Discussion

Taking in consideration the number of cases identified, the outcome of this review has presented catatonia as a possible complication of COVID-19, regardless of age, gender and the background of the physical or mental health status of patients. However, this review indicates that the strength of evidence for catatonia in COVID-19 was poor, as there are no robust observational studies available. The below discussion represents the 34 patients whose data were available. The presentation of catatonia in COVID-19 varied in onset, severity and duration. Catatonic states were reported throughout the acute and subacute phases of COVID-19, as well as a long-term post-encephalitis neuropsychiatric complication. Catatonia occurred in combination or independently of any other psychiatric symptoms. However, catatonia mainly arose concurrent with the acute phase of COVID-19, but was reported as a long-term complication for COVID-19 (Table 1).

Lorazepam was used in 22 patients, and demonstrated notable and even rapid improvements in the core symptoms of catatonia, including mutism, echolalia, rigidity, waxy flexibility and automatic obedience in 18 patients; the remaining four patients needed further electroconvulsive therapy (ECT).^{Reference Deocleciano de Araujo, Schlittler, Sguario, Tsukumo, Dalgalarrondo and Banzato21,Reference Kaur, Khavarian, Basith, Faruki and Mormando29,Reference Sakhardande, Pathak, Mahadevan, Muliyala, Moirangthem and Reddi32} Furthermore, lorazepam led to mild improvements in delirium in one patient,^{Reference Amouri, Andrews, Heckers, Ely and Wilson23} and improvement in agitation and paranoia in another.^{Reference Zain, Muthukanagaraj and Rahman14} Oral or intramuscular lorazepam challenge tests led to lysis of catatonia after 10–30 min in most cases. For example, a report from the Kern Medical Centre in California described two cases of suspected catatonia associated with COVID-19 who responded immediately to lorazepam injections, with marked improvement in their symptom profile.^{Reference Torrico, Kiong, D'Assumpcao, Aisueni, Jaber and Sabetian9} Delaying treatment with benzodiazepines because of worries about worsening delirium might be followed by serious physical complications, such as pulmonary embolism.^{Reference Kwon, Patel, Ramirez and McFarlane11} Steroid therapies were trialled in seven patients that were diagnosed with COVID-19-induced encephalopathy, which proved useful in four (57%) patients.^{Reference Torrico, Kiong, D'Assumpcao, Aisueni, Jaber and Sabetian9,Reference Mulder, Feresiadou, Fällmar, Frithiof, Virhammar and Rasmusson10,Reference Vazquez-Guevara, Badial-Ochoa, Caceres-Rajo and Rodriguez-Leyva12,Reference Jaber, Aisueni, Torrico, D'Assumpcao, Kiong and Sabetian16,Reference Pilotto, Odolini, Masciocchi, Comelli, Volonghi and Gazzina24,Reference Austgen, Meyers, Gordon and Livingston28} In the remaining three (43%) patients, steroid therapy failure was followed by successful lorazepam treatment.^{Reference Torrico, Kiong, D'Assumpcao, Aisueni, Jaber and Sabetian9,Reference Jaber, Aisueni, Torrico, D'Assumpcao, Kiong and Sabetian16,Reference Austgen, Meyers, Gordon and Livingston28} This finding suggests that the well-known efficacious responses to lorazepam therapy in catatonia is still valid in COVID-19, with almost a complete resolution of all catatonic signs in most cases. No serious unwanted side-effects were recorded. Although lorazepam is helpful in treating catatonia, lorazepam alone might not suffice. ECT should always have serious early consideration in catatonia, as it showed good results and safety even with the physical health complications of COVID-19.^{Reference Johnson, Kapoor and Kim17,Reference Deocleciano de Araujo, Schlittler, Sguario, Tsukumo, Dalgalarrondo and Banzato21,Reference Palomar-Ciria, Alonso-Álvarez, Vázquez-Beltrán and Blanco Del Valle27–Reference Kaur, Khavarian, Basith, Faruki and Mormando29,Reference Sakhardande, Pathak, Mahadevan, Muliyala, Moirangthem and Reddi32} In one patient, nonetheless, ECT was declined because of concerns regarding physical health problems.^{Reference Gouse, Spears and Nieves Archibald22} Despite the controversy surrounding antipsychotics in catatonia, two case reports described efficacious treatments utilising the antipsychotics olanzapine, asenapine and ziprasidone.^{Reference Vazquez-Guevara, Badial-Ochoa, Caceres-Rajo and Rodriguez-Leyva12,Reference Huarcaya-Victoria, Meneses-Saco and Luna-Cuadros25}

In another aspect, COVID-19 has the potential to negatively affect the clinical course of established catatonia, as highlighted by the study by Johnson et al^{Reference Johnson, Kapoor and Kim17} which described a 27-year-old male with a past medical history of normal pressure hydrocephalous and polycythaemia. He was first admitted for depression and increasing catatonic symptoms. He tested negative for COVID-19 on admission, but was infected during in-patient stay, and his catatonia deteriorated to malignant catatonia. The COVID-19 vaccinewas also reported as a possible cause for the catatonia presentation and it was treated with rituximab, an antipsychotic and steroids.^{Reference Flannery, Yang, Keyvani and Sakoulas30}

Nersesjan et al^{Reference Nersesjan, Amiri, Lebech, Roed, Mens and Russell19} enrolled 61 patients with COVID-19 who were admitted to Rigshospitalet, Copenhagen University Hospital, a tertiary referral centre in Denmark; the group identified encephalopathy in 19 patients, eight (42%) of whom were apathetic and severely hypokinetic or akinetic, with almost no voluntary movements and no verbal output. However, these eight patients were conscious and appeared aware of their surroundings through intelligible gaze responses. Those patients were given the diagnosis of akinetic mutism, and these symptoms lasted for a median of 4 days. These clinical observations could raise the possibility of unspecified catatonia. The Guidelines and Evidence-Based Medicine Subcommittee of the Academy of Psychosomatic Medicine states that the disorder fulfils DSM-5 criteria for ‘catatonic disorder due to another medical condition’, as all cases of akinetic mutism involve stupor, immobility and mutism,^{Reference Denysenko, Sica, Penders, Philbrick, Walker and Shaffer33} However, the guidelines recognise that this definition is complicated by the fact that some medical conditions can cause both akinetic mutism and catatonia.^{Reference Denysenko, Sica, Penders, Philbrick, Walker and Shaffer33}

Additionally, Pilotto et al^{Reference Pilotto, Odolini, Masciocchi, Comelli, Volonghi and Gazzina24} described a case of a 60-year-old patient with severe acute respiratory syndrome owing to COVID-19, who had only mild respiratory abnormalities and developed an akinetic mutism with abulia. He was considered as suffering from encephalitis and delirium secondary to COVID-19; however, this case report's clinical description fulfilled at least two of the diagnostic criteria of catatonia. Additionally, 3 days after admission, given the persistence of clinical symptoms, high-dose intravenous steroid treatment was started (methylprednisolone 1 g per day for 5 days) and was effective. In an exploratory study, Grover et al^{Reference Grover, Ghosh and Ghormode34} systematically demonstrated that 30.2% of patients with delirium, regardless of aetiology, met the criteria for catatonia by scoring positive on two of the first 14 items of the Bush–Francis Catatonia Rating Scale. These findings suggest that catatonia can coexist with delirium.^{Reference Denysenko, Sica, Penders, Philbrick, Walker and Shaffer33,Reference Grover, Ghosh and Ghormode34} Following Grover et al's report, several successive case reports were published describing encephalitis and delirium with catatonia in the context of COVID-19 infection.^{Reference Mulder, Feresiadou, Fällmar, Frithiof, Virhammar and Rasmusson10,Reference Vazquez-Guevara, Badial-Ochoa, Caceres-Rajo and Rodriguez-Leyva12,Reference Jaber, Soliman, Campo and Mader15,Reference Kaur, Khavarian, Basith, Faruki and Mormando29} Lorazepam challenge test is widely used to either confirm or exclude catatonia.^{Reference Muliyala, Reddi and Bhaskaran35} In such ambiguous presentations, a challenge test with lorazepam would be beneficial.

Catatonia shares symptoms with a wide spectrum of physical and mental illnesses, such as status epilepticus, akinetic mutism, delirium, metabolic conditions (e.g. diabetic ketoacidosis), neuroleptic malignant syndrome, Parkinson's disease, extrapyramidal side-effects, substance misuse disorders, depressive disorders and psychosis. These examples are common illnesses that could be part of the aetiology for the progression and presentation of catatonia.^{Reference Wilcox and Reid36} Many of these conditions were described in patients with COVID-19 identified in our review.^{Reference Taquet, Geddes, Husain, Luciano and Harrison37–Reference Smith, Gilbert and Riordan40} Consequently, misclassification or missed diagnoses of catatonia is a possibility, and many cases fall within the grey zones of disease classification. Grey zones in medicine represent a complex situation and a great challenge to the diagnostic classification and subsequent treatment of patients.^{Reference Naylor41}

In conclusion, our review was limited by the paucity of cohort studies and case–control studies designed to evaluate the epidemiology of catatonia and its course in COVID-19. The diagnostic problem was explored mainly through case reports, and the majority did not use a diagnostic rating scale. The diagnostic uncertainty extends to the cohort study included in this review that reported akinetic mutism in patients with COVID-19, which did not use diagnostic methods to examine the differential diagnosis and determine a precise and exclusive diagnosis.

Nevertheless, according to the reports available, evaluation of the possibility of catatonia in patients with COVID-19 infection and those presenting with mutism and hypokinesia or other symptoms of catatonia is important. As the pandemic continues, increasing the awareness of the diagnosis of catatonia among medical staff who are working with patients with COVID-19 would facilitate a timely identification and management of catatonia, which will have significant and lifesaving outcomes on the acute treatment of these cases.

Most patients with catatonia responded substantially and rapidly to benzodiazepines. The role of antipsychotic agents in treatment is controversial. ECT was effective, but would present a challenging circumstance in the prevention and treatment of medical complications of COVID-19.