COVID-19 associated psychosis

ABSTRACT

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic was declared, cases of psychosis, delusions, hallucinations, and disorganized behavior have been reported worldwide, both during the acute phase of COVID-19 and after recovery. Given the recent emergence of COVID-19, data are still accumulating, and it is premature to correlate COVID-19 with psychotic disorders causally. However, SARS-CoV-2 has been shown to have the ability to cross the blood-brain barrier and penetrate neurons. This finding and the amount of published work on COVID-19 and psychotic disorders compel special attention to elucidate the link between SARS-CoV-2 and the occurrence of psychotic symptoms. In this article, several reviews and case reports that have analyzed the link between COVID-19 and psychotic disorders are reviewed. In light of the data that have emerged at the present time, study criteria were proposed to identify COVID-19-related psychosis.

Studies have pointed out a potential link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and psychotic disorders;[1,2] however, this is an emerging case. Recently as SARS-CoV-2 spreads worldwide, reports are beginning to surface that link the onset of infection with the development of psychotic symptoms. Psychiatric findings and historical pandemic epidemiological data suggest that viral infection may play a role in the onset of psychosis. Already Honigsbaum,[3] referring to the flu, affirmed that it is not to be considered merely a respiratory disease but a systemic syndrome that can be associated with psychiatric manifestations. Likewise, Karl Menninger[4] reported psychotic syndrome after the Spanish flu.

These dates suggest investigating if there is the possibility of experiencing psychosis for the first time during coronavirus disease-19 infection (COVID-19). Although the focus of pandemic has been on systemic problems, increasing research provides data on potential SARS-CoV-2 neurotropic effects. These data are crucial for detecting the growing social and health consequences of the COVID-19 pandemic early and responding appropriately. In this review, we explore literature data about SARS-CoV-2 infection and its causal role in developing paranoia, delusion, hallucination, and disorganized behavior.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

SARS-CoV-2, identified in January 2020, is the variant that infects human cells, and it is an RNA virus belonging to the family of Coronaviridae, with an unstable genome and a high mutation rate, making it easily adaptable to different organisms.[5,6] The single strand of RNA is enveloped by a phospholipidic layer, on which are anchored spike proteins constituted by two subunits: S1 and S2. The latter allows the virus to bind to the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell membrane.[7]

The other two proteins M (membrane) and E (envelope) are integrated into the phospholipid layer of the envelope, while inside the nucleocapsid are proteins closely associated with RNA.[7]

Transmission of the virus occurs by inhalation of droplet particles, in which the virus is present, or through contact of surfaces contaminated by the droplet particles with mucous membranes. Primarily, the virus has a tropism for respiratory mucous membranes resulting in symptomatology that, in mild forms, is characterized by exclusive involvement of the upper airways, with cough, rhinorrhea, and pharyngitis.[5]

In patients older than 60, symptomatology may be more severe to the point of pulmonary involvement with the possibility of evolution to respiratory failure.[5]

First episode of psychosis during COVID-19

Studies have found that COVID-19 is linked to early psychotic symptoms. A survey by Łoś et al.[8] found that the COVID-19 pandemic has increased the risk of developing first-episodic psychosis (FEP), particularly among individuals who are predisposed to mental health problems. The study also found that the pandemic has had a negative impact on the mental health of people who have recovered from COVID-19 infection, with an increased risk of developing posttraumatic stress disorder (PTSD) and depression. As part of early-to-late onset psychotic symptoms, paranoia, and delusions have increased with COVID-19 infection.

Lyons et al.[9] investigated psychotic symptoms among persons with COVID-19 through an online public forum. The study found that delusions and hallucinations were additional signs of the deteriorating mental health of these individuals. Consistent with the self-blaming attributional biases seen in psychosis, many participants blamed themselves for the pandemic. The “voices” often represented internalized blame, with each speaker claiming responsibility for the global pandemic. The hallucinations of certain people were explored, namely how they had shifted to include images of death and pollution as a result of the pandemic. The forum participants not only revealed a change in their psychotic episodes but also showed a lack of faith in the government or brought up COVID-related conspiracy theories. In line with previous quantitative studies, these results support the hypothesis that schizotypal personality, paranoia, and COVID conspiracies are intertwined in the general population.[10]

Ferreira et al.[10] further indicate that two of the three patients they examined were disorganized and, while wholly oriented, could not otherwise participate in bedside cognitive testing, which is consistent with the diagnosis of delirium, as is the fact that they had recently had sudden-onset psychosis.

Suthaharan et al.[11] also explored the link between COVID-19 and paranoia and found insights that are consistent with other research.[9,10] The authors compared self-rated paranoia before, during, and after the pandemic lockdown. The study demonstrates that people’s paranoia and belief updating were more irregular throughout the pandemic’s early stages in 2020. People’s notion of altering their beliefs became less extreme once a proactive lockdown was instituted. However, the mandatory use of masks exacerbated paranoia and led to more irrational actions on the part of the population. The results indicate that between January and July 2020, there was a statistically significant rise in the number of patients presenting to psychiatric emergency rooms with first-episode psychoses or mania. This increase was demonstrable not only in relative terms but also in absolute terms. The researchers’ findings reveal an even steeper rise in the frequency of new-onset episodes than in previous research, which also increased the number of persons presenting with psychotic features. New patients who developed psychoses and mania in 2020 also showed a decrease in age at the time of onset.[11,12] These data overlapping with studies conducted in other parts of the world during the early phase of the pandemic that dramatically affected northern Italy; diagnoses of the first psychotic episode, which are usually more frequent in early adulthood, were more likely to be made at an older age (mean age of FEP 34 year in 2019 versus 43.5 mean age of FEP in 2020) than in previous years.[13]

The COVID-19 virus can be associated with early psychotic symptoms even if the patient does not have a personal or family history of mental illness. In their article, Smith et al.[14] describe a patient with psychotic symptoms brought on by exposure to COVID-19 who had no history of mental disease in their own or their family’s past. The symptomatic COVID-19 infection was first identified in a 36-year-old previously healthy woman with no personal or family history of mental illness. Furthermore, the beginning of psychosis coincided with upper respiratory symptoms, and she did not have a history of substance abuse or medication (such as steroids) usage. After antipsychotics and benzodiazepines helped stabilize her, her psychotic symptoms finally subsided when her COVID-19 symptoms subsided.[14]

Lim et al.[15] reported similar evidence linking COVID-19 infection with the onset of psychotic symptoms in patients with no mental history.[15] The study presents the case of a female patient with COVID-19 infection who, after an initial period of delirium, developed persistent and florid psychotic symptoms, including persecutory delusion, complex visual and auditory hallucinations, and Capgras delusion.[15] The patient presented with COVID-19 while being in good physical health; there was no psychiatric history or indications to indicate a predisposition toward psychiatric issues. These signs and symptoms persisted after COVID-19. At first, there was likely delirium, but the psychotic symptoms remained even after the disorientation subsided. About three weeks after her delirium had subsided, she began experiencing psychotic symptoms. Due to the effectiveness of the neuroleptic medication, she was able to stop using it.[15]

Early onset symptoms of psychosis can occur at any age and result from underlying illnesses. Chandra et al.[16] argue that a person’s first episode of psychosis could strike at any age, and its underlying cause could be psychological or medical. However, the risk of developing psychosis in those with COVID-19 increases with age and may be higher among men than among women.[16] Taquet et al.[17] found that in adults, a COVID-19 diagnosis is associated with a roughly two-fold increase in the chance of a subsequent diagnosis of a psychosis disorder. Parra et al.[18] investigated 16 people with COVID-19 who exhibited new-onset psychotic symptoms. Six of them thus were excluded from the trial. The average age was 54.1, and 60% of the participants were men. Age was also revealed to be a key risk factor for new-onset psychosis associated with COVID, with the mean age of first episode psychosis increasing dramatically from 39 (2017–2019) to 50 (2020).[19]

Not only can women without a mental history exhibit onset psychotic symptoms, men can also exhibit these symptoms. Kozato et al.[20] examined the impact of COVID-19 on psychotic symptoms in a middle-aged man with no psychiatric history. The COVID-19 patient arrived with acute anxiety and psychotic symptoms. His inability to sleep and growing agitation after being released from the intensive care unit led him to repeatedly strike his head against the walls, resulting in hematomas. He continued to suffer from extreme anxiety and was eventually admitted to a psychiatric ward after experiencing paranoid delusions and auditory and tactile hallucinations. His symptoms eased over the course of a few weeks with the help of antipsychotic medication. In this case study, the researchers concluded that COVID-19 infection could cause a sudden onset of psychosis. The researchers argue that their findings are not new but confirm previous findings on the association of other coronaviruses with psychosis.[20]

Gao et al.[19] also present interesting findings linking COVID-19 infection with early symptoms of psychosis, such as loss of smell and taste, confusion, and inability to concentrate. The case presented findings similar to those of the case studies described by Smith et al.[14] and Lim et al.,[15] both had new-onset psychosis following COVID-19 infection. The patient with new-onset psychosis who tested positive for COVID-19 in the study by Smith et al.[14] did not exhibit any respiratory signs. Delusions of persecution were evident in all three of these patients. In their case study, Gao et al.[19] report that there was no psychiatric history and no psychiatric illness in the patient’s family, according to collateral from the patient’s mother. It was possible that a new case of schizophrenia was the cause.

Acute suicidal/homicidal thoughts and other extreme perceptual and behavioral abnormalities make the virus’ potential to induce psychosis of primary interest for research. Clinical cases have been described that presented severe psychotic symptomatology. Chacko et al.[21] also report the case of a 52-year-old man with no known mental history who developed extreme paranoia and attempted suicide due to COVID-19. Other authors reported a high risk of suicide associated with psychosis in patients with COVID-19.[22] In two case reports, the authors also reported the presence of Cotard’s syndrome, characterized by dead and nihilistic delusions.[23,24]

In addition to rigging early-onset psychotic symptoms, COVID-19 is also linked to late-onset psychosis. In their case study, Parker et al.[25] report that after experiencing modest symptoms of COVID-19 and testing positive for the virus, the patient’s psychiatric presentation was consistent with the cases described in previous studies. Positive psychotic symptoms such as delusions, hallucinations, and disorganized thinking and behavior have been observed in patients with no prior history of psychosis, as confirmed by this study. However, this case stands out due to the patient’s middle age. The patient’s history of neurological symptoms, including anosmia and ageusia, consistent with COVID-19, points to SARS-2-CoV involvement in the nervous system.[25]

SARS-CoV-2 could also facilitate the appearance of psychosis in women who gave birth to COVID infection. In this regard, some authors observed an approximately four-fold increase from 2020 to 2021 in postpartum psychosis diagnoses compared with previous years. The authors concluded that SARS-CoV-2 should be considered a risk factor for postpartum psychosis.[26]

Moreover, psychotic symptoms with a rapid onset in the absence of a prodromal phase, fluctuating and with unstructured delusions, symptoms that can be framed in cycloid psychosis, were observed in the first two months of the pandemic; the study authors attributed them to stress related to the resilience difficulties of some individuals, linked to the pandemic-related conditions of isolation and stress.[27] Smith et al.[28] in an extensive review that selected 2,396 articles, of which 40 met the criteria according to the PRISMA guidelines, note that a causal correlation between COVID-19 and the onset of psychosis cannot be demonstrated and that in many cases of patients with symptoms such as delusion, hallucination, agitation, the diagnosis of delirium was not always ruled out (Smith, 2021).[28] Probably the actual cases of psychosis resulting from direct coronavirus infection are numerically limited. Often preexisting concomitant and predisposing factors, such as treatment with corticosteroid drugs, psychosocial stresses (prolonged hospitalization, social isolation), or genetic vulnerability during COVID-19, may facilitate the onset of psychotic symptomatology.[1]

Long COVID-19 syndrome

Psychosis may be associated with acute COVID-19 disease or long COVID-19 syndrome, linked to a chronic neuroinflammation and neurodegeneration process.[29]

In COVID-19 individuals, psychosis commonly manifests as delusions alongside other confused symptoms.[30] According to this study, approximately 72% of patients showed complete improvement, while the rest continued to experience some degree of depression, anxiety, or psychosis. However, the need for close supervision and longer follow-up is highlighted by the persistence of depressive, anxious, or psychotic symptoms in a significant percentage of patients.

Another study by Ravindran et al.[31] conducted a qualitative analysis of literature linking psychosis to post-COVID-19 infection. The study found a growing body of evidence linking the virus with psychosis, with several case reports and case series that describe the onset of psychosis in individuals recovering from COVID-19 infection. The study also found that the onset of psychosis in COVID-19 patients is often associated with other neurological symptoms, such as confusion, delirium, and hallucinations. In general, the review suggests that COVID-19 infection can increase the risk of developing first psychotic disorders and can lead to psychosis in individuals who have recovered from the virus. The authors recommend further research to better understand the mechanisms underlying this relationship and develop effective interventions for people at risk of psychosis after COVID-19 infection.[31]

Alnefeesi et al.[32] systematically searched electronic databases and hand-searched relevant journals to identify relevant studies. They included observational and interventional studies reporting cognitive function in individuals with SARS-CoV-2 infection. The review results showed that 43%–66.8% of hospitalized patients with COVID-19 had a negative impact on cognitive function, including attention, executive function, memory, and processing speed, also after infection recovery. The studies included in the review also suggested that the severity of the infection, age, and preexisting medical conditions may play a role in the extent of cognitive impairment.[32]

During other medical conditions, such as urolithiasis and diabetes, the risk of these diseases that increase with COVID-19 infection can also trigger psychotic symptoms. According to Taquet et al.,[17] patients without a mental health history were more likely to receive their first psychiatric diagnosis between 14 and 90 days after a COVID-19 diagnosis, relative to the occurrence of six other health events, including influenza virus, skin infection, cholelithiasis, urolithiasis, and other respiratory tract infections. Anxiety problems, sleeplessness, and dementia were the highest risk hazard in patients with COVID-19 compared to other illnesses. The study concludes that a psychiatric diagnosis may be an independent risk factor for COVID-19, and survivors of this virus appear to have an increased risk of long-term psychiatric consequences.[17]

Reactive psychosis

Existing literature shows that COVID-19 infection is associated with psychotic symptoms due to its stressor-trigging effect. There was an estimated incidence of 0.42% for a first diagnosis of psychotic illness, and the hazard risk (HR) of presenting psychotic symptoms was substantially higher among patients with COVID-19 than among patients with flu (HR 2.27; HR 1.49 for other respiratory tract infections), in a retrospective cohort research assessing neurological and psychiatric consequences among 236,379 COVID-19 patients over a six-month follow-up.[2] Individuals infected with SARS-CoV-19 had multiple stressors during the pandemic, including those associated with quarantine, problems in the treatment setting, and a lack of knowledge about the virus it self’s own prognosis.[2] Extensive research on the link between psychosis and various psychosocial factors, such as stressful life events, suggests that these stressors play a significant role in the development and worsening of psychotic symptoms. Dopaminergic signaling and other biological pathways involved in psychosis are particularly vulnerable to the disruptive effects of social stress.[2]

Stress elements of COVID-19 infection act as a stimulating factor for the development of early psychosis. Stressors that may cause some people to succumb to poor mental health may be caused, at least in part, by the externally imposed social isolation and lockdown, which may impair the habitual interpersonal relationships that people commonly engage in.[25,33,34] The disintegration of one’s mental faculties, as seen by irrational behavior and altered states of consciousness, may be precipitated by a cocktail of high COVID-19-related stress and social isolation. There is some evidence in the preclinical literature that suggests that social isolation may exacerbate symptoms of schizophrenia.[25,33,34]

Psychosis COVID-19 neuropathology

The inflammation of the central nervous system as the cause of psychotic episode has been discussed by some authors.[35,36]

Multiple pathways exist by which COVID-19 may cause mental health problems. Several infectious agents, such as HIV, Toxoplasma gondii, Treponema pallidum, Chlamydia trachomatis and Brucella, have been associated with psychosis.[15] The SARS-CoV-2 strain is neurotropic and potentially neurotoxic.[35,36] To explain the neuropsychiatric symptoms of COVID-19 infection, two broad theories of central nervous system involvement have been postulated. Two factors contribute to the severity of COVID-19 disease: (1) direct viral invasion of the central nervous system: (a) through the olfactory bulb, through the cribriform plate and into the cerebrospinal fluid or the frontal lobe; or (b) through hematogenous dissemination across the blood-brain barrier.[25] However, psychosocial stress from the pandemic has been associated with the worsening or onset of psychiatric disorders, regardless of the state of the infection.[25]

Storm of cytokines is postulated as a second indirect method by which COVID-19 may generate psychosis.[19,33,34] This mechanism arises from an aberrant immune response to this novel and unknown pathogen. When the immune system malfunctions, it creates a chain reaction that ultimately harms the brain tissue such as the excessive production of excitatory amino acids (glutamate).[19,33,34] Such occurrences may damage neural pathways, increasing the risk of psychosis. These conclusions are supported by some authors who argue that SARS-CoV-2, either by direct neurotoxicity or by an exacerbated immunological response, could cause psychosis.[19] For example, SARS-CoV-2 RNA was recently extracted from a patient’s brain, demonstrating that coronaviruses can spread to the neurological system.[37]

Post-mortem studies of patients who died because of complications from COVID-19 have shown the presence of perivascular lymphocytic[38] infiltrates, microglia activation, microgliosis, and astrogliosis, evident signs of a neuroinflammatory process triggered by peripheral inflammation, or direct virus action in brain tissue.[39] The increase in permeability of the blood-brain barrier[40] caused by the ongoing cytokine storm associated with COVID-19 facilitates the entry of the virus into the SNC.[39]

Brain tissue injury may express itself with an acute encephalitic pattern. Moreover, it is not excluded that Sars-CoV-2 may lead to long-term neuroinflammation with consequences in the same way as neurodegenerative diseases.[41] During COVID-19, the involvement of the olfactory epithelium with the subsequent anosmia, associated with an intense immune response, would be indicative of nerve tissue involvement and could therefore assume prognostic significance.[41]

Psychosis and drugs

Studies link SARS-CoV-2 with psychotic symptoms through pharmacological treatment. The article by van Vuren et al.[42] examines the neuropsychiatric manifestations of COVID-19, focusing on how they interact with preexisting psychiatric illnesses and pharmacological treatments. Antibiotics such as ceftriaxone and azithromycin, which were administered to this patient, are known to have iatrogenic effects, with the appearance of psychosis associated with antibiotics known to vary between 0.3% and 3.8%, so that they may have had a part.[2] Systemic corticosteroid use is associated with sleeplessness, mood swings, depression, and psychosis, all of which could have affected our patient throughout her treatment with dexamethasone.[19,42]

These findings elucidate the implications of pharmacological treatment in patients with COVID-19, including the potential for drug interactions and the need for close monitoring of adverse effects. They also emphasized the importance of providing complete care to patients with COVID-19 and psychiatric illness, including the use of pharmacotherapy, psychotherapy, and lifestyle modifications.[12]

Prognosis of psychosis-COVID-19-related

Many studies have reported that COVID-19 is linked to short or temporary psychosis. Few studies are yet to establish persistent psychotic symptoms. Lim et al.[15] found that the psychotic symptoms persisted for about 40 days; Kozato et al.[20] found that the psychotic symptoms improved within a few weeks of COVID-19 treatment; and Smith et al.[14] indicate that psychotic symptoms improved after seven days. Several psychiatric disorders that manifest simultaneously with or after hospitalization and treatment for COVID-19 are part of the differential diagnosis of psychotic symptoms. Due to the patient’s rapid start of symptoms immediately after he had recovered from pneumonia and the durability of his altered mental status while on our unit without a waxing and waning quality, we determined that delirium was not the cause of his psychosis.

Haddad et al.[43] also reported brief psychotic disorders associated with quarantine and mild COVID-19 confirming the previous results. The study reported a case study of a 30-year-old male who continued to worry excessively, and one week later, he began experiencing paranoid delusions and auditory hallucinations, confirming his first psychotic episode. The researchers add that it took a week for his psychotic symptoms to diminish. After four weeks, he was able to drop the psychiatric drugs and at his three-month check-up he was doing well. They concluded that the patient was diagnosed with brief reactive psychosis, classified as a psychotic disease with a stressor trigger in the DSM-5. Anxiety and social alienation appeared to be the leading causes of the patient’s psychosis, although an inflammatory factor cannot be ruled out.[43]

CONCLUSION

In conclusion, this review has confirmed that the COVID-19 virus is associated with various psychotic symptoms, including hallucinations, delusions, disorganized behavior, and paranoia. Certainly, it is still debated whether psychosis is caused by COVID-19 or is a consequence of the drugs used for COVID-19 treatment (corticosteroids, antibiotics), internist conditions (hypoxemia, hydroelectrolyte imbalance), or related to stress due to long hospitalization or isolation. It is mandatory to exclude delirium before a diagnosis of psychosis is made [see Table 1].

Table 1.

Study criteria for the diagnosis of COVID-19-related psychosis

Sudden onset without a prodromal phase of at least one of the following symptoms:

Structured or unstructured delusions

Auditory and visual hallucinations

Disorganized speech and behavior.

Often fluctuation of symptoms and fast recovery.

The following should be excluded:

Delirium

Psychiatric family history

Personal psychiatric history

Recent substance use

Recent corticosteroid use

Alterations in consciousness or disorientation

Consider that long periods of hospitalization could promote the onset of reactive seclusion psychosis.

The findings of this review, while still debatable, show that COVID-19 stimulates psychotic symptoms in three main ways: direct action of the virus, deregulation of the cytokine network, and stressors and uncertainty related to prognosis disease.[44] Many studies in this review indicate that COVID-19-induced psychotic symptoms are only short-lived and end within a few days of treatment. Furthermore, most studies agree that COVID-19 infection can cause early-onset psychosis and other psychotic symptoms, even among people without a history of mental illness, substance abuse, or medical condition. However, gaps still exist in this area and should be a place for further research. Nonetheless, this review suggests that future research should rigorously investigate the incidence of psychiatric symptoms in individuals with coronavirus infections, and a prospective cohort of SARS-CoV-2 patients should be formed.

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Conflicts of interest

There are no conflicts of interest.