Hyperactive delirium in patients with COVID-19 is highly prevalent, and manifests with severe agitation that can be difficult to treat, leading to dangerous behaviors such as removing oxygen or assaulting staff.

Most C-L psychiatrists consider antipsychotics such as haloperidol the gold standard for managing agitation in delirious patients. But in this patient population there may be greater than usual risk.

C-L psychiatrists should familiarize themselves with how the virus and its proposed treatments can affect psychotropic management—so they are ready to help the medical team reason through the risks balanced against effective agitation management, say colleagues from Icahn School of Medicine at Mount Sinai, New York—an epicenter for the COVID-19 outbreak.

They have therefore set out in detail the major safety considerations for prescribing psychotropics to patients with the virus. Their paper, Psychopharmacology of COVID-19, published in a September/October COVID-19 special edition of Psychosomatics, has two 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 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 and its treatments can impact many organ systems and contribute to a host of drug interactions and neuropsychiatric effects,” say the authors. “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.”

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.

“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,” say the authors.

While there are no absolute contraindications to the use of psychotropics in patients with COVID-19, they say, psychiatrists must be mindful of potential adverse effects and conduct a thoughtful risk-benefit analysis as part of their clinical decision-making. For example, chloroquine, hydroxychloroquine, and azithromycin have the potential for QT prolongation, which can be problematic in patients with tenuous cardiac status.

When reasoning alternative treatment, 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,” say the authors.

Early delirium screening and nonpharmacological strategies to prevent or treat delirium, such as frequent orientation and early mobilization, should be used if practically feasible.

Some COVID-19 patients present not with delirium but with significant anxiety from 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,” say the authors.

“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,” say the authors. “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.”

For their paper, the authors undertook structured literature searches 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 only US Food and Drug Administration-approved treatment to date to treat severe COVID-19 is Remdesivir. Many other medications are either being studied in clinical trials or being used off-label and/or for compassionate use.

Psychopharmacology of COVID-19 by Melanie Bilbul, MD, CM, FRCP(C); Patricia Paparone, MD; Anna Kim, MD; Shruti Mutalik, MD, and Carrie Ernst, MD, is here.