key: cord-0733602-bnapx665 authors: Baller, Erica B.; Hogan, Charlotte S.; Fusunyan, Mark A.; Ivkovic, Ana; Luccarelli, James W.; Madva, Elizabeth; Nisavic, Mladen; Praschan, Nathaniel; Quijije, Nadia V.; Beach, Scott R.; Smith, Felicia A. title: Neurocovid: Pharmacological recommendations for delirium associated with COVID-19 date: 2020-05-21 journal: Psychosomatics DOI: 10.1016/j.psym.2020.05.013 sha: 61eb1162055581d9051c76928327e366fdd4861a doc_id: 733602 cord_uid: bnapx665 BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the biggest health threats of our generation. A significant portion of patients are presenting with delirium and neuropsychiatric sequelae of the disease. Unique exam findings and responses to treatment have been identified. We seek to provide pharmacologic and treatment recommendations specific to delirium in patients with COVID-19. METHODS: We performed a literature search reviewing the neuropsychiatric complications and treatments in prior coronavirus epidemics including middle eastern respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronaviruses as well as the emerging literature regarding COVID-19. We also convened a work group of consultation-liaison psychiatrists actively managing COVID-19 patients in our hospital. Finally, we synthesized these findings to provide preliminary pharmacologic recommendations for treating delirium in these patients. RESULTS: Delirium is frequently found in patients who test positive for COVID-19, even in the absence of respiratory symptoms. There appears to be a higher rate of agitation, myoclonus, abulia, and alogia. No data are currently available on the treatment of delirium in COVID-19 patients. Extrapolating from general delirium treatment, MERS/SARS case reports, and our experience, preliminary recommendations for pharmacologic management have been assembled. CONCLUSIONS: COVID-19 is associated with neuropsychiatric symptoms. Low potency neuroleptics and alpha-2 adrenergic agents may be especially useful in this setting. Further research into the pathophysiology of COVID-19 will be key in developing more targeted treatment guidelines. The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the biggest health threats of our generation. A significant portion of patients are presenting with delirium and neuropsychiatric sequelae of the disease. Unique exam findings and responses to treatment have been identified. We seek to provide pharmacologic and treatment recommendations specific to delirium in patients with COVID-19. We performed a literature search reviewing the neuropsychiatric complications and treatments in prior coronavirus epidemics including middle eastern respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronaviruses as well as the emerging literature regarding COVID-19. We also convened a work group of consultation-liaison psychiatrists actively managing COVID-19 patients in our hospital. Finally, we synthesized these findings to provide preliminary pharmacologic recommendations for treating delirium in these patients. Delirium is frequently found in patients who test positive for COVID-19, even in the absence of respiratory symptoms. There appears to be a higher rate of agitation, myoclonus, abulia, and alogia. No data are currently available on the treatment of delirium in COVID-19 patients. Extrapolating from general delirium treatment, MERS/SARS case reports, and our experience, preliminary recommendations for pharmacologic management have been assembled. COVID-19 is associated with neuropsychiatric symptoms. Low potency neuroleptics and alpha-2 adrenergic agents may be especially useful in this setting. Further research into the pathophysiology of COVID-19 will be key in developing more targeted treatment guidelines. The pandemic of coronavirus disease marks the emergence of the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and has been associated with significant global morbidity and mortality (1) . Clinical presentations associated with COVID-19 are variable in severity, ranging from asymptomatic cases to severe pneumonia and acute respiratory distress syndrome (ARDS) requiring intensive care (2, 3) . In symptomatic individuals, COVID-19 typically manifests as an influenza-like respiratory illness, with fever, cough, dyspnea, and malaise/myalgias (4) . Atypical presentations, however, are frequent and include extrapulmonary involvement such as gastrointestinal symptoms, multi-organ failure (liver, kidneys, heart), and neurologic manifestations (5-7) ( Figure 1 ). Recently, there has been increasing recognition of neuropsychiatric manifestations of COVID-19, prompting this review of treatment strategies for the management of delirium in these patients. Human coronaviruses are known to have neuroinvasive potential (8) . SARS-CoV was associated with cases of polyneuropathy, myopathy, and large artery ischemic stroke, and autopsy studies identified SARS-CoV RNA in hypothalamic and cortical neurons (9, 10) . Middle East Respiratory Syndrome (MERS) coronavirus may have been linked to even greater central nervous system (CNS) involvement; a retrospective study in Saudi Arabia found that a fourth of cases developed "confusion" and nearly 9% experienced seizures (11) . Coma, ataxia, focal motor deficits, weakness, and neuropathies have also been described (12, 13) . Early literature is also recognizing the neuropsychiatric manifestations of COVID-19. A recent case series in Wuhan, China described the occurrence of neurological syndromes such as altered mental status and ischemic stroke in 36% of all admitted COVID-19 patients (3). A case series of ICU patients from Strasbourg, France similarly reported a high incidence of altered mental status (85%) (14) . This encephalopathy was often characterized by agitation (69%), corticospinal tract signs (67%), and executive dysfunction (36%). In this cohort, 8 patients had enhancement of the leptomeningeal spaces, and 11 had bilateral frontotemporal hypoperfusion on perfusion imaging. Many patients continued to experience altered cognition even upon discharge (14) . To date, no pharmacologic guidelines have been published for the treatment of delirium specifically associated with COVID-19. In this narrative review, we synthesize the current literature regarding the neurologic manifestations of COVID-19, propose a possible pathophysiologic hypothesis, and provide preliminary guidance for management. First, we performed a literature search for reviews, case reports, case series, and pharmacologic trials related to MERS, SARS and COVID-19. The literature search took place between April 1, 2020 and April 29, 2020 (see Supplement for details). Database search yielded a total of 43 articles. We excluded articles that were not written in English. In addition to a literature review, we formed a Consultation-Liaison Psychiatry COVID-19 Workgroup. The workgroup consisted of a panel of expert consultation-liaison psychiatrists in the Massachusetts General Hospital (MGH) Department of Psychiatry who were actively engaged in the care of patients with COVID-19 on inpatient medical units. Treatment courses were discussed and summarized by the workgroup. Lastly, literature review and anecdotal evidence from emerging cases were synthesized to provide a working hypothesis of neurocovid pathophysiology as well as pharmacologic guidance for the treatment of delirium in COVID-19 patients. Practicing on a psychiatry consult service in a large general hospital, we have seen 19 patients with delirium in the setting of COVID as of 5/1/2020. It is the experience of these authors that there may be unique characteristics of delirium in some patients with SARS-CoV-2. We have seen that some patients are admitted with confusion and agitation as their presenting symptom, in the absence of respiratory symptoms or other signs of infection. In addition to significant agitation and attentional impairment, exams have been notable in varying degrees for myoclonus, rigidity, alogia, and abulia (15) . As such, we have tailored our exams to specifically evaluate for catatonia and akinetic mutism. We also focus our chart review on ruling out alternative causes of delirium and potential neurologic manifestations of COVID-19 (i.e. stroke, seizure). The pathophysiology by which SARS-CoV-2 causes encephalopathy has yet to be elucidated. The severity of systemic illness (and the associated metabolic derangements and inflammatory cascades) in some COVID-19 patients is likely sufficient to cause the toxicmetabolic encephalopathy often seen in hospitalized patients. However, some features of SARS-CoV-2 and specifically the presentation of patients with severe confusional states in the absence of respiratory symptoms or other organ failure, have raised questions about possible alternative mechanisms of CNS injury. Cases of SARS-CoV-2-associated encephalitis (16) and Guillain-Barré syndrome have been recently described (17) . Anosmia and ageusia may be early features of SARS-CoV-2 infection (18) , implying direct invasion of the olfactory bulb. These revelations have led several investigators to propose multiple potential mechanisms by which SARS-CoV-2 may induce mental status changes in its victims, including infectious spread to the CNS by retrograde transport or hematogenous spread, dysregulation of cytokine activation leading to CNS inflammation, induction of cell-mediated CNS inflammation, post-infectious autoimmune reactions via molecular mimicry, and hypoxemic/thrombotic neuronal injury (5, 19) . Some authors have also hypothesized that hematogenous spread of SARS-CoV-2 through the periventricular system may lead a clinical picture of akinetic mutism even in the absence of a lesion detected on neuroimaging (15) . Given our cursory understanding of the pathophysiology of delirium in COVID-19 patients, treatment decisions must be based on symptom presentation, underlying medical comorbidities, and consideration of medication interactions. Similar to general delirium management, behavioral modifications are first line, but pharmacologic options may be needed for management of agitation and perceptual disturbances. Every patient who is admitted to the hospital with COVID-19 should be considered at high risk for developing delirium and prevention should be optimized (20) . Given new limitations and challenges related to staffing and visitor restrictions in the hospital during COVID-19, we also recommend ensuring patients have supervised access to charged phones or a tablet for communication with families, in addition to typical environmental and stimulus control, early ambulation, and care clustering to daytime (20) . When observation is needed, baby monitors can be used if available. If a patient is severely agitated for a prolonged time, net beds can reduce the risk of rhabdomyolysis and thrombosis by decreasing time in restraints. When behavioral strategies alone are not sufficient to keep patients and staff safe, pharmacologic management is necessary. Of note, there are no FDA approved treatments for delirium and to our knowledge, there is no literature reviewing management of agitation in COVID-19. The recommendations below are for off-label use (Table 1) . They have been extrapolated from SARS and MERS literature, and reflect the general practice patterns of the Consultation-Liaison Psychiatry COVID-19 Delirium Workgroup at Massachusetts General Hospital. Figure 2 outlines a potential management algorithm for COVID-19 delirium. There is significant interest in using melatonin and melatonin-receptor agonists in delirium management (21, 22) . More recent data also suggests specific utility in COVID-19, perhaps due to its sleep-regulating, immunomodulatory, and neuroprotective factors (21) (22) (23) . In theory, the age-related decline in melatonin levels may be one factor contributing to increased delirium risk and worse COVID-19 outcomes among elderly patients. Melatonin exerts its soporific effects through circadian entrainment and may also offer neuroprotection via increased BDNF expression and attenuation of N-methyl-D-Aspartate (NMDA) receptor-mediated glutamate excitotoxicity, as well as the prevention of kainic acid-induced neuronal lesions, glutathione depletion, and reactive oxygen species-mediated apoptotic nerve cell death (24) (25) (26) . It also has a relatively good safety profile. We recommend considering the addition of melatonin in all COVID-19 patients. It is worth noting, however, that for patients with severe immunocompromise, the immunosuppressive effects of melatonin may be detrimental. Though speculative, it is possible that there is heterogeneity in the COVID-19 patients who develop ARDS -those who do not mount enough of an immune response, and those whose overactive immune response leads to cytokine storm. Melatonin might be particularly useful in the latter group. As a class, alpha-2 agonists have been shown to be effective as prophylaxis against delirium as well as management of agitation related to delirium (26, 27) . Given their relatively safe side-effect profile for patients with SARS-CoV-2, we recommend them as first-line agents for management of delirium in this population. Dexmedetomidine may be particularly useful in COVID-19 delirium and is actively being studied (27) . Critical care literature suggests that dexmedetomidine may improve delirium and shorten the time to recovery (28) (29) (30) . While critical care teams most commonly manage dosing of the agent, consultation-liaison psychiatrists may play a role in advocating for dexmedetomidine over other sedating agents, helping to manage dexmedetomidine in combination with other psychotropic agents, and providing guidance for weaning dexmedetomidine. Dexmedetomidine is an alpha-2 adrenergic agonist that decreases norepinephrine release and sympathetic tone both centrally and peripherally. Intravenous infusion allows for quick titration, and it also has analgesic properties. Unlike other sedative agents, dexmedetomidine does not cause respiratory depression, which may be particularly advantageous for patients with ARDS. Use of dexmedetomidine is currently restricted to intensive care settings, though a sublingual form is under investigation. Relative to other sedatives, dexmedetomidine is expensive and occasionally subject to hospital shortages. Notably, dexmedetomidine can cause hypotension and bradycardia. Anecdotal experience suggests that clonidine may also be an appropriate first line treatment for COVID-19 delirium. Clonidine has efficacy in delirium as well as alcohol and opioid withdrawal (31) (32) (33) . Like dexmedetomidine, clonidine decreases central norepinephrine production at the locus coeruleus via negative feedback pre-synaptically (34) . Clonidine is available in pill and patch form and is useful in transitioning patients off dexmedetomidine. The patch typically takes 12 hours to impact behavior once applied. Clonidine may cause hypotension and bradycardia; rebound hypertension and tachycardia may occur with rapid taper. Guanfacine has a similar mechanism of action to clonidine, but a longer half-life (allowing for once daily dosing) (35) . It also causes less hypotension than clonidine and has less potential for rebound tachycardia. While these properties make it theoretically appealing, it should be noted that there is currently no evidence for guanfacine in delirium. In addition, it can only be given orally, and it is more difficult to rapidly titrate when transitioning a patient from dexmedetomidine. Antipsychotics may be used for management of behavioral dysregulation or perceptual disturbances. Based on clinical manifestations of COVID-19 delirium and possible pathophysiology, we recommend starting with low potency antipsychotics to minimize the risk of extrapyramidal side effects and catatonia. As always, psychiatrists should use additional caution in treating elderly patients with antipsychotics given warnings related to increased risk of death and stroke in patients with dementia (36) . Patients with chronic obstructive pulmonary disease are at increased risk of respiratory failure and should be monitored closely (37) . Though antipsychotics are not routinely recommended in hypoactive delirium, two openlabel trials have suggested possible efficacy in the use of aripiprazole (38, 39) . Because aripiprazole acts as a partial agonist at the dopamine receptor, it may be a good choice for patients experiencing perceptual disturbances caused by hypoactive delirium or for those in a dopamine-depleted state and displaying hypokinetic movements or rigidity on exam. While dystonic reactions and parkinsonism are uncommon, akathisia may occur, and aripiprazole is only available in pill form on most hospital formularies. Chlorpromazine Chlorpromazine, one of the oldest neuroleptics, is known for its rapid sedating effects. As a low potency agent, it carries less risk for extrapyramidal symptoms (EPS) and has the added advantages of being available in parenteral form and having a wide dose range, allowing for dose escalation. In addition to effects on 5HT 2A and D 2 receptors, chlorpromazine also has antihistaminergic, anticholinergic and alpha-1 blocking effects, which can lead to hypotension, urinary retention and constipation (40) . Haloperidol is typically the first line agent for management of agitation in delirium (41) . Given preliminary observations that COVID-19 patients may be at higher risk for motor symptoms suggesting a dopamine depletion state, we recommend using it with caution. As a high potency agent, haloperidol carries a significant risk of EPS and catatonia. That being said, the intravenous formulation appears to carry a much lower risk of these side-effects (42) . Intravenous haloperidol is blood pressure neutral, without anticholinergic side effects, calming but not sedating, and has a wide dose range. Interestingly, in recently accepted publication in Nature, Gordon et al.'s group was able to demonstrate that medications which affect Sigma1/Sigma2 receptors including haloperidol may have antiviral activity against SARS-Cov-2 (43) . Future studies clarifying the role of haloperidol will be extremely important. Olanzapine is often used for sedation and management of agitation in delirious patients (44) . Like quetiapine, it has actions on a number of different receptors though it is more anticholinergic. In contrast to quetiapine, it is relatively quick-acting, and the availability of a dissolvable form allows for use in patients who cannot swallow pills. Intramuscular olanzapine can be administered in severely agitated patients but should not be combined with benzodiazepines (45) . Some physicians have administered intramuscular olanzapine intravenously but this is not a common or recommended strategy given lack of safety data (46) . Quetiapine is commonly used to manage symptoms related to delirium in the hospital setting (47, 48) . It is a relatively low potency agent and has a wide dose range. At low doses, it primarily acts as an anti-histamine; at doses at or above 100 mg it exerts alpha-1 blockade; from 150-300 mg it additionally binds to 5HT 2A and numerous other serotonergic targets; and at doses 400 mg and above, it antagonizes D 2 receptors. Quetiapine is only available in oral form and can take an hour from administration to exert effect. Hypotension is an additional risk, particularly in older patients. Risperidone is considered to be the most haloperidol-like of the atypical antipsychotics given its tight binding and antagonism at the D 2 receptor, which makes it less compelling in COVID-19 patients (49) . However, flexibility in routes of administration, including dissolvable tablets, may make it useful in certain circumstances. In psychosis and acute agitation settings, ziprasidone can be very useful. However, we recommend against using it routinely for COVID-19 delirium given its more significant effects on the QT interval (50) . Trazodone is often used for management of sleep and behavioral dysregulation in the hospital setting. It can be particularly effective for daytime impulsivity and restlessness in older patients who may not tolerate antipsychotic agents, a profile consistent with many patients experiencing COVID-19 delirium (51) . Trazodone is thought to exert its action through effects on 5HT 2A and has relatively few side effects. It has a wide dose range but is only available in pill form. Valproic acid (VPA) has demonstrated utility in managing impulsivity and dysexecutive syndromes in patients with traumatic brain injury, and this approach has been extended to the treatment of behavioral dysregulation in delirious patients (52) . In a retrospective study of critically ill patients, VPA was associated with a reduction in agitation, delirium, and concomitant neuroleptic use (53) . Similar to SARS and MERS literature, early COVID-19 literature has demonstrated a variety of neurological findings, including increased risk of strokes and some reports of seizures and abnormal electroencephalogram findings, suggesting that VPA could be especially useful in these patients. VPA is thought to exert its actions through effects on dopamine, glutamate, norepinephrine and serotonin and may decrease CNS oxidative stress and neurotoxicity (54) . In addition to being available in intravenous form, VPA has a wide dose range. In COVID-19 patients, monitoring for pancreatitis and liver dysfunction may be particularly important. If mental status worsens and hyperammonemia develops, valproic acid should be discontinued. Dopamine agonists, including amantadine and methylphenidate, should be considered in patients with akinetic mutism or catatonia. All dopamine agonists have the potential to worsen delirium and perceptual disturbances, however. Amantadine is FDA approved for the treatment of influenza A, drug-induced EPS, and Parkinson's disease, and has also been used in patients with low dopamine conditions like Parkinson's Disease and Dementia with Lewy Bodies (55) . It is sometimes used off-label to stimulate activity in patients with hypoactive delirium. Amantadine has a dual mechanism of action, serving as an NMDA-receptor antagonist and a dopamine-receptor agonist. It has a wide dose range and is usually well-tolerated, though it can lower the seizure threshold and is contraindicated in end stage renal disease (55) . Rapid tapering can lead to a withdrawal delirium (56) . Though an intravenous form is available internationally, only the pill form is available in the US. Amantadine may be especially useful for treating catatonia in a patient with COVID-19 pneumonia, as benzodiazepines would be relatively contraindicated due to respiratory suppression, and electroconvulsive therapy can aerosolize virus particles (57) . Methylphenidate has been used anecdotally for behavioral activation in patients with hypoactive delirium or apathy states. It blocks the reuptake of dopamine without increasing dopamine release and has the distinct advantage of being available in a long-acting patch form. It can cause a mild increase in heart rate and blood pressure. Notably, methylphenidate was used during the early AIDS epidemic, when patients were exhibiting symptoms similar to those described in some COVID-19 delirium cases, including depression, abulia, and alogia (58) . Methylphenidate has also been used in catatonia, though commonly with worsening of underlying psychosis (59) . Classically, benzodiazepines are felt to be "bad" for delirium, outside of GABAwithdrawal states. While a recent meta-analysis suggests that haloperidol in combination with lorazepam may be the best management strategy for acute agitation in delirium, it is also wellknown that benzodiazepines can worsen delirium and cause paradoxical behavioral dysregulation (60) . Nonetheless, for COVID-19 patients with severe agitation, the use of lorazepam in combination with antipsychotic agents may allow for greater sedation and lower the risk of EPS. This is especially true for patients who have been on prolonged high dose benzodiazepine drips in the ICU setting and may experience withdrawal if tapered too quickly. Recommendations for the management of delirium in the United Kingdom have also commented on the potential utility of benzodiazepines in COVID-19 delirium (61) . Lorazepam has the advantage of being quickacting and available in a variety of forms. Lorazepam may still be useful for catatonia assessment in patients with abulia and alogia, but extreme caution is necessary given the risk of respiratory suppression in patients with pneumonia or ARDS. Vitamin or other micronutrient administration is not presently a standard of care for delirium management, except for situations when a particular deficiency is thought to explain the cause of the delirium (e.g., thiamine deficiency causing Wernicke encephalopathy). However, given the pro-oxidant, pro-inflammatory state that accompanies COVID-19 delirium, and given the limited knowledge surrounding effective treatments, we advocate that a lower threshold be maintained for the use of safe and relatively inexpensive nutritional interventions with known antioxidant and anti-inflammatory benefits. A recent meta-regression analysis demonstrated strong evidence that vitamin C shortens the duration of mechanical ventilation in critically ill patients, particularly severely ill patients who required mechanical ventilation for more than ten hours, and it is currently being studied as a COVID-19 intervention (62, 63) . Low levels of Vitamin D have been correlated with risk of delirium (64, 65) , and omega-3 fatty acids significantly reduced patient-days with delirium and mechanical ventilation (66) . Indeed, vitamin C, vitamin D, and omega-3 fatty acids have all been shown to inhibit the NLRP3 inflammasome and may work synergistically against the cytokine storm associated with COVID-19 and specifically against the neuro-inflammation associated with its delirium (67) (68) (69) . Patients with COVID-19 are at increased risk of QT prolongation and torsades de pointes (TdP) by virtue of their age, illness burden including direct effects of COVID-19 on the heart, electrolyte disturbances, and other medications, including hydroxychloroquine and azithromycin (6, 70) . It is challenging to risk-stratify antipsychotic agents, but current evidence suggests that chlorpromazine and ziprasidone may carry a greater risk of QT prolongation, whereas aripiprazole appears to carry a lower risk (50) . All other antipsychotics, including IV haloperidol, probably cannot be separated out in terms of overall risk. It should also be noted that although dexmedetomidine and clonidine do not prolong the QT interval, they can increase the risk for TdP by virtue of bradycardia (71) . Anecdotal reports of catatonia-like syndromes, which are also considered to be low dopamine states, have been reported in COVID-19 delirium (15) . It remains unclear whether these patients are suffering from catatonia, which may be related to underlying psychiatric illness, delirium, or the infection itself, or a related phenomenon, such as akinetic mutism, which may have features overlapping with catatonia. For patients exhibiting alogia, abulia, immobility and withdrawal, consultation-liaison psychiatrists should consider using dopamine agonists and avoiding antipsychotics. Amantadine has been recommended as a third line agent in catatonia and is also the treatment of choice for akinetic mutism (59, 72) . Benzodiazepines may also be useful in this setting, despite the potential to worsen delirium. Remdesivir, an antiviral that was originally designed for the treatment of Ebola virus, was granted emergency authorization by the FDA for the treatment of COVID-19 on May 1, 2020. Many patients admitted with COVID-19 will likely receive this medication. Remdesivir is metabolized by CYP450 2C8, 2D6, and 3A4, and could potentially interact with psychiatric medications; blood levels of remdesivir may decrease when administered with CYP450 inducers such as phenobarbital and carbamazepine (73). Consultation-psychiatrists are strongly encouraged to perform an interaction check when selecting pharmacologic agents for delirium in patients receiving remdesivir. Of note, we performed a Lexicomp interaction check for all medications reviewed in this article with remdesivir and found no significant interactions. To date, there are no guidelines for the management of delirium in patients with COVID-19, and the evidence-base is exceedingly thin. In our narrative review of the literature and clinical experience, we have provided a possible framework and algorithm for pharmacologic selection in COVID-19 delirium. Our recommendations take into account anecdotal observations that some patients with COVID-19 delirium appear to have increased rates of myoclonus, rigidity, alogia, and abulia, suggesting a dopamine depletion state or catatonia-spectrum condition. When there are no absolute contraindications to any particular class of medication, we preferentially use alpha-2 agonists and low potency antipsychotics to manage behavioral disturbance. We nonetheless recommend a thoughtful, individualized, step-based approach to management. It is probable that there is heterogeneity in COVID-19 delirium. Whereas some patients may become delirious due to the likely pro-inflammatory burden of ARDS, it may be that others experience direct invasion of the virus into the CNS, though this is yet to be determined. Future directions include amassing a more extensive collection of COVID-19 delirium cases. Objective measures such as MRI, EEG and cerebrospinal fluid studies would be particularly useful in understanding the neurobiology of the condition but are currently limited by the necessity of minimizing staff exposure to COVID-19. We expect that as more cases are identified and treated, our understanding of the pathophysiology will improve, and recommendations for managing delirium may evolve. Appendices/Supplement: Supplemental_Material.docx Table 1 . Pharmacologic Agents with potential utility in treating delirium in COVID-19. We review and summarize medications commonly used in the treatment of delirium. Attention is given to the advantages and disadvantages of medications specific to their use in patients with COVID-19. Step 2 Consider using dexmedetomidine for ICU patients. Wean by no more than 20% per day. Can cross taper with clonidine patch, starting 0.1mg patch the night before wean attempt. Oral clonidine 0.1-0.3mg three times per day can also be used for agitation. Step 1 Start melatonin at 1-3mg daily at 1800 hours. Dose regularly at the same time. Exercise caution in patients for whom there is evidence of inadequate immune response. Step 3 Consider antipsychotic agent for ongoing agitation. Low-potency agents preferred. May consider aripiprazole specifically for hypoactive delirium with perceptual disturbance. Use caution with antipsychotics if evidence of EPS, akinetic mutism or catatonia. If additional agents required, or if antipsychotic agents are relatively contraindicated, consider using valproic acid 15mg/kg per day in 3 divided doses PO or IV daily or trazodone 12.5-50mg every 6 hours as needed. Titrate to effect. Step 5 If evidence of akinetic mutism or catatonia, consider adding amantadine 100mg daily (titrated over 3-4 days to 600mg daily) or methylphenidate 5-10mg twice daily. Monitor for seizures with amantadine and worsening psychosis. The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: what lessons have we learned? Presumed Asymptomatic Carrier Transmission of COVID-19 Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease Clinical Characteristics of Coronavirus Disease 2019 in China Nervous system involvement after infection with COVID-19 and other coronaviruses Comorbidities and multi-organ injuries in the treatment of COVID-19 Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease Human coronaviruses: viral and cellular factors involved in neuroinvasiveness and neuropathogenesis Neurological manifestations in severe acute respiratory syndrome Multiple organ infection and the pathogenesis of SARS Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV) Neurological Complications during Treatment of Middle East Respiratory Syndrome Neurologic Features in Severe SARS-CoV-2 Infection Delirium in COVID-19: A Case Series and Exploration of Potential Mechanisms for Central Nervous System Involvement. (Under review at General Hospital Psychiatry) A first Case of Meningitis/Encephalitis associated with SARS-Coronavirus-2 Guillain Barre syndrome associated with COVID-19 infection: A case report Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain, Behavior, and Immunity Collaborative Delirium Prevention in the Age of COVID-19 Effect of Administration of Ramelteon, a Melatonin Receptor Agonist, on the Duration of Stay in the ICU: A Single-Center Randomized Placebo-Controlled Trial* Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial COVID-19: Melatonin as a potential adjuvant treatment Effect of Melatonin on Glutamate: BDNF Signaling in the Cerebral Cortex of Polychlorinated Biphenyls (PCBs)-Exposed Adult Male Rats Excitotoxicity, oxidative stress, and the neuroprotective potential of melatonin Melatonin regulates neuroinflammation ischemic stroke damage through interactions with microglia in reperfusion phase Use of Dexmedetomidine in Light to Moderate Sedation in the Patient in the Palliative Situation of a Sars-cov-2 / COVID-19 Infection -Full Text View -ClinicalTrials.gov Dexmedetomidine in the prevention of postoperative delirium in elderly patients following non-cardiac surgery: A systematic review and meta-analysis Low-Dose Nocturnal Dexmedetomidine Prevents ICU Delirium. A Randomized, Placebo-controlled Trial Neurocognitive Dysfunction Risk Alleviation With the Use of Dexmedetomidine in Perioperative Conditions or as ICU Sedation Intrathecal and oral clonidine as prophylaxis for postoperative alcohol withdrawal syndrome: a randomized double-blinded study Impact of clonidine administration on delirium and related respiratory weaning after surgical correction of acute type-A aortic dissection: results of a pilot study Alpha₂-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev Evidence that locus coeruleus is the site where clonidine and drugs acting at alpha 1-and alpha 2-adrenoceptors affect sleep and arousal mechanisms Pharmacology of guanfacine ATYPICAL ANTIPSYCHOTIC USE IN PATIENTS WITH DEMENTIA: MANAGING SAFETY CONCERNS Association Between Antipsychotic Agents and Risk of Acute Respiratory Failure in Patients With Chronic Obstructive Pulmonary Disease An open trial of aripiprazole for the treatment of delirium in hospitalized cancer patients Aripiprazole in the treatment of delirium Effects of Haloperidol on Delirium in Adult Patients: A Systematic Review and Meta-Analysis Decreased extrapyramidal symptoms with intravenous haloperidol A SARS-CoV-2 protein interaction map reveals targets for drug repurposing Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Medicine Olanzapine Pharmacokinetics -Psychopharmacology Institute Intravenous Olanzapine for the Management of Agitation: Review of the Literature Quetiapine for delirium prophylaxis in high-risk critically ill patients. Surgeon Treasure Island (FL): StatPearls Publishing Effect of risperidone on high-affinity state of dopamine D2 receptors: a PET study with agonist ligand [11C](R)-2-CH3O-N-n-propylnorapomorphine QTc prolongation, torsades de pointes, and psychotropic medications Sequential drug treatment algorithm for agitation and aggression in Alzheimer's and mixed dementia Valproic Acid for Treatment of Hyperactive or Mixed Delirium: Rationale and Literature Review Valproate for agitation in critically ill patients: A retrospective study Valproic Treasure Island (FL): StatPearls Publishing The Role of Amantadine Withdrawal in 3 Cases of Treatment-Refractory Altered Mental Status Excellent response to amantadine in a patient with bipolar disorder and catatonia Effects of methylphenidate in HIV-related depression: a comparative trial with desipramine Alternative treatment strategies for catatonia: A systematic review Association of Delirium Response and Safety of Pharmacological Interventions for the Management and Prevention of Delirium: A Network Meta-analysis NICE) in collaboration with NE and N. Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis A new clinical trial to test high-dose vitamin C in patients with COVID-19. Crit Care Vitamin D levels and risk of delirium: A mendelian randomization study in the UK Biobank Association between pre-hospital vitamin D status and hospital-acquired new-onset delirium Role of omega-3 fatty acids in the prevention of delirium in mechanically ventilated patients Quercetin and Ascorbic Acid Suppress Fructose-Induced NLRP3 Inflammasome Activation by Blocking Intracellular Shuttling of TXNIP in Human Macrophage Cell Lines Vitamin D3 Protects against Diabetic Retinopathy by Inhibiting High-Glucose-Induced Activation of the ROS/TXNIP/NLRP3 Inflammasome Pathway Dietary PUFAs attenuate NLRP3 inflammasome activation via enhancing macrophage autophagy Ventricular Arrhythmia Risk Due to Hydroxychloroquine-Azithromycin Treatment For COVID-19 Available from: http%3a%2f%2fwww.acc.org%2flatest-in-cardiology%2farticles%2f2020%2f03%2f27%2f14%2f00%2fventricular-arrhythmia-riskdue-to-hydroxychloroquine-azithromycin-treatment-for Poly Pharmacy-Induced Long-QT Syndrome and Torsades de Pointes: A Case Report Telephone Effect in Akinetic Mutism From Traumatic Brain Injury Advantages Disadvantages Abbreviations: NE -norepinephrine; H -histamine; αalpha; 5HT -5-hyrdoxytryptamine; D -dopamine; NMDA -N-methyl-D-aspartate; GABA -gamma aminobutyric acid; PO -per oral; IV -intravenous; IM -intramuscular; IR -immediate release; ER -extended release; EPSextrapyramidal symptoms; TBI -traumatic brain injury; ECT -electroconvulsive therapy; ICU -intensive care unit.