key: cord-0914832-q82p5bo3 authors: Bilbul, Melanie; Paparone, Patricia; Kim, Anna M.; Mutalik, Shruti; Ernst, Carrie L. title: Psychopharmacology of COVID-19 date: 2020-05-18 journal: Psychosomatics DOI: 10.1016/j.psym.2020.05.006 sha: 61e9427085f209ebbca170b0cdbd378ec8c0d25b doc_id: 914832 cord_uid: q82p5bo3 BACKGROUND: With the rapid, global spread of SARS-CoV-2, hospitals have become inundated with patients suffering from COVID-19. Consultation-liaison psychiatrists are actively involved in managing these patients and should familiarize themselves with how the virus and its proposed treatments can affect psychotropic management. The only FDA approved drug to treat COVID-19 is remdesivir, and other off-label medications used include chloroquine and hydroxychloroquine, tocilizumab, lopinavir/ritonavir, favipiravir, convalescent plasma therapy, azithromycin, vitamin C, corticosteroids, interferon and colchicine. PURPOSE: To provide an overview of the major safety considerations relevant to clinicians who prescribe psychotropics to patients with COVID-19, both related to the illness and its proposed treatments. METHODS: In this targeted review we performed structured literature searches in PubMed to identify articles describing the impacts of COVID-19 on different organ systems, the neuropsychiatric adverse effects of treatments, and any potential drug interactions with psychotropics. The articles most relevant to this manuscript were included. RESULTS: COVID-19 impacts multiple organ systems, including gastrointestinal, renal, cardiovascular, pulmonary, immunological, and hematological systems. This may lead to pharmacokinetic changes that impact psychotropic medications and increase sensitivity to psychotropic-related adverse effects. Additionally, several proposed treatments for COVID-19 have neuropsychiatric effects and potential interactions with commonly used psychotropics. CONCLUSION: Clinicians should be aware of the need to adjust existing psychotropics or avoid using certain medications in some COVID-19 patients. They should also be familiar with neuropsychiatric effects of medications being used to treat this disease. Further research is needed to identify strategies to manage psychiatric issues in this population. With the rapid, global spread of SARS-CoV-2, hospitals have become inundated with patients suffering from COVID-19 infection. Remdesivir was recently approved by the US Food and Drug Administration (FDA) to treat severe COVID-19 (1) , and many other medications are either being studied in clinical trials or being used off-label and/or for compassionate use (2) . As the pandemic spreads, Consultation Liaison (CL) psychiatrists are being called upon to help manage the psychiatric conditions of individuals with COVID-19 and are encountering challenging clinical scenarios of multiple medical comorbidities and unfamiliar drugs. Psychiatrists should familiarize themselves with the mechanism of action of these treatments, neuropsychiatric side effects and possible interactions with psychotropics. Additionally, since COVID-19 affects multiple organ systems, psychiatrists will need to be aware of safety concerns inherent in prescribing psychotropics to these patients. This article is divided into 2 main sections. The first provides an update on the organ systems that may be negatively impacted by COVID-19 and recommendations for safer use of psychotropics in these patients. The second section reviews potential neuropsychiatric side effects of the early approved and investigational treatments for COVID-19 as well as pharmacokinetic and pharmacodynamic drug-interactions when used concurrently with psychotropics. COVID-19 therapies reviewed include remdesivir, chloroquine, hydroxychloroquine, azithromycin, tocilizumab, lopinavir/ritonavir, favipiravir, convalescent plasma therapy, corticosteroids, interferon, vitamin C, and colchicine. Given the limited literature in this area, we undertook a non-systematic narrative review that was focused on practical clinical concerns. We utilized a structured PubMed search using the following search terms in combination with the names of the medications mentioned above: "COVID-19," "coronavirus," "Psychotropic medications," "QT prolongation," "Psychiatric side effects," "Neuropsychiatric side effects," "drug interactions," and pertinent organ systems, e.g. "hepatic," "renal," "hematological," "pulmonary," and "cardiac." This was followed by a search of manufacturer's package inserts for pertinent facts about specific medications, including drug interactions. We selected the above medications as they were the ones most commonly being used in healthcare settings and clinical trials at the time of preparation of this manuscript, although we are aware that this is a rapidly evolving field and thus this list is not meant to be comprehensive. COVID-19 is believed to impact multiple organs, including the liver, kidneys, lungs and heart, as well as the immune and hematological systems (3) . Damage to these organs or systems may lead to pharmacokinetic changes that impact absorption, distribution, metabolism and/or excretion of psychotropic medications as well as increased sensitivity to certain psychotropic-related adverse effects. As such, clinicians should be aware of the potential need to make adjustments to existing psychotropic regimens or avoid using certain psychotropic agents if such safety concerns arise (Tables 1 and 2) . An early report noted the presence of lymphopenia (lymphocyte count less than 1.0 x 109/L) in 63% and leukopenia (white blood cell count less than 4 x109/L) in 25% of COVID-19 patients (4) . It has been proposed that lymphopenia is a feature of severe COVID-19 cases and may serve as a poor prognostic factor. Contributing factors likely include direct infection of lymphocytes and cytokine storm (5) It therefore seems prudent to utilize caution and consider avoiding medications which have the potential to further impact white blood cell production, particularly lymphocytes. By contrast, clinicians might determine that it is acceptable from a safety standpoint to continue psychotropics which have only been associated with agranulocytosis and neutropenia, assuming the patient does not have a secondary bacterial infection. Several psychotropics have been implicated in hematological adverse effects, including leukopenia, neutropenia, and agranulocytosis. The most commonly implicated psychotropics include carbamazepine and clozapine, but there is a class effect FDA warning on all first and secondary generation antipsychotics for the potential association with leukopenia, neutropenia and agranulocytosis as well as a number of published case reports. Carbamazepine is more likely to be associated with an early transient leukopenia, but has also been associated with agranulocytosis and aplastic anemia (6) . While the leukopenia and lymphopenia observed in COVID-19 patients may be less of a concern for clozapine prescribers in the setting of a normal neutrophil count, clozapine deserves unique mention given several potential challenges associated with its use during the COVID-19 pandemic. These challenges have been recently reviewed along with recommendations for management in a consensus statement by Siskind and colleagues (7) . Patients on clozapine may have difficulty accessing routine absolute neutrophil count (ANC) monitoring and the Food and Drug Administration (FDA) has released guidance allowing healthcare providers to use medical judgment to delay laboratory testing for drugs subject to Risk Evaluation and Mitigation Strategy (REMS) (8) . While there is no data yet available on COVID-19 in patients on clozapine, it has been suggested that clozapine is associated with a higher risk of pneumonia and its complications. Explanations include aspiration, sialorrhea, sedation, and poorly understood effects on the immune system (7, 9) . Patients should be educated on symptoms of pneumonia and urgently evaluated by a clinician if symptoms of infection emerge. Complicating the picture further, elevation of clozapine levels has been observed with multiple acute viral and bacterial infections. This may in part be related to effects of systemic infection and inflammation on CYP450 enzymes (10) . Clinicians should closely monitor clozapine levels and consider reducing the dose by up to a half in patients with fever and other signs of infection. Coagulation abnormalities such as PT and aPTT prolongation, thrombocytopenia and disseminated intravascular coagulation (DIC) are also frequently observed in COVID-19 patients. At the same time, many COVID-19 patients experience increased thrombotic risk and may be prescribed prophylactic anti-coagulants (5) . These factors may impact the decision to prescribe psychotropics that have been associated with platelet dysfunction and increased bleeding risk (e.g. selective serotonin reuptake inhibitors and valproic acid). Clinicians should be especially mindful of using these medications in patients who have other risk factors for bleeding, such as concomitant anti-coagulation therapy and history of significant bleeding event. There is limited available information regarding cardiovascular involvement due to COVID-19 infection, although tachyarrhythmias and heart failure have been described with other severe acute respiratory syndrome (SARS) beta-coronavirus infections (11) . A recent report described acute myopericarditis in a patient with COVID-19 (12) and a meta-analysis found acute cardiac injury in at least 8% of patients with COVID-19 (13) . It has been suggested that COVID-19 most likely has an arrhythmogenic effect (14) . Proposed mechanisms of myocardial injury include derangement of Angiotensin Converting Enzyme 2 (ACE2) signal pathways, cytokine storm and myocarditis. Additionally, several medications being utilized off-label in the management of COVID-19 (azithromycin, hydroxychloroquine, chloroquine, and lopinavir/ritonavir) have been reported to prolong the QT interval. QT prolongation, particularly in those with underlying medical risk factors, has been linked to lethal ventricular arrhythmias, such as Torsades de Pointes (TdP). A complete discussion of the cardiac side effects of psychotropics is beyond the scope of this paper, except to note that it has been well described in the literature that a number of psychotropic medications can prolong the QT interval. Although the data are often difficult to interpret due to confounding factors, antipsychotics, tricyclic antidepressants and the SSRI citalopram, appear to be the agents of most concern. It is difficult to stratify antipsychotic medications by QT prolongation risk. Of the typical antipsychotics, thioridazine causes the greatest QT prolongation, although IV haloperidol has also been implicated. The greatest risk among the atypicals appears to be related to ziprasidone and possibly iloperidone. Aripiprazole and possibly lurasidone have been associated with the lowest risk based on available data (15) . Health care providers should be aware of the baseline corrected QT interval (QTc) and all concomitant medications, labs, medical comorbidities and family history prior to prescribing psychotropics in COVID-19 patients. Caution should be used in patients with a baseline prolonged QTc and/or other risk factors for drug-induced QT prolongation and TdP: use of QT prolonging medications, cardiac comorbidities, age >65, female sex, family history of sudden cardiac death, hypokalemia/hypomagnesemia, and illicit substance use. If QT-prolonging medications are used in a patient with a QTc>500ms or other significant risk factors, ECGs should be monitored frequently (daily in high risk cases), potassium and magnesium should be repleted, cardiology involvement should be considered, and every attempt made to reduce risk factors (15) . In patients who test positive for COVID-19 but are already taking a psychotropic drug that has inherent potential for QTc prolongation, risk-benefit decisions must be made on a case-by-case basis regarding continuation versus switching to an alternative medication. Several studies have reported acute liver injury, particularly in severe COVID-19 cases (4, 16, 17) . The etiology of the liver injury is not known and hypotheses include viral infection, drug-induced liver injury, and systemic inflammation due to cytokine storm or hypoxia (16) . Lab abnormalities observed include elevated AST, ALT and bilirubin (17) . Liver function tests should be monitored and, if abnormal, consideration given to avoiding psychotropics that can also cause hepatic injury or making dose adjustments if heavily dependent on hepatic metabolism. Since most psychotropics are lipid soluble and require hepatic metabolism prior to clearance, clinicians should review the package insert to determine if a dose adjustment is needed. Additionally, many psychotropics (valproate, carbamazepine, tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors and second-generation antipsychotics) have been associated with mild hepatoxicity that manifests with modest, transient increases in liver enzymes. Only a few, are thought to have a high risk of causing serious drug-induced liver injury (DILI), including chlorpromazine, carbamazepine, valproate, duloxetine and nefazodone (18, 19) . Such high risk psychotropics should be preferentially avoided in patients with COVID-19 associated liver disease. Acute kidney injury has been observed, particularly in patients with COVID-19-associated acute respiratory distress syndrome (ARDS) and pre-existing chronic kidney disease. Several causes have been proposed, including impaired gas exchange, hemodynamic alterations, sepsis, and an inflammatory/immune reaction involving release of circulating mediators that cause injury to kidney cells (20) . In such patients, avoiding potentially nephrotoxic drugs, such as lithium, may be required. Additionally, psychiatrists should be aware of any renal impairment and make necessary dose adjustments as per the manufacturer's prescribing information. Psychotropics highly dependent on renal excretion include lithium, gabapentin, topiramate, pregabalin and paliperidone. Many other psychotropics have renally excreted active metabolites. Levels of these medications or their metabolites can increase in the setting of impaired renal clearance such that reduced dosing or avoiding the medication may be required. For example, administration of duloxetine is not recommended for patients with severe renal impairment (CrCL of <30 mL/min) (18) . Based on similarities between SARS-CoV2 and other coronaviruses, it is thought likely that SARS-CoV2 has neuroinvasive potential (21) but there remain many unanswered questions about neurological manifestations of COVID-19. Initial observations note a variety of neurological syndromes in COVID-19 patients, particularly the more severely affected. These include stroke, delirium, seizures, and an encephalitis-type presentation. A recent paper from Wuhan (22) reports neurologic symptoms in 36.4% of COVID-19 patients, falling into 3 categories: 1) Central nervous system symptoms or diseases (headache, dizziness, impaired consciousness, ataxia, acute cerebrovascular disease, and seizure); 2) Peripheral nervous system symptoms (impairment in taste, vision and smell, neuropathic pain) and 3) Skeletal muscular injury. It is not known whether these neurologic syndromes are a direct effect of the virus entering the central nervous system or an indirect response to the cytokine storm that patients are experiencing. A specific prevalence rate of delirium was not reported but is presumed to be very high and to contribute to poor adherence with care and other safety concerns. Certainly, for patients with severe COVID-19 infections, there are many other potential etiologies of delirium, including organ failure, hypoxia, sepsis, medication effects, and electrolyte/metabolic abnormalities. Observational studies have in fact reported high rates of benzodiazepine use for sedation in ventilator-dependent COVID-19 patients (23) . Environmental factors such as isolation from family members and difficulty mobilizing patients also contribute (24). In COVID-19 patients with delirium, clinicians should be mindful about prescribing benzodiazepines, opioids and drugs with strong anticholinergic properties (tertiary amine tricyclic antidepressants, low potency antipsychotics, benztropine and diphenhydramine) as these medications have the potential to cause or exacerbate confusion, sedation and/or falls. Clinicians should also be cautious about prescribing psychotropics that can lower the seizure threshold in patients with seizures or structural brain lesions. Such medications include most antipsychotics (especially clozapine, quetiapine, olanzapine and first generation antipsychotics) (25) and certain antidepressants (bupropion, tricyclics) (26) . As the lung is considered the primary organ that is affected by COVID-19, most patients present with respiratory symptoms, such as cough and shortness of breath. Affected individuals may develop pneumonia and acute respiratory distress syndrome leading to high supplemental oxygen requirements and in the most severe cases, invasive ventilation (4). Psychiatric consultants may be asked to evaluate and manage COVID-19 patients with anxiety or panic symptoms in addition to respiratory distress. While there may be circumstances in which the use of small doses of a benzodiazepine is appropriate, it is important to be aware of the potential for benzodiazepines to suppress respiratory drive, particularly at higher doses. Clinicians therefore need to consider risks versus benefits in using benzodiazepines in patients with prominent respiratory symptoms. Many of the proposed COVID-19 treatments have the potential for neuropsychiatric side effects as well as drug-drug interactions. These are reviewed in the section below and summarized in Table 3 . Remdesivir is an antiviral medication that interacts with RNA polymerase and evades proofreading by viral exonuclease leading to a decrease in viral RNA (27) . On May 1, 2020, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) to use remdesivir for treatment of suspected or confirmed severe COVID-19 infection (1), with severe defined as "patients with an oxygen saturation ≤ 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO)". The EUA was based on early promising data from a randomized doubleblinded, placebo-controlled (28) and an open-label trial (29) . Remdesivir is administered by infusion, with a treatment course of 5 or 10 days, depending on severity of disease. No information is available regarding neuropsychiatric side effects, but administration has been associated with infusion-related reactions that can present with hypotension, diaphoresis and shivering (1) . Such symptoms might be misconstrued as a panic attack. Remdesivir carries a risk of transaminase elevations (30), specifically but not limited to alanine aminotransferase (ALT) elevations up to 20 times the upper limit of normal (1) . This may impact the decision to use hepatically metabolized psychotropics, such as valproic acid. Chloroquine, a synthetic form of quinine used for the treatment and prophylaxis of malaria, and hydroxychloroquine a derivative compound used in the treatment of inflammatory disorders such as rheumatic arthritis and systemic lupus erythematosus, are being considered as a possible treatment for COVID-19 infection. Interest in these medications is in part due to their potential for interference with virus-receptor binding and immune-modulating effects (31) . The most promising study is a small open-label trial from France (32), although a recent large observational study showed that the risk of intubation or death was not significantly higher or lower among patients who received the drug than among those who did not (33) . The authors suggest that their findings do not support continued use of the drug in COVID-19 patients outside of clinical trials. Neuropsychiatric effects Neuropsychiatric side effects of chloroquine and hydroxychloroquine include psychosis, delirium, agitation, suicidality, personality changes, depression, and sleep disturbances (34, 35) . Risk factors for hydroxychloroquine-induced neuropsychiatric effects may be concurrent use of CYP3A4 inhibitors or low-dose glucocorticoids, alcohol intake, family history of psychiatric disease, female gender, low body weight and supratherapeutic dosing (36) . A number of mechanisms have been postulated for the pathogenesis of hydroxychloroquineinduced neuropsychiatric effects, such as cholinergic imbalance due to acetylcholinesterase inhibition, inhibition of the serotonin transporter protein, and NMDA and GABA antagonism (34) . Hydroxychloroquine and chloroquine can cause heart conduction disorders, including QT interval prolongation, bundle branch block, AV block, and torsades de pointes (37) . On April 24, 2020, the FDA issued a safety announcement against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems (38) . Caution should be used when combining them with QT prolonging psychotropics. These agents can also be hepatotoxic (39) and epileptogenic (40) , so caution should be exercised in patients with hepatic disease, or in conjunction with psychotropics that may be hepatotoxic or may lower the seizure threshold. Both chloroquine and hydroxychloroquine are metabolized by CYP3A4 (41), so CYP3A4 inhibitors (e.g. fluvoxamine), could raise plasma levels and increase the potential for adverse effects. By contrast, CYP3A4 inducers, such as carbamazepine, oxcarbazepine and modafinil could decrease levels of chloroquine or hydroxychloroquine, potentially rendering them less effective. Given hydroxychloroquine's long half-life (40 hours), the potential for continued adverse effects and drug-interactions may continue for days after the drug has been discontinued (35) . Tocilizumab is a recombinant humanized monoclonal antibody that acts as an interleukin-6 (IL-6) receptor inhibitor (42) and is FDA approved to treat several types of arthritis (43) . Tocilizumab is being trialed in severe COVID-19 patients with elevated IL-6 because IL-6 appears to be involved in cytokine storms that have been observed in critically ill patients with COVID-19 (44) . Data from rheumatic arthritis patients suggest that Tocilizumab may have some positive effects on depressive symptoms in rheumatoid arthritis (45, 46) , however unpublished data from a small study surprisingly suggests that patients who received tocilizumab following allogeneic hematopoietic cell transplantation experienced worse symptoms of depression, anxiety, pain, and sleep (47) . No major interactions have been reported. 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. No published information is available. There is no published information available. One published case report suggested a mild QT prolongation in an Ebola virus patient who received favipiravir (49) . Lopinavir/Ritonavir is an antiviral medication used to treat HIV-1 infection (50) The two medications work synergistically: lopinavir is a protease inhibitor and ritonavir helps to boost plasma levels of lopinavir by inhibiting its metabolism (50) . Unfortunately, a recently published randomized, controlled, open-label trial found no additional benefit with lopinavir-ritonavir treatment in hospitalized patients with SARS-CoV-2 as compared with standard care (51) . The manufacturer's prescribing information lists possible psychiatric side effects, including abnormal dreams, agitation, anxiety, confusion and emotional lability although there is limited information in published case reports or trials regarding the incidence of such effects (50) . Protease inhibitors as a class have been associated with neurological adverse events, such as paresthesias, taste alterations, and neurotoxicity (52) . Protease inhibitors are extensively metabolized by the cytochrome P450 system and have been shown to interact with many drugs, including psychotropics (53) . Use of Ritonavir may lead to increased concentrations of co-administered drugs that are CYP3A4 or CYP2D6 substrates or decreased concentrations of CYP1A2 or CYP2B6 substrates, many of which are psychotropics. Use of Lopinavir/Ritonavir is contraindicated with medications that include pimozide, midazolam, and triazolam due to increased drug levels and potentiation of adverse effects. Use of benzodiazepines not dependent on CYP metabolism (lorazepam, temazepam or oxazepam) is recommended. Due to CYP450 enzyme or glucuronidation inducing effects, Ritonavir-boosted protease inhibitors also have been shown to lower concentrations of some psychotropics (e.g. bupropion, methadone, lamotrigine and olanzapine), thus leading to increased dose requirements for these medications (53) . Since most psychotropics are substrates for CYP isoenzymes, there are many additional theoretical interactions, but the clinical significance varies by agent. Clinicians should assess each potential interaction individually by reviewing available literature and manufacturer prescribing information. Other potential non-psychiatric side effects that may have implications for psychiatrists include the following: Stevens Johnson syndrome, diabetes mellitus, QTc prolongation, pancreatitis, neutropenia, hepatotoxicity and chronic kidney disease (50) . Antibody containing convalescent plasma from recovered patients has been used with some success as a last resort to treat severe viral respiratory infections such as SARS-CoV, MERS-CoV, and Ebola although large clinical trials are absent (54) . Trials are currently underway to study the effectiveness of convalescent plasma therapy in the treatment of individuals with severe respiratory failure associated with COVID-19. When used for the treatment of other severe acute viral respiratory infections, convalescent plasma therapy was not associated with serious adverse events (55) , although in general, plasma transfusions can cause a range of adverse events from mild fever and allergic reactions to life threatening bronchospasm/anaphylaxis, transfusion-related acute lung injury and transfusion associated circulatory overload (56) . Specific neuropsychiatric effects have not been reported, although allergic reactions, cardiovascular complications and bronchospasm can produce symptoms such as shortness of breath and palpitations that mimic panic attacks. A potential psychological adverse effect of convalescent plasma therapy relates to ethical concerns about coercion, confidentiality, and privacy for the prospective donors that were initially raised during the Ebola outbreak (57) and led to a World Health Organization document providing guidance on the ethical use of convalescent plasma (58) . 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 is an antibacterial agent which may have antiviral and anti-inflammatory activity (32) . It is under investigational use for treatment of COVID-19 when given in conjunction with chloroquine or hydroxychloroquine. In one small French study (n=20), azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination as compared to hydroxychloroquine alone (32) . Side effects that have been reported include psychotic depression, catatonia, delirium, aggressive reaction, anxiety, dizziness, headache, vertigo and somnolence (59, 60) . Azithromycin has not been implicated in pharmacokinetic interactions with psychotropics but has been associated with QTc prolongation and life-threatening TdP arrhythmias. It has also been associated with hepatotoxicity (61). High dose intravenous vitamin C (ascorbic acid), an antioxidant and reducing agent, has been investigated in the treatment of sepsis due to its enhancement of the immune response (62) . In the intensive care setting, vitamin C administration has been correlated with preventing progressive organ dysfunction and reducing mortality in sepsis and acute respiratory distress syndrome (ARDS) (63) , and is being investigated in critically ill patients with COVID-19. There are no known adverse neuropsychiatric consequences of high-dose IV vitamin C administration, but some studies have associated lower levels of vitamin C with depression, confusion and anger (64) . Vitamin C deficiency has also been identified as a possible risk factor for delirium (65) . Coadministration with barbiturates may decrease the effects of vitamin C (62). Corticosteroids are involved in immune function, inflammation, and carbohydrate metabolism and are used in the treatment of endocrinopathies, autoimmune disorders, and asthma/allergies (66) . In previous pandemics, such as SARS and MERS, corticosteroids were not recommended due to concern that they may exacerbate lung injury (67) . Given evidence suggesting that severe COVID-19 may be associated with a cytokine storm and hyperinflammation syndrome (67), corticosteroids may have a role in treatment. The neuropsychiatric side effects of corticosteroids have been well described in the literature and include depression, mania, agitation, mood lability, anxiety, insomnia, catatonia, depersonalization, delirium, and psychosis (66) . The majority of neuropsychiatric side effects occur early in treatment course, usually within days, and dosing is the most significant risk factor (i.e. at prednisone equivalents of >40mg/day) (66) . Corticosteroids have been inconsistently reported to be weak CYP 3A4 and CYP2C19 inducers (68) , which could lead to decreased effects of CYP3A4 or CYP2C19 substrate psychotropics (69) . Additionally, phenytoin has been shown to increase hepatic metabolism of systemic corticosteroids (70) . Interferons (IFNs) are glycoproteins that have immunomodulatory, antiproliferative, and hormone-like activities (71) . IFN alpha and beta have anti-SARS-CoV-1 activity in vitro and IFN beta reduces the replication of MERS-CoV (72, 73) in vitro. Based on this information, IFN has been considered as a potential treatment for COVID-19, including in combination with Ribavirin, a guanosine analogue with broad spectrum antiviral potency (74) . IFN alpha has a boxed warning for "life threatening or fatal neuropsychiatric disorders" (75) . Specific effects include fatigue, mood disorders, suicidality, anxiety disorders, irritability, lability, apathy, sleep disturbance, and cognitive deficits (76) . Side effects of IFN beta can include fatigue, weight loss, myalgia and arthralgia (77), but not generally depression. Given the potential for significant psychiatric side effects of IFN alpha, it is important for clinicians to screen for baseline psychiatric history and monitor closely for emergence of any symptoms. There are no known pharmacokinetic interactions with psychotropics but clinicians should be mindful of the potential for bone marrow suppression which may raise safety concerns with concurrent use of psychotropics, such as carbamazepine, valproate and clozapine. Additionally, seizures in conjunction with bupropion use have been reported (78) . Colchicine is a plant-derived alkaloid with anti-inflammatory properties that is used for a variety of rheumatological and cardiac conditions (79) . It is hypothesized that colchicine could treat COVID-19 through targeting the overactive IL-6 pathway (80). Colchicine does not typically produce any neuropsychiatric effects, but at toxic doses, can cause delirium, seizures and muscle weakness.. (81) . Colchicine has a narrow therapeutic index and attention must be paid to potential drug interactions that might increase cause toxicity. Colchicine is metabolized by CYP3A4 and excreted via the P-glycoprotein (P-gp) transport system as well as cleared by the kidneys through glomerular filtration. Dose adjustment is recommended with concurrent use of CYP 3A4 or P-gp inhibitors as well as in patients with hepatic or renal impairment (82) . CYP3A4 inducers can lead to increased metabolism, and theoretically decreased effectiveness of colchicine. COVID-19 and its treatments can impact many organ systems and contribute to a host of drug interactions and neuropsychiatric effects. This can have safety implications for use of psychotropics, which are highly metabolized by the hepatic cytochrome p450 system and carry their own potential for drug-interactions and end-organ adverse effects. While there are no absolute contraindications to use of psychotropics in COVID-19 patients, psychiatrists must be mindful of potential adverse effects and conduct a thoughtful risk-benefit analysis as part of their clinical decision-making process. For example, chloroquine, hydroxychloroquine, and azithromycin have the potential for QT prolongation, which can be problematic in patients with tenuous cardiac status. Generally, psychiatrists might avoid antipsychotic medications in the setting of a prolonged QT interval. However, in our experience, hyperactive delirium in COVID-19 patients is highly prevalent and manifests with severe agitation that can be difficult to treat and leads to dangerous behaviors such as removing oxygen or assaulting staff. While there is limited evidence to support the use of any interventions in the management of agitation in COVID-19 associated delirium, most CL psychiatrists consider antipsychotics such as haloperidol the gold standard for managing agitation in delirious patients. In these situations, the CL psychiatrist should assist the medical team in reasoning through the cardiac risks of using an antipsychotic balanced against effective management of the agitation. Use of an antipsychotic with cardiology involvement and frequent EKG monitoring or telemetry may be deemed acceptable. Alternatives such as alpha-2 agonists (dexmedetomidine and clonidine) or anti-epileptics (valproic acid) should be considered if the individual patient's cardiac risk is determined to be high and/or if the antipsychotic is clinically ineffective. Melatonin has been proposed for addressing consciousness and sleep-wake cycle disturbances in delirious COVID-19 patients, especially given its potential for anti-oxidative, anti-inflammatory and immune-enhancing effects (83) . With the exception of patients who chronically use alcohol or benzodiazepines and may be at risk for withdrawal, benzodiazepines should be avoided if possible and considered only as a last resort for highly agitated delirious patients for whom other treatments are unavailable or ineffective. Early delirium screening and non-pharmacological strategies to prevent or treat delirium such as frequent orientation and early mobilization should be employed if practically feasible (24) . As another example, we have observed many non-delirious COVID-19 patients with significant anxiety in the setting of respiratory distress. In some cases, the anxiety leads to requests to leave against medical advice or refusal to remain isolated. For these patients, psychiatrists should consider whether the benefit of a low dose benzodiazepine outweighs the potential risk of respiratory depression. Use of benzodiazepines may be reasonable in patients with adequate oxygen saturation and absence of confusion or a depressed sensorium. Depending on the individual patient's circumstances and symptoms, alternative medications such as gabapentin, buspirone, hydroxyzine, a low dose atypical antipsychotic, or a selective serotonin reuptake inhibitor (SSRI) may be appropriate. Non pharmacological/psychosocial interventions (eg, behaviorally oriented therapies) should also be utilized. Other important tasks for the psychiatrist treating a COVID-19 patient include review of all medications, monitoring for neuropsychiatric side effects of medications such as hydroxychloroquine or corticosteroids and differentiating between primary psychiatric symptoms versus those that are secondary to COVID-19 or other medications. Interestingly, several psychotropics, including haloperidol and valproic acid were recently named on a list of FDA approved medications with potential for in vitro action against SARS-CoV-2 (84) Fluvoxamine is also under investigation for its potential to reduce the inflammatory response during sepsis by inhibiting cytokine production (85) , and melatonin for its anti-oxidative and anti-inflammatory properties (86) . If more data becomes available, psychiatrists might consider preferentially using these agents if clinically appropriate. In summary, psychiatrists must be aware of the likelihood of encountering patients with COVID-19 infection and must remain cognizant of the neuropsychiatric effects and drug-drug interactions of COVID-19 treatments as well as the end-organ effects of COVID-19. In COVID-19 patients with anxiety or panic symptoms, weigh risks vs benefits in using benzodiazepines in patients with prominent respiratory symptoms, given potential to suppress respiratory drive Fact Sheet for Healthcare Providers -Emergency Use Authorization (EUA) of Remdesivir (GS-5734 TM ) Food and Drug Administration (FDA) Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics Comorbidities and multi-organ injuries in the treatment of COVID-19 Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Hematological findings and complications of COVID-19 Hematologic Side Effects of Psychotropics Consensus statement on the use of clozapine during the COVID-19 pandemic Policy for Certain REMS Requirements During the COVID19 Public Health Emergency Pneumonia may be more frequent and have more fatal outcomes with clozapine than with other second-generation antipsychotics Elevated clozapine levels associated with infection: a systematic review Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19) Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China SARS-CoV-2, COVID-19 and inherited arrhythmia syndromes. Hear Rhythm QT Prolongation, Torsades de Pointes, and Psychotropic Medications: A 5-Year Update Gastrointestinal and Liver Manifestations in Patients with COVID-19 Clinical characteristics of non-ICU hospitalized patients with coronavirus disease 2019 and liver injury: A retrospective study Managing the Side Effects of Psychotropic Medications Psychotropic drugs and liver disease: A critical review of pharmacokinetics and liver toxicity Acute kidney injury in SARS-CoV-2 infected patients The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients Neurologic manifestations of hospitalized patients with coronavirus disease Neurologic features in severe SARS-CoV-2 infection COVID-19: ICU delirium management during SARS-CoV-2 pandemic Comparative risk of seizure with use of first-and second-generation antipsychotics in patients with schizophrenia and mood disorders Proconvulsant effects of antidepressants -What is the current evidence? Epilepsy Behav Remdesivir as a possible therapeutic option for the COVID-19 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) Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734 TM ) in Participants With Severe Coronavirus Disease First 12 patients with coronavirus disease 2019 (COVID-19) in the United States. medRxiv Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an openlabel non-randomized clinical trial Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 Behavioral toxicity and equivocal suicide associated with chloroquine and its derivatives Manufacter's Package Insert Neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: a review article Electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems Fulminant hepatic failure secondary to hydroxychloroquine Seizures as a rare adverse effect of chloroquine therapy in systemic lupus erythematosus patients: a case report and literature survey Tocilizumab (Actemra) Manufacterer's Packge Insert, Actemra (tocilizumab) Tocilizumab treatment in COVID-19: A single center experience Tocilizumab for Rheumatoid Arthritis: A Cochrane Systematic Review Impact of Tocilizumab Monotherapy on Clinical and Patient-Reported Quality-of-Life Outcomes in Patients with Rheumatoid Arthritis Inflammation and the brain: tocilizumab may redefine our understanding of depression and related symptoms in the medically ill Discovering drugs to treat coronavirus disease 2019 (COVID-19) QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient Manufacturer's prescribing information A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 Neurological and psychiatric adverse effects of antiretroviral drugs Drug-drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs Convalescent plasma as a potential therapy for COVID-19 Treatment of COVID-19: old tricks for new challenges The use of Ebola convalescent plasma to treat Ebola virus disease in resource-constrained settings: a perspective from the field Ethics of using convalescent whole blood and convalescent plasma during the Ebola epidemic ZITHROMAX® (azithromycin tablets) and (azithromycin for oral suspension) Azithromycin-induced psychotic depression and catatonia Hepatotoxicity of Antibacterials: Pathomechanisms and Clinical Data 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 High vitamin C status is associated with elevated mood in male tertiary students Vitamin deficiency as a risk factor for delirium The neuropsychiatric complications of glucocorticoid use: steroid psychosis revisited COVID-19: consider cytokine storm syndromes and immunosuppression Cytochrome P450-mediated drug interactions Effect of methylprednisolone on CYP3A4-mediated drug metabolism in vivo Phenytoin/dexamethasone interaction: a clinical problem A brief history of the use of interferons as treatment of multiple sclerosis Interferon-β 1a and SARS coronavirus replication Severe acute respiratory syndrome-related coronavirus is inhibited by interferon-α Potential therapeutic agents against COVID-19: What we know so far PEGASYS (peginterferon alfa-2a) injection -HIGHLIGHTS OF PRESCRIBING INFORMATION Psychiatric side effects of pegylated interferon-α and ribavirin therapy in Iranian patients with chronic hepatitis C: A meta-analysis How type I interferons work in multiple sclerosis and other diseases: some unexpected mechanisms Seizures during pegylated interferon and ribavirin therapy for chronic Hepatitis C: observations from the WIN-R trial Update on colchicine Colchicine Coronavirus SARS-CoV2 Trial (COLCORONA) (COVID-19) Colchicine poisoning: the dark side of an ancient drug Colchicine: Its mechanism of action and efficacy in crystal-induced inflammation Delirium and sleep disturbances in COVID-19: a possible role for melatonin in hospitalized patients A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing. bioRxiv Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis COVID-19: Melatonin as a potential adjuvant treatment Dr. Ernst receives royalty payments from American Psychiatric Publishing, Inc. The other authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.