Psychiatric Manifestations of COVID-19

Introduction

Neuropsychiatric sequelae of viral infections have been described in the literature and are well known from studies of influenza pandemics ^, , human immunodeficiency virus (HIV) infections, and viral encephalitis. Perhaps the most researched neuropsychiatric disorder after a viral infection was the development of encephalitis lethargica after the Spanish flu outbreak in the last century. Encephalitis lethargica had prominent parkinsonian symptoms, psychosis, and catatonia.

Prominent neuropsychiatric syndromes were described in two more current coronavirus pandemics: severe acute respiratory syndrome (SARS) in 2002 and Middle Eastern respiratory syndrome (MERS) in 2012. In the acute stage of SARS or MERS infections, confusion (suggesting delirium) occurred in 27.9% of patients, and depression, anxiety, and insomnia were relatively common. In follow-up studies of patients who had contracted SARS or MERS that ranged from 6 weeks to 39 months after recovery from the acute infection, more than 15% of patients reported sleep disorders, recurrent traumatic memories, emotional lability, impaired concentration, fatigue, or impaired memory. Survivors of critical illnesses had the most risk for psychiatric comorbidities at 1 year, with about one-third experiencing significant anxiety, depression, or posttraumatic symptoms.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in Wuhan, China in late 2019, and it soon became clear that the virus can spread beyond the respiratory tract to other vital organs, including the central nervous system (CNS). Clinical evidence of CNS involvement was substantiated by the detection of coronaviruses in the cerebrospinal fluid of patients with neuropsychiatric sequelae ; early cases of dizziness, headache, delirium, cerebrovascular disease, encephalopathy, neuromuscular disorders, anosmia, and ageusia ^, ; and psychiatric disorders, including suicides among older adults.

In terms of psychiatric disorders, the infection presents two potential risks. The risk for psychiatric sequelae is clearly increased by the psychosocial and economic stress associated with the COVID-19 pandemic. In addition, the viral infection of the CNS, the hyperinflammatory state, and medications used to treat the infection (e.g., exogenous corticosteroids) increased the risk for the development of acute psychiatric disorders.

The COVID-19 pandemic is associated with an increase in psychiatric symptoms, most notably anxiety, depression, and posttraumatic stress disorder (PTSD), and these symptoms are disabling. ^{, ,} Some patients who recovered from the acute phase of COVID-19 had continued neuropsychiatric symptoms. These patients were described in the literature as “long haulers,” who over time develop a variety of neuropsychological symptoms, including poor concentration (or “brain fog”), fatigue, and multiple psychiatric symptoms such as depression, anxiety, PTSD, obsessive-compulsive symptoms, psychosis, and an increased risk for suicide ( Fig. 12.1 ). These patients also have symptoms that can masquerade as psychiatric symptoms (e.g., chronic fatigue, insomnia, concentration difficulties) and lead to significant disability. ^, This chapter will present the available data on both the acute and long-term incidence of psychiatric diagnoses related to SARS-CoV-2 infections.

Delirium

Coronaviruses target the angiotensin-converting enzyme-2 receptor (ACE2), which is found on glial cells in the brain. SARS-CoV-2 has been shown to enter the CNS though the olfactory epithelium or cribriform bone, by a breakdown of the blood–brain barrier during a viremic phase of the illness, or by peripheral nerve terminals. Once the virus enters neuronal cells, viral RNA replicates and is released into the cerebrovascular circulation.

Delirium is an acute sign of brain dysfunction and has been reported in up to 50% of mechanically ventilated patients. In some patients, particularly the elderly, delirium may be the initial or only presenting symptom of acute COVID-19. ^, Awareness of delirium as a common symptom of COVID-19 is even more essential in these patients for early diagnosis, treatment, and prevention of further spread of the virus.

In a retrospective study in Italy, over a quarter of patients hospitalized for neurological conditions associated with COVID-19 experienced delirium. This rate was over three times the incidence of delirium in patients hospitalized for other neurological conditions who had not contracted COVID-19 during the same time. A group in the United Kingdom (UK) reported that over 30% of patients hospitalized with COVID-19 experienced altered mental status and more than half (59%) met criteria for a psychiatric diagnosis, including psychosis and affective symptoms. About half of the patients with altered mental status were under 60 years old.

Delirium is associated with higher mortality and long-term cognitive and functional decline. COVID-19 patients are at particularly high risk for delirium given that they are often prescribed higher doses of sedating medication (e.g., benzodiazepines and propofol) than other mechanically ventilated patients and have a higher risk for delirium because of multiple medical complications (e.g., neuroinflammation, cerebrovascular accidents from hypercoagulability, multisystem organ failure, and social isolation). Agitated delirium tends to be the more prominent type of delirium in patients with COVID-19 and has been reported in nearly 70% of patients hospitalized with severe COVID-19 symptoms. This type of delirium is more overt and easily identifiable than hypoactive delirium, and therefore it is likely that patients with hypoactive delirium are underreported.

COVID-19 patients are also at a higher risk for hypoxic brain injury from an immune-mediated reaction described as a cytokine storm. A cytokine storm is the result of the inflammatory response to the infection and can result in vascular leakage and end organ damage. Delirium also can be the primary manifesting syndrome in COVID-19 patients even before the respiratory symptoms are apparent.

Importantly, delirium during hospitalization in COVID-19 patients is linked to an increased risk for death during hospitalization and an increased need for support on discharge from the hospital. Physical functioning after discharge was notably impaired in patients who were diagnosed with delirium during their hospitalization. A COVID-19 post–intensive care syndrome has been identified that includes cognitive impairment, depression, anxiety, and physical signs such as weakness.

In a multicenter cohort study conducted in 69 adult intensive care units (ICUs) with 2000 patients across 14 countries (half the patients were in Spain) admitted with COVID-19, investigators identified variables associated with delirium and coma. In this study, 55% of patients were delirious for an average duration of 3 days. Significant factors associated with delirium included older age, higher Simplified Acute Physiology Score (assessing the risk for death in ICU patients), male sex, smoking or alcohol abuse at baseline, use of vasopressors on day 1, and invasive mechanical ventilation on day 1 (all P < .01). In this study, the investigators identified two modifiable risk factors associated with a decreased incidence of delirium: lower benzodiazepine use and more frequent family visitations in the ICU (either in person or virtually). The investigators outlined interventions to lower the incidence of delirium, including decreasing sedatives, increasing mobility, breathing trials off ventilation, and encouraging families to visit. Other strategies could include circadian rhythm regulation using medications such as melatonin.

The US Food and Drug Administration has not approved any medications to treat delirium. The primary interventions recommended are behavioral, including family involvement. Off-label medication treatments used to manage COVID-19–related delirium include alpha-2 agonists, low-potency antipsychotics, valproic acid, and trazodone.