key: cord-0906829-tloa99ik
authors: Martinotti, Giovanni; Barlati, Stefano; Prestia, Davide; Palumbo, Claudia; Giordani, Matteo; Cuomo, Alessandro; Miuli, Andrea; Paladini, Carlo; Amore, Mario; Bondi, Emi; Vita, Antonio; Fagiolini, Andrea; Di Giannantonio, Massimo
title: Psychomotor agitation and hyperactive delirium in COVID-19 patients treated with aripiprazole 9.75 mg/1.3 ml immediate release
date: 2020-08-21
journal: Psychopharmacology (Berl)
DOI: 10.1007/s00213-020-05644-3
sha: 091b4b91e0984709a72a429e45806cf270bc9c91
doc_id: 906829
cord_uid: tloa99ik

nan

Delirium and psychomotor agitation are relevant clinical conditions that may develop during COVID-19 infection, especially in intensive care unit (ICU) settings, in patients with acute respiratory distress and in isolation environments (Qiu et al. 2020) . Delirium is characterized by a state of acute confusion presenting with a change in mental status, associated with altered level of consciousness, impaired attention and concentration, and disorganized thinking (American Psychiatric Association 2013). Hallucinations, illusions, or delusions may also occur. For a number of patients, delirium is reversible within a period of days. However, for other patients, it may progress to permanent brain failure. Florid delirium with intense agitation in a combative patient is often described as hyperactive delirium, whereas the clinical picture in which delirium presents in a calm and quiet patient is often referred to as hypoactive delirium.

Both hyperactive and hypoactive delirium subtypes may be among the presenting symptom of the underlying infectious disease, particularly in the elderly in the ICU (Marcantonio 2018) . Delirium may also develop during the course of COVID-19 infection, significantly complicating disease management. As for several other respiratory viruses, accruing evidence indicates that human coronaviruses (HCoVs) are not always confined to the upper respiratory tract but have neuroinvasive properties (Desforges et al. 2020) and are potentially associated with short-and long-term neurological sequelae, including an acute encephalopathy that manifests clinically with delirium (Algahtani et al. 2016) . The development of delirium follows a stress-vulnerability model with precipitating factors that include severe infection, acute respiratory distress, invasive ventilation in ICU settings, and old age (Quinlan et al. 2011) . These potential risk factors characterize the epidemiology and clinical spectrum of the current COVID-19 outbreak in Italy. Furthermore, medications used as first-line treatment in COVID-19 patients, like antiretroviral, can cause or contribute to delirium (Ely et al. 2004) . Moreover, psychiatric patients are at a greater risk of infection and their psychopathological proneness may increase the likelihood of psychomotor agitation, even in patients with mild symptoms (Yao et al. 2020) .

Medication treatment of delirium needs to be weighed against the risk of side effects. Where non-pharmacological measures are unsuccessful or rapid control is required, it may be necessary to provide a pharmacological management earlier than would routinely be considered. The high transmission rate of COVID-19 and the resulting risk of harm to others may exceed risk of harm to the individual, further prompting earlier use of pharmacological treatments for potentially risky behaviors. In this context, the NICE guidelines on violence and aggression may help clinical management (National Institute for Health and Care Excellence 2015). Pharmacological interventions must also take into account the specific clinical features of COVID-19 infections, namely the high risk of respiratory depression and the possible pharmacokinetic interactions with antiviral agents, especially in the elderly (Schoen et al. 2013) . Available injectable medications for delirium and psychomotor agitation include (1) dexmedetomidine, an alpha 2 agonist with sedative and anxiolytic properties that is associated with a low risk of inducing respiratory depression but possible pharmacokinetic interactions with antiviral agents as well as hypotension, hypertension, and bradycardia; (2) haloperidol, often used for hyperactive delirium, associated with QTc prolongation, arrhythmias, and extrapyramidal symptoms;

(3) promazine and (4) tiapride that may be both associated with increased risk of arrhythmias and respiratory depression; (5) olanzapine, a second-generation antipsychotic; and (6) aripiprazole, a third-generation antipsychotic agent with a dopamine receptor-binding profile distinct from other antipsychotics. Small non-inferiority trials have shown that these agents are equally effective in delirium and choice is based on adverse effects, although a recent study proposed aripiprazole as the potential drug of choice for the management of delirium (Prommer 2017) .

We hereby describe the case of 16 consecutive patients with COVID-19 whose hyperactive delirium (psychomotor agitation with restlessness and/or aggressiveness, hyper-vigilance, and hallucinations/delusion) was treated with aripiprazole 9.75-mg/1.3-ml intramuscular injections in the hospitals of Bergamo, Brescia, Genoa, Ancona, and Chieti, inside the Italian "red area," at the beginning of the epidemic phase (Table 1) . Of these patients, 11 were admitted in an ICU. Aripiprazole was chosen in light of its pharmacodynamic and pharmacokinetic properties (low antihistaminic effects, absence of anticholinergic effects, low risk of interaction (Liverpool Drug Interaction Group 2 0 20 ) w i th an ti v ir al a g e nt s a nd c hl or o qu i ne / hydroxychloroquine), and relatively favorable adverse effect profile (low risk of arrhythmias, low risk of respiratory depression), and in accordance with recommendations recently issued from the Italian Society of Epidemiology and Psychiatry (Ostuzzi et al. 2020) .

Aripiprazole injection rapidly and significantly reduced signs and symptoms of delirium and psychomotor agitation, as measured by using the Intensive Care Delirium Screening Checklist (ICDS) (t = 1.86; p < 0.05) and the Modified Overt Aggression Scale (MOAS) (t = 8.95; p < 0.001). Tolerability was high, and no severe adverse events were observed, even in severely ill patients in ICU settings, in treatment with antiviral drugs, antimalarial agents (hydroxychloroquine), and immunosuppressive drug (tocilizumab). From a pharmacokinetic point of view, the elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4 (Boulton et al. 2008) . Intramuscular aripiprazole demonstrated more rapid attainment of plasma aripiprazole concentrations than oral aripiprazole, being able to determine a faster clinical response in terms of efficacy (Boulton et al. 2008) .

Bearing in mind that there are no FDA medications that are specifically indicated for the treatment of delirium (for instance, aripiprazole injection is indicated for agitation associated with schizophrenia or bipolar mania), the present case series provides preliminary evidence on the safety and effectiveness of injectable aripiprazole use for patients with COVID-19, delirium, and/or psychomotor agitation. These data could be of interest for those psychiatrists that will face the development of delirium/psychomotor agitation in COVID-19 patients requiring rapid and prompt treatment, when the presence of physical comorbidities and concomitant medications can complicate the choice of the right pharmacological intervention. Future data from RCTs are requested to confirm and further develop this pharmacological intervention.

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Acknowledgments In memory of all Italian medical doctors who died for COVID-19.

Conflict of interest Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen, Lundbeck, Otsuka, and Pfizer. Stefano Barlati has been a speaker for Angelini, Janssen, Lundbeck, and Otsuka. Mario Amore has been a speaker for GSK. Alessandro Cuomo has been a consultant and/or a speaker for Angelini, Lundbeck, and Otsuka. Andrea Fagiolini has been a consultant and/or a speaker and/or has received research grants from Allergan, Angelini, Apsen, Boheringer Ingelheim, Daiichi Sankyo Brasil Farmacêutica, Doc Generici, FB-Health, Italfarmaco, Janssen, Lundbeck, Mylan, Otsuka, Pfizer, Recordati, Sanofi Aventis, Sunovion, and Vifor. Massimo di Giannantonio has been a consultant and/or a speaker and/or has received research grants from Angelini, Janssen, Lundbeck, Otsuka, Pfizer, and Recordati.