COVID-19 related Psychotic Disorder: Symptomatology in Infected and Uninfected Patients

Introduction: Psychotic disorder has rarely been reported in patients with COVID-19 infection and patients affected by the pandemic but who do not have COVID-19 infection. It is unclear if the disorder occurs due to the stress of the pandemic or due to a cerebral infection of the virus. Methods: on PubMed, we searched for all reports of patients who developed a new psychosis during the COVID-19 pandemic to review their symptomatology. Results: Psychotic symptoms were similar in onset, description, duration, and severity in patients who had been infected and those who were affected by the pandemic but did not have the infection. In both groups, most patients were young, without previous psychiatric history, had experienced severe external stress due to the pandemic, had an abrupt onset of symptoms, had intense hallucinations and delusions, and needed psychiatric hospitalization. The disorder commonly lasted about a week, after which antipsychotic medications could be stopped. Conclusion: External psychological stress and not cerebral COVID-19 infection is the likely cause of psychotic disorder in both infected and uninfected patients.


INTRODUCTION
Globally, in September 2021, about 218 million people have had the COVID- 19 infection, and about 4.5 million have died due to the infection [1]. Since early 2020 when the pandemic spread, its fear was pervasive and constant [2]. Loss of income, being confined to the house, decreased access to healthcare, social distancing, and masking all led to mass hysteria and hopelessness throughout the world [3]. Anxiety and depression rates increased in the nonpsychiatric population [4,5], and patients with mental illness also experienced exacerbation [6]. Moreover, healthcare providers were not only worried about catching the infection themselves but were also disturbed by the guilt that they could pass it on to their loved ones Abhishek Mohan MD et al. COVID-19 related Psychotic Disorder: Symptomatology in Infected and Uninfected Patients at home [7]. Infected patients and their families worried about death and dreaded and felt depressed at the prospect of separation if hospitalization would be needed [8]. The cough, dyspnea, hypoxia, confusion, and the sight of healthcare providers in the hospital in hazmat suits and masks added to the fear and confusion [9], and delirium was found to be common in COVID-19 patients who were admitted in the ICU [10]. Psychotic disorder related to  has been reported at a case report and case series level. Since case reports are sporadic, it is unclear how common the disorder is. Previous reviews were commonly on neurological manifestations [3,[11][12][13][14], a review on the mental health of COVID-19 patients did not specifically address psychosis [5], and some cases of psychosis were almost exclusively in patients who had been infected with other coronaviruses [15,16]. In one review of psychotic disorder in patients infected by a coronavirus, all 24 patients had either SARS-CoV or MERS [15]. In another study [16], only 1 of 14 patients with coronavirus infection had SARS CoV2, the virus which causes COVID-19. Since delirium can be a confounder in the diagnosis of psychotic disorder, some case series used strict criteria to exclude patients with delirium [17,18]. Still, delirium and psychosis were challenging to separate in one series [19], and another series included nine patients who had delirium and one who had psychosis in a single category of "encephalopathy" [20]. Whether most neuropsychiatric symptoms are due to an infection of the brain has been debated [3,21]. It has been speculated that infection of the medullary centers for respiration could be an additional reason for respiratory failure in patients with COVID-19 pneumonia [22]. However, the evidence suggests that anxiety, hypoxia, microemboli, and cytokine storm are the more likely explanations [17]. The psychotic disorder is reported in SARS-Cov2 infected patients and patients who have not been infected but have been socially affected by the pandemic. A comparison of psychotic symptoms in infected and uninfected patients can help determine if psychotic disorder in SARS-CoV2 infected patients could be due to the infection. Some case series [23] and review articles [24] have included infected and uninfected patients. Still, they have not compared these two groups, and it is unclear if their symptomatology is similar and if the severity, duration, and response to treatment are identical.
In this review, our aim was to include all published case reports of patients who had a diagnosis of new psychosis without concurrent delirium and in whom patients either had COVID-19 infection themselves or they had a very close relationship with infection in family members, workplace, in the community, or who were in other ways severely affected by the pandemic.

METHODS
Our primary objective was to find case reports and case series of patients who had SARS-Cov2 (i.e.,  infection, and secondarily to find case reports and case series of patients who had psychosis in the context of the COVID-19 pandemic but who did not have COVID-19 infection themselves. We searched the PubMed database with only two terms: [COVID] and [PSYCHOSIS]. In April 2021, this identified 220 publications. We scrutinized all these publications and excluded those with no or little relation to our primary or secondary objectives. We reviewed the remaining journals in their full length and reviewed their relevant references to exhaustively find all case reports of new psychosis related to COVID-19 infection. We categorized patients who had the COVID-19 disease and those who did not in separate groups. We summarized the narratives of patients to find similarities and differences in these two groups. We also focused on finding how long psychotic symptoms lasted and how they were treated.

RESULTS
We could find 13

13.
Corres-palacio et al., [37] reported a 43 year old male who, about a week after an 8-day admission for COVID-19 pneumonia after which steroids were continued for 4 days, had to be brought back to the hospital due to verbal and physical aggression and who resisted arrest with two swords he had in his house. He had persecutory delusions with medical staff and police, visual and auditory hallucinations, did not sleep for days, and had a megalomaniac belief of "communicating directly with God". His psychiatric hospitalization lasted 1 month, and he was discharged on valproic acid 500 mg every 8 hours, paliperidone 15 mg a day, olanzapine 5 mg a day, and Lorazepam 1 mg prn. His diagnosis was substance/medicationinduced manic episodes with psychotic features. Case series of new psychosis without concurrent delirium in COVID-19 patients 1. Parra A et al., [17], after excluding 6 patients with delirium, reported 10 patients who had a psychotic disorder. The mean age was 54 years, patients developed psychotic symptoms after about 2 weeks of COVID-19 symptoms. All patients had delusions, 40% had auditory and 10% had visual hallucinations, 50% had been in the ICU for pneumonia, 70% had been taking corticosteroids, and 60 % also had confusional/attentional symptoms. All patients recovered in a maximum of 2 weeks, were treated with low antipsychotic doses, and their delusional symptoms had lasted longer than confusional symptoms.

2.
Vartharaj A et al., [38] reported that in a UK-wide surveillance study of hospitalized COVID-19 patients, 23 patients had new-onset psychosis, 5 had a dementia-like syndrome, and 4 had an affective disorder. New-onset psychoses were more frequently seen in younger patients.

3.
Iqbal Y et al., [18] reported on 9 COVID-19 patients who had no delirium but had new mania or psychosis.

4.
Fernando SL et al., [39] reported on 3 COVID-19 patients, of whom 2 had a prior psychiatric history. These were: a 30 year old male who had auditory hallucinations, saw people chasing him, and he consumed excessive amounts of Pedialyte; a 34 year old female, who had sensations of a "fire burning up inside"; and a 33 year old male who had auditory hallucinations and delusions of his ex-wife and believed that "people with knives and guns in a blue van outside" were trying to kill him.

5.
Noone R et al., [40] reported on 2 patients. Patient A, a 49-year old male, was oriented only to the year, heard voices, had grand delusions of being the devil, confabulated stories of violence at home, and had passive suicidal ideation. Patient B, a 34 year old female, would disrobe in front of strangers, felt she was watched, had persecutory ideas about her landlord, was carrying a knife, and was putting hand sanitizer in her food. 6. Subramanyam AA et al., [41] reported 3 women in India who had asymptomatic COVID-19 infection and developed new brief psychotic episodes after giving birth. 2 patients had delusions concerning the virus, one believed that medical professionals were trying to infect her baby, and another was acutely paranoid that staff believed that she was spreading COVID-19. 7. Paterson R et al., [20] reported 10 COVID-19 patients who had transient encephalopathies with features of delirium in 9 patients, and psychosis in one patient. This patient, a 55-yearold female, had ritualistic behavior, delusional thinking, and visual and auditory hallucinations, including seeing lions and monkeys in her house. Her psychotic state persisted past the acute confusional state and resolved after 3 weeks of haloperidol and risperidone treatment. 8. Rentero D et al., [19] reported new-onset psychosis in COVID-19 patients in Madrid but did not mention the number of patients or the kind of symptoms they had. 9. Jawororwski et al., [42] reported on 3 male patients who had COVID-19 infection. All had a brief psychotic disorder that resolved over 2 days with parenteral neuroleptic medication. All three had grandiose and religious delusions. One had been fined for transgressing social distancing restrictions, and had been using cannabis daily. Case reports or case series of new psychosis related to the COVID-19 pandemic in patients who themselves did not have COVID-19 infection 1. Oca Rivas VC et al., [43]reported a patient who was a healthcare professional who did not have COVID-19 infection but had reactive psychosis, including a conviction that his death due to COVID-19 was near. He dramatically searched online for information about COVID-19, and had a psychiatric hospitalization for depersonalization, thought blocking, and delusions. After one month of olanzapine intake, he was better but had not yet returned to work.

2.
Hurcaya-Victoria J et al., [44] reported a 38-year-old female in Peru who became anxious after visiting a dentist who had returned from France and did not wear a mask. She had no COVID-19 infection but was in a 15-day quarantine for malaise when she complied with increasing voices commanding her to be re-tested. "An evil demonic force possessed her  [23] reported on 3 cases. Case 1 was a 48-year-old male hospitalized for COVID-19 and whose mother died simultaneously due to COVID-19. He had grandiose ideas and wanted to instruct the Prime Minister on how to manage the pandemic. He had mania which lasted two weeks. He had been treated with olanzapine 15 mg a day and titrated clonazepam. Cases 2 and 3 were 14 year and 9-year-old girls, respectively, and both did not have COVID-19. The 14-year old was treated with risperidone and lorazepam for a oneweek episode of psychosis that developed after she could not keep up with online school lesions during the lockdown. The 9-year old developed fainting spells after her family's finances plummeted during the lockdown, and she needed a month of psychotherapy for conversion disorder. 9. Lazzari C et al. [50] reported on 6 cases who did not have COVID-19 but had paranoid delusions, and two patients had olfactory and visual hallucinations. One tried to kill his family to save them from the consequences of COVID-19. All patients had mania, violence, disinhibition, severe anxiety, and loss of financial wisdom. All responded well to varying regimens of antipsychotic, antidepressant, antianxiety, and mood-stabilizing medications. All recovered fully after a week of hospitalization.  [52] reported 4 cases. Case A was a 33-year old male whose job was under threat due to the pandemic; he thought his loved ones were controlled by machines and tried to commit suicide. Case B was a 43-year-old female with a history of bipolar disorder who had a psychotic relapse due to home confinement. Case C was a 43-year-old female who had a delusion that she was a COVID-19 carrier and her friend had died due to this. Case D was a 45-year-old male who obsessively followed the global death toll of the pandemic, which he thought was caused by the Illuminati; he could hear his neighbors commenting on his thoughts and attempted suicide and thought he would be tortured. All cases were treated with usual antipsychotic medications and recovered fully in 2 days to 3 weeks.

Our findings
Our review found that psychotic disorder related to COVID-19 is reported rarely, and infected versus uninfected patients have a similar frequency, severity, and duration of psychotic symptoms. Most patients in both groups had an abrupt onset of a first-time extreme psychiatric dysfunction. However, they usually recovered in about a week and barring exceptions all patients recovered almost fully in about a month. We did not do a systematic review because the number of infected or uninfected patients in case reports and case series is minimal. It is impossible to make a statistical comparison of infected and uninfected patients' qualitative experiences and circumstances. However, for these reasons, our inferences can also be only subjective. Also, there might be unpublished case reports or ones that we could not find. Although the severity of symptoms is such that all patients will present for emergent care, their case histories may not get reported due to the constraints of the pandemic. In our review, case reports of psychotic disorder were fewer in patients who did not have COVID-19 infection. This may have occurred because patients without COVID-19 disease may get reported less often. If more cases are reported, then more differences might be found in the narratives of infected and uninfected patients.

Psychotic disorder is reported rarely in COVID-19 related patients
We found case reports or case series of only 103 patients who had a new psychotic disorder in the context of COVID-19 whether or not they had COVID-19 infection. The diagnosis of the psychotic disorder may have been missed in unpublished reports since milder confusion is widespread in COVID-19 patients, and delirium is common in COVID-19 patients in the ICU. Even in the few case reports, we found some patients had delirium or had transitioned from delirium [20,30,33,34,36]. In one series, it was challenging to separate delirium from psychosis [19]. One of the DSM-5 criteria for delirium is a disturbance in cognition [e.g., memory deficit, disorientation, language, visuospatial ability, or perception]. This overlaps with psychotic disorders, which involve hallucinations, delusions, disorganized thinking, or grossly disorganized motor behavior [53]. Diagnostic criteria should be strictly applied since antipsychotics are not recommended for patients in delirium. [54]. If cases with delirium are excluded, then as compared to the 4.4 12-month prevalence rate of psychotic disorder per 1000 people in the population [55], and as compared to the millions of patients who have had COVID-19 infection, COVID-19 patients appear to develop psychotic disorder very rarely. This is consistent with a review that found that 0.9% to 4% of patients develop psychotic symptoms [3]. Mania, psychosis, and delirium were reported in patients who had the Spanish Flu in 1918 [56,57], and focus or psychosis occurred in only 0.7% of SARS and MERS patients [3].

Symptomatology was similar in infected and uninfected patients
In the case reports we reviewed, in both infected and uninfected patients, the narrative, duration of symptoms, response to treatment, and the COVID-19 context in their symptomatology appeared similar to the point of being indistinguishable. Patients who had the infection experienced a new striking and severe but relatively brief and easily treated psychotic disorder within days of acquiring the infection. The temporal relationship with the infection strongly suggests a causative role, either as a direct neurotoxic effect or indirectly through an effect on other body systems or inflammation. However, this assertion becomes questionable since almost the same kind of brief psychotic disorder occurred in patients with no infection. Since patients without the infection also had no prior psychiatric history, their new psychotic disorder must have occurred due to anxiety alone, especially because in all these patients the pandemic had disastrously affected their family or their own life. This is not surprising since the pandemic has been highly threatening to all people, and even those who are highly balanced psychologically have had to be strong. [4,5,58]. Our findings suggest that psychotic disorder in infected patients, as in uninfected patients, was likely due to extreme mental stress and circumstances related to the COVID-19 pandemic and not due to the infection by the virus per se. Additionally, infected patients may experience posttraumatic stress disorder, which occurs in almost a third of patients who have had critical illness due to any cause [59]. In one series of COVID-19 patients, delirium was followed by psychotic disorder [19].

Multifactorial delirium does occur commonly in COVID-19 patients in the ICU
Delirium is reported much more commonly, and 65% to 70% of COVID-19 patients in the ICU had delirium [13]. Although transient disorientation and perceptual disturbances can occur in both [60,61], unlike psychosis, delirium has underlying factors, increasing in ICU patients with COVID-19 [62]. These include hypoxia, co-morbidities related to advanced age, metabolic abnormalities, polypharmacy including the use of steroids and experimental antimalarial and antiviral medications [16], presumably the effect of isolation due to the inability for the family to visit and of alienation, because providers of health care can be unrecognizable in their hazmat suits and masks.

Neuropsychiatric symptoms and psychotic disorder in COVID-19 patients in media
COVID-19 is a new challenge. Even though many patients have been infected and have died, the pandemic is only 1.5 years old, and there has not been enough time to know all details about how the virus affects us. Due to this lack of information and the fear of the virus, many opinions have surfaced in public. Some of them are incorrect [63,64]. It is well known that the respiratory and digestive tracts are affected. But a new loss of taste or smell, confusion, "brain fog," and inability to stay awake are also characteristic [65]. These symptoms have raised the concern that the virus can also affect the nervous system and that patients can have psychiatric effects [66]. A news item [67] in November 2020 reported that "about 20-25% of patients are getting psychosis diagnosis months after recovery" in patients who have had no previous psychiatric history. In our review, we found a much lower frequency and duration of symptoms. In December 2020, the New York Times reported that a small number of patients developed psychosis but presented examples of very severe psychosis in many patients [68]. However, a subsequent news report in January 2021 emphasized that psychotic disorder is infrequent in COVID-19 patients [69].

Neurological effects are common but evidence is weak for a neurological infection by the virus
The concern that the COVID-19 virus can cause psychotic disorder could be because of the neurological effects of COVID-19, which are much more common and were reported in 36.4% of all and 88% of severe ill COVID-19 patients [70]. Strokes, seizures, encephalitis, Gullian-Barre like nerve damage, and severe forms of meningio-encephalitis have been frequently reported [11,12,71]. Biological evidence for neurotropism of the virus is conflicting. The virus was found in the CSF of some COVID-19 patients [11,72,73], and it was reported in the CSF of SARS and MERS patients [74]. Still, it was not found in any of the seven patients with neurological symptoms in which it was tested [13], in a patient with encephalitis, [72] or in other series and reviews [15,24,75]. On brain autopsies, the virus was found at very low levels, and that too was reported to be likely contamination from blood [76]. ACE-2 receptors, which are required for the virus to attach to host cells, are present on brain cells in very low amounts, although a few are present on oligodendrocytes [75]. In vitro evidence of neuroinvasion by the virus has also been reported in one study [77]. A cardinal early symptom in COVID-19 is the loss of smell. Still, the virus does this through damaging olfactory epithelial cells, which express ACE-2 receptors and not by affecting olfactory neurons, which it cannot invade since they do not express ACE-2 receptors [66]. Injury to the brain due to hypoxia, microthrombi, sepsis, and cytokine storm [75,78] are hypothesized to be more likely factors than a neuronal infection. In the vast majority of patients, there is no evidence of viral CNS access [24]. In summary, although neurological symptoms are prevalent, the laboratory evidence is currently weak for a direct invasion by the virus into the CNS [3,14,20].

Etiology of psychotic disorder in COVID-19 patients
Whether the virus infects the CNS in COVID-19 patients and whether CNS infection is the cause of psychotic symptoms have been the subjects of previous reviews [3,24,66]. Historically, the risk of a diagnosis of psychotic disorder is high after severe infections, especially viral respiratory infections and influenza-like epidemics [3]. However, the evidence is scant for any neuronal invasion by the COVID-19 virus. This is true for COVID-19 patients with either neurological or psychotic symptoms [3,20,24,66]. Autoantibodies against brain antigens can be an explanation for psychotic symptoms in COVID-19 patients since they meet several criteria for the diagnosis of cycloid psychosis [79], which is similar in presentation to autoimmune NMDA [N-methyl-D-aspartate] receptor antibody encephalitis [NMDARA encephalitis] [79]. In cyclops psychosis, patients have episodic psychosis with complete and rapid recovery between episodes, and in DSM-5 cyclops psychosis, patients have brief or unspecified psychotic disorders [80]. In NMDARA encephalitis, autoantibodies that block the glutamate NMDA type receptor are found in serum and CSF, and the blockade can lead to hallucinations [81] and some symptoms of schizophrenia [82]. NMDA receptor antibody was found in CSF in a patient with COVID-19 infection [83], in the CSF of a patient who was not infected with COVID-19 but was affected by the COVID-19 pandemic, [84], and in the serum or CSF of all 11 patients who were critically ill due to COVID-19 infection but without psychotic symptoms [85]. However, autoantibodies to brain antigens are also found in healthy people, and their prevalence in psychosis and the general population was found to be almost the same [86]. In our review, we found that the symptom profile of COVID-19 patients with psychosis matched the profile [79] of patients who had NMDARA encephalitis in many ways:[a] no previous psychiatric disease, [b] young age usually between 15 to 50 years of age, [c] onset of acute psychotic symptoms within hours to days, [d] symptoms of confusion, hallucinations, delusions, paranoia, and a concern with death. They also had a "postinfectious" onset and a preceding flu-like prodrome [24,87] similar to COVID-19 infected patients or had external or family stress [79] as a trigger as in COVID-19 uninfected but affected patients. However, very few NMDARA patients have only acute psychosis [87], and unlike COVID-19 patients, many NMDARA encephalitis patients have progressive neurological worsening with seizures, catatonia, hypoventilation, and even death [87]. Also, unlike patients with COVID-19 related psychosis, NMDARA encephalitis patients are intolerant of antipsychotic medications and respond better to anti-inflammatory medication. [79,87].

Psychotic disorder in COVID-19 patients may be due to the stress of the pandemic
We found very few case reports of psychotic disorder in COVID-19 patients, and the disease is rare considering how common the infection has been. We found even fewer case reports of patients who had no COVID-19 infection. The disorder was short-lasting in the vast majority of patients in both groups. We also found that subjective symptomatology, severity, duration, and response to treatment are very similar in infected and uninfected patients. This similarity of rare occurrence, short period, and severity suggests that symptoms in infected patients are also due to external stress related to the pandemic and not due to a CNS infection by the virus.

CONCLUSION
Case reports of psychosis are rare in patients with and without COVID-19 infection. In both groups, the severity and abrupt onset of extreme symptoms made psychiatric admission essential. Also, almost always, in both groups, symptoms dissipated quickly within days to weeks, and anti-psychotic medication could be stopped. The etiology remains elusive. Symptoms were unlikely due to a CNS infection by the virus because infected and uninfected patients experienced similar symptoms, and the standard trigger in both groups was the external stress due to the pandemic.