COVID-19-induced psychosis: new challenges for early career psychiatrists

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COVID-19, a global pandemic, started in late 2019, soon got spread all over the world and hit the entire population more than just an infection. Worrisomely yet very importantly, both the burden of mental health problems and already existing morbidities has piled up to an unimaginable level along with global concern for the same. As an obvious, the public health concern of this global mental health scenario has seeked attention to many clinicians and researchers; with variable literature has been published from the entire globe. Both the neurotic as well as psychotic spectrum disorders have been reported and here we discuss the existing literature on COVID-19 related psychosis and psychotic reaction/exacerbations including neurobiology and treatment of the same. In this article, we choose the aim — to review the first available data on COVID-19 induced psychoses and the impact of these data on the development of theory and practice. We collaborated in worldwide Task Force of early career psychiatrists and prepared the definition of our point of view.

Neurobiology of COVID-induced psychosis

Establishing a causality relationship in a rare outcome is a challenging task and mandates more extensive experimental research. Historical studies from past viral pandemics and ongoing neurobiological evidence extrapolated from current COVID-19 small studies point towards a causal relationship between SARS-CoV-2 infection and psychosis. However, establishing that new-onset psychosis in previously asymptomatic individuals is either due to the direct neurotrophic effects of the virus or due to unmasking of psychosis in vulnerable individuals, both require further underpinning. The relationship between virus and immune dysregulation in psychosis has been well studied in the past [1] especially during the early utero-development phase. Recently a critical appraisal of reported cases for COVID-induced psychosis postulated several underlying mechanisms for psychosis in COVID-19 patients [2]. Although it is difficult to demarcate whether these alterations in mental state are sequelae of systemic infection, direct neuro-invasion, stress-triggered predisposition in genetically vulnerable, or a combination of all above factors, further research is required. The several potential mechanisms are discussed:

1. Direct neural infection. The key receptor, ACE-2, which is important for SARS-CoV-2 intracellular invasion, is also expressed on neural cells in the brain. Exploratory reports from intranasal inoculation of SARS-CoV-1 infection in ACE2 transgenic mice showed evidence of neuronal loss and upregulation of pro-inflammatory discharge from glial and astrocytes cells in the brain [3]. Micro-invasive potential of SARS-CoV-2 RNA have been reported in CSF of COVID-19 patients [4] and this acute neurotrophic invasion can cause neuropsychiatric symptoms.
2. Cytokine storm and proinflammatory response. One of the more accepted hypotheses that could account for psychosis in COVID-19 patients is 'cytokine storm,' systemic hyper-inflammation which can occur in certain groups of seriously ill patients. There are reports of elevated inflammatory markers in the acute stage of COVID-19, e.g. CRP, serum ferritin, interleukin and an association of these markers with severity of illness [5]. Meta-analyses supporting relevant neurobiological mechanisms linking primary psychotic disorder and cytokine dysregulation have been well studied in the past. Schizophrenia is related to aberrant immune system dysfunction, including cytokine levels [6]. Increased level of a few cytokines might be state markers of the acute phase (IL-6, IL-1β, and TGF- β), while other increased levels of IL-12, IFN-γ and TNF-α may be trait markers of inflammation [5]. Accumulating evidence from COVID-19 studies suggests that the level of proinflammatory cytokines is increased during infection. Further, a subgroup of COVID-19 patients might face cytokine storm [7], which can lead to immune dysregulation and predispose patients to altered mental state.
3. Autoimmunity and iatrogenic. Another potential mechanism that might potentiate the development of neuropsychiatric sequela is molecular mimicry with host self-antigen. CoV infection may mislead the host immune response in susceptible individuals towards autoimmunity and can trigger the cascade of neuronal death in the CNS [8]. Certain medications used for COVID-19 treatment can precipitate a psychotic episode. There is an abundance of reports of corticosteroid-induced psychosis in the past [9]. The potential risk due to high doses of corticosteroid or quinolone use during acute phase SARS CoV-1 infection warrants judicious use of medications.
4. Unmasking hidden vulnerability. COVID-19 is a known psychosocial stressor and this state of heightened stress during a pandemic could trigger the well-established association between stress and psychosis. Increased substance use, isolation, social deprivation, and socio-economic hardship can unmask other relevant causes of psychosis [10].

Clinical manifestations

There have been various reports of people developing psychotic symptoms during the pandemic which were seemingly prompted by the profound and significant distress caused by it [11–14]. These psychotic episodes are often manifested through hallucinations and delusions which tend to be focused on COVID-related themes. For example, Huarcaya-Victoria, Herrera, and Castillo (2020) reported a case of a person listening to a voice which persistently ordered her to be tested for COVID-19. Valdés-Florido and colleagues (2020) also reported a series of four brief reactive psychosis prompted by the distress associated with the ongoing pandemic, with symptoms that included delusions about one's family being infected by the COVID-19 virus, and an extreme worry about being a contagious asymptomatic carrier and an increased emotional reactivity. Rentero and colleagues (2020) suggested that episodes of psychosis triggered by the pandemic are characterised by a subacute onset of psychotic symptoms and quick recovery on low antipsychotic doses.

Brown et al. (2020) also discusses the effect of covid-19 on psychosis and given an incident rate with a range of 0.9% to 4%. The mentioned association with viral exposure treatment used to manage the infection and potential role of psychosocial stresses behind this.

On the other hand, psychotic episodes associated with COVID-19 infection seem to be characterised by a rapid instauration, and they also appear to resolute with low antipsychotic doses [16-19]. Other symptoms associated with COVID-19 associated psychosis are also hallucinations in various sensory modalities, delusions, and disorganized speech; although disorganized behaviours and confusional features appear to be more prominent in these cases [20, 21]. There could also be confusional symptoms, however, these appear to be more related to having received ICU-treatment and the accompanying clinical manifestations of COVID-19 infection [18]. Nevertheless, it should be highlighted that whether there is a direct biological relationship between COVID-19 and psychosis remains unclear [19, 22].

Example of affective induced psychosis: A. Correa-Palacio, et al. (2020) reported about a 43 year old gentleman with history of aggressive abusive behavior (both physically and verbally, up to using two swords to fend his arrest) which needed emergency intervention by local police followed by admission at psychiatric in patient unit. Post admission, MSE findings of a hyper alert oriented patient, who was collaborative but with a moderate level of psychomotor restlessness. His speech was loud, re- iterative and logorrheic, with megalomaniac beliefs of «communicating directly with God», and persecutory delusions with medical and police staff. He was expansive and anxious with a high level of self-perceived energy. Visual and auditory hallucinations were recognized by the patient as well as eight-day global insomnia. One mood stabiliser, two antipsychotics and benzodiazepine were needed for his management as well.

Treatment

With regards to psychosis in the context of COVID-19, we find that the treatment, like more traditional forms of psychosis, calls for low dose antipsychotics [18]. Aripiprazole has been noted to be effective in patients who are psychotic either immediately due to an infectious disease or those who are rendered psychotic due to psychosocial stress associated with an infectious disease [15]. For patients who had risk factors for developing psychosis before the pandemic, the literature has recommended being wary of drug induced psychosis (the potential impact) during the COVID-19 pandemic. And finally, for patients with existing psychosis before COVID-19, it has been alluded that clinicians actively advise patients to physically distance and isolate due to the decreased likelihood of patients with psychosis adhering to protective measures [15]. In terms of pharmacotherapy for patients who were treated with clozapine, it was recommended absolute neutrophil count monitoring could be done up to once in three months in certain conditions [24]. In addition, for these same patients, the literature has advised bridging existing technological divide [25] by promoting technological opportunities as this would provide patients with more opportunities with e-health follow up [26]. Ultimately, it is also worth mentioning that patients who are on drugs ought to be monitored for pharmacodynamic and pharmacokinetic interactions between those drugs when it comes to cardiac arrythmia, hematological side effects and effects on the CYP system [15].

CONCLUSION

COVID-19 induced psychosis has piqued the interest of many doctors and researchers, Historical research from previous viral pandemics, as well as ongoing neurobiological evidence inferred from current COVID-19 small studies, suggest that SARS-CoV-2 infection and psychosis are linked. However, determining whether new-onset psychosis in previously asymptomatic people are caused by the virus's direct neurotrophic effects or by the virus's unmasking of psychosis in vulnerable people requires more research. More research is needed to determine if these changes in mental state are the result of systemic infection, direct neuro-invasion, stress-triggered predisposition in genetically predisposed people, or a combination of all the aforementioned variables, and for management of this condition. Also, a mentally health-y public health approach with appropriate policy making and preparedness for emergency mental health services as a part of any similar disaster management needs a serious attention worldwide.

ADDITIONALLY

Finanсing of study. The work was carried out without sponsorship, within the framework of international cooperation of Task Force of early career psychiatrists.

Conflict of interests. The authors declare no actual and potential conflict of interests which should be stated in connection with publication of the article.

Participation of authors: I.A. Fedotov — concept of consensus, text writing, text coordination, editing, T. Maiti, L. Essam, L. Orsolini, R. Ramalho, S. El Halabi, V.-S. Nguyen, A. Gürcan, J. Jakhar, M. Pinto da Costa, M.I. Ojeahere, S. Shoib — literature analysis, text writing, text coordination.

About the authors

Tanay Maiti

JIMSH

Author for correspondence.
Email: drtanaymaiti@gmail.com
ORCID iD: 0000-0001-8880-8773

MD, DPM, DNB, MNAMS, Assistant Professor

India, Kolkata

Lamiaà Essam

GSMHAT

Email: drtanaymaiti@gmail.com
ORCID iD: 0000-0002-5657-2388

MD, Dr.Sci.(Med.), Junior Neuropsychiatry Resident

Egypt, Cairo

Laura Orsolini

Hertfordshire University; Polytechnic University of Marche

Email: drtanaymaiti@gmail.com

MB ChB (Hons), MScCrim, PGCert (Forensic PSY), Psychiatrist and Clinical Researcher, Department of Clinical Neurosciences/DIMSC, School of Medicine

United Kingdom, Hatfield; Ancona

Rodrigo Ramalho

University of Auckland

Email: drtanaymaiti@gmail.com
ORCID iD: 0000-0002-2372-6854

MD, Dr.Sci.(Med.), Psychiatrist, Department of Social and Community Health, School of Population Health

New Zealand, Auckland

Sarah El Halabi

Westchester Medical Center

Email: drtanaymaiti@gmail.com
ORCID iD: 0000-0003-2012-6041

MD, Dr.Sci.(Med.), Psychiatrist, Psychiatry Department

United States, New York

Vinh-Son Nguyen

Baylor College of Medicine

Email: drtanaymaiti@gmail.com
ORCID iD: 0000-0003-4340-995X

MD, Dr.Sci.(Med.), Resident Physician, Menninger Department of Psychiatry and Behavioral Sciences

United States, Houston

Ahmet Gürcan

Koru Ankara Hospital

Email: drtanaymaiti@gmail.com

MD, Dr.Sci.(Med.), Psychiatrists, Department of Psychiatry

Turkey, Ankara

Jitender Jakhar

Govind Ballabh Pant Institute of Postgraduate Medical Education and Research

Email: drtanaymaiti@gmail.com
ORCID iD: 0000-0003-1655-7930

MD, Dr.Sci.(Med.), Senior resident, Department of psychiatry

India, Delphi

Mariana Pinto da Costa

Institute of Psychiatry, Psychology & Neuroscience, King’s College London; Institute of Biomedical Sciences Abel Salazar; University of Porto

Email: drtanaymaiti@gmail.com
ORCID iD: 0000-0002-5966-5723

MD, Dr.Sci.(Med.), Researcher

United Kingdom, London; Porto

Margaret I. Ojeahere

Jos University Teaching Hospital

Email: drtanaymaiti@gmail.com

MBBS, FWACP, Psychiatrist and Clinical researcher, Department of Psychiatry

Nigeria, Jos, Plateau State

Sheikh Shoib

Jawahar Lal Nehru Memorial Hospital

Email: drtanaymaiti@gmail.com

MD, Dr.Sci.(Med.), Department of Psychiatry

India, Srinagar, Kashmir

Iliya A. Fedotov

Ryazan State Medical University

Email: drtanaymaiti@gmail.com
ORCID iD: 0000-0002-2791-7180

MD, Cand.Sci.(Med.), Associate Professor of Psychiatry Department

Russian Federation, Ryazan

References

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