properties. 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 neuropsychiatric effects and drug-drug interactions of COVID-19 treatments as well as the end-organ effects of COVID-19.