Menachem Moshe Liss, DO

The link between viral infections and effects on the central nervous system has been studied with viruses such as influenza, H1N1, and previous coronaviruses, including SARS and MERS. It has been documented that like 

, these viruses have been able to produce symptoms of psychosis in patients with no prior psychiatric conditions.

 Recently published studies have shown that COVID-19 can cause severe neuropsychological stress-inducing psychosis in affected patients.

 The literature covering correlations between COVID-19 and psychosis has demonstrated that there has been an increase in the rate of psychotic symptoms such as paranoia, delusions of persecution, and auditory and visual hallucinations in populations with high incidence rates of COVID-19 infection.

Researchers have also identified COVID-19’s ability to invade the central nervous system, thereby producing a significant inflammatory response from the body that results in a wide array of neurological symptoms, including anosmia and ageusia.

COVID-19 is a highly transmissible viral disease, part of the large family of coronaviruses that infect many types of animals such as camels, cattle, cats, and bats.

Coronaviruses are generally considered nonlethal and result in 15% of common colds. Animal coronaviruses can infect people and spread, as we have seen with MERS-CoV, SARS-CoV, and most recently with SARS-CoV-2, which originated from bats. The human coronaviruses were first identified in the 1960s. There are now 7 known coronaviruses that can infect humans, and they are divided into 4 main subgroups: alpha, beta, gamma, and delta. SARS-CoV-2 is part of the beta group and has been found to have a higher transmission rate than its predecessor, SARS-CoV. Current worldwide case count is reported in the hundreds of millions with more than 6 million deaths. Reported cases in the US continue to grow, with more than 80 million cases and a mortality count well over 980,000 as this went to print.

COVID-19, or the disease caused by SARS-CoV-2, is named for the crownlike spikes on the viral surface.

 Researchers have identified that the envelope spike (S) glycoprotein binds to human cellular receptors ACE-2 and DDP4, allowing membrane fusions to occur and viral replication to proceed. Patients infected with COVID-19 can develop atypical pneumonia, acute lung injury, and acute respiratory distress syndrome. The virus leads to dysfunction of type I and type II pneumocytes, which causes reduction in gas exchange and eventual collapse of the lungs. The pathology specimens of lung tissue displayed desquamation of pneumocytes, hyaline membrane formation, and interstitial lymphocyte inflammation in patients who died from the infection.

Early in the pandemic, patients infected with the COVID-19 virus were managed with supportive care, antiretroviral agents, immunosuppressants, steroids, plasma of recovered patients, and psychological support.

 However, treatment has improved significantly and the emergence of vaccines has proven vital in limiting deaths and serious infections from COVID-19.

Several studies have reported an increased rate of 

 in populations with high incidence rates of COVID-19 infection.

 There is also evidence that the neuropsychological stress associated with the diagnosis as well as the therapeutic use of corticosteroids during care can induce psychosis,

 which has been suggested to present during an acute or postinfectious state. In addition, there have been reports of patients developing psychotic symptoms such as paranoia, delusions of persecution, and auditory and visual hallucinations, even in the absence of systemic symptoms of SARS-CoV-2 infection.

Researchers have identified COVID-19’s ability to invade the brain through various mechanisms, including the olfactory neural pathway

 and brain capillary endothelial cells through the transmembrane ACE-2 receptors, thus producing a significant inflammatory response, neurotransmitter depletion, and neuronal dysfunction and loss.

 The significant neuroinflammatory response, coupled with systemic inflammation and hypoxic injury, may induce new onset or exacerbation of psychiatric diseases.

Anti-NMDA receptor encephalitis with mood and behavioral changes has also been reported in individuals infected with SARS-CoV-2.

 The link between viral infections and their effects on the central nervous system has been studied with viruses such as influenza, H1N1, and previous coronaviruses such as SARS and MERS.

 It has been documented that these viruses produced psychotic symptoms even in patients with no prior psychiatric conditions.

 The increasing case count presents the challenge and likelihood of increasing neuropsychiatric manifestations in affected individuals. Here we present a case of a patient with no prior psychiatric history who developed psychosis after COVID-19 infection.

“Mr Moreno” is an 82-year-old Hispanic male with no prior psychiatric history, brought in by emergency medical services for bizarre behavior, such as wandering barefoot between cars. He was admitted to the emergency department of the hospital for altered mental status and a psychiatric consult was requested.

Upon psychiatric evaluation, Mr Moreno was grossly psychotic with somatic delusions of electrical currents spreading from his mattress to his body. He endorsed typing messages with his fingers on his palms, which were heard by his absent brother-in-law. Furthermore, he reported hearing the voice of his brother-in-law threatening to inject blood into his rectum. Mini cognitive examination was normal.

Collateral information from the patient’s daughter confirmed no prior psychiatric history, a sudden loss of appetite, auditory hallucinations, and behavioral changes, which prompted his physician to refer him for COVID-19 testing. Mr Moreno’s condition deteriorated, which led to a brief psychiatric hospitalization. After a positive COVID-19 test, he was transferred to a medical hospital floor for 2 weeks of quarantine. He never experienced fever, cough, or dyspnea, and he did not require steroid treatments. Prior to COVID-19 infection, the patient was cognitively intact at baseline but preoccupied with visiting his deceased wife’s grave in Peru.

Despite being medically stable, Mr Moreno exhibited gross symptoms of psychosis that could not be managed in the community and led to another hospitalization at our medical center. Considering the collateral information, our consultation team recommended a medical workup to rule out organic psychosis. He was treated with oral risperidone 3 mg daily and oral sertraline 100 mg daily. A lumbar puncture, heavy metal panel, urine porphyrins, chest x-ray, urinalysis, and brain MRI were all within normal limits.

Full cerebrospinal fluid (CSF) panel including NMDA receptor antibody (Ab), varicella-zoster virus, Lyme polymerase chain reaction (PCR), herpes simplex virus PCR, HIV Ab, West Nile virus Ab, cryptococcal antigen, venereal disease research laboratory, and COVID-19 PCR were all negative. All other labs were completely normal except for a nonspecific elevated erythrocyte sedimentation rate. Because Mr Moreno remained floridly psychotic, he was transferred to the inpatient psychiatry unit, where he was further stabilized and discharged home with outpatient psychiatric aftercare.

This case we present here describes a male patient who did not exhibit any of the commonly associated clinical manifestations of COVID-19, but rather, he presented with an array of new-onset psychotic symptoms. Thus, we believe that COVID-19 infection may present without the typical clinical manifestations of fever, cough, sore throat, anosmia, and gastrointestinal disturbances. Instead, patients may solely exhibit symptoms and behavioral changes that include depression, delirium, or, as in this case, psychosis.

Mr Moreno had an extensive workup while he was admitted in the hospital, including brain MRI, heavy metal screening, and a thorough battery of antibody/PCR tests from his cerebrospinal fluids. This extensive testing allowed us to determine that COVID-19–induced psychosis was the most plausible clinical diagnosis. As research on COVID-19 continues to grow, and as additional cases of new-onset psychosis in the setting of COVID-19 infection amount in the contemporary literature, we will be able to share our clinical expertise with other clinicians in psychiatry and other fields. This collaborative awareness of a new entity of neuropsychiatric illness resulting from COVID-19 could ideally lead to better diagnostic modalities such as advanced brain imaging techniques, SARS-CoV2 CSF PCR tests, and potential future peer-reviewed, evidence-based treatment recommendations for this emerging psychopathology. In this case, treatment with oral risperidone 3 mg daily and oral sertraline 100 mg daily alleviated some of our patient’s overt persecutory and referential delusions. However, he remained with flat affect, social withdrawal, and psychotic levels of excessive guilt with a decreased function from baseline.

Another important aspect of this case was the lack of evidence of severe systemic illness or respiratory illness and no reported use of steroids or other medications, which could have been confounding factors regarding Mr Moreno’s ability to precipitate psychotic symptoms. Scientifically, we are at the frontier of trying to decipher the mechanistic underpinnings of the neuropsychiatric sequelae of COVID-19 infections. At least 1 study has demonstrated detection of SARS-COV-2 RNA in a COVID-19 patient’s CSF presenting with acute neurologic symptoms.

Interestingly, in a study of 2 patients who had severe clinical meninge-encephalitic changes as a result of COVID-19, there was no viral detection in the patient’s CSF.

 Explanations for this range from the lack of adequate testing techniques for SARS-CoV-2’s presence in the CSF to the possibility that peripheral nervous system invasion may lead to cytokine dysregulation within the CSF itself. This can lead to neuropsychiatric sequelae including psychosis without direct presence of the virus within the CNS. ACE-2, the key receptor that SARS-CoV viruses latch onto to invade neurons, is expressed on neurons and glia.

 Previous studies showed that in ACE-2 transgenic mice that were intranasally inoculated with SARS-CoV-1, this infection led to neuronal death and elevated proinflammatory cytokine response, including secretion of IL-1, IL-6, and TNF alpha.

 Such proinflammatory responses—which may be triggered by SARS-COV-2 neuro-invasion via ACE-2 receptor—can lead to transmigration of peripheral neurons, astrocytes, and peripheral nervous system immune cells into the CNS in hosts with compromised blood brain barrier, thereby manifesting as a wide array of neuropsychiatric sequelae ranging from depression, delirium, and perplexing neurologic manifestations to full-blown psychosis.

Mr Moreno’s case highlights the propensity of COVID-19 for producing psychosis in a previously stable older patient with no prior psychiatric history. As we know, psychosis is an emergent condition that must be treated appropriately for the safety of the patient and others. It is important to note that the pandemic has been associated with isolation or self-quarantining, and individuals may be particularly vulnerable to neuropsychiatric complications from being confined to a limited space and having less face-to-face contact.

This pandemic represents an unprecedented time that requires a psychiatrist’s vigilance in identifying patients at risk for COVID-19–induced psychosis. As such, education is needed regarding the atypical presentations of a masked infection for the best possible patient care. Early identification and appropriate treatment will reduce the longevity of psychotic episodes and prevent any long-term neuropsychiatric sequelae from the disease. By sharing clinical experiences and promoting ongoing research on SARS-CoV-2 and its neuroinvasive mechanisms, we will gain better knowledge about effective therapeutic modalities to treat the emerging neuropsychiatric complications of COVID-19 and better support our patients.

is the clinical assistant director of the consultation-liaison psychiatry service at Nassau University Medical Center. 

 is affiliated with Nassau University Medical Center.

 is affiliated with East Carolina University. 

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"This pandemic represents an unprecedented time that requires a psychiatrist’s vigilance in identifying patients at risk for COVID-19–induced psychosis."

Menachem Moshe Liss, DO

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