Hervé Javelot
email: herve.javelot@ch-epsan.fr

Céline Straczek

Guillaume Meyer

Clara Gitahy

Falcao Faria

Luisa Weiner

Dominique Drapier

Eric Fakra

Philippe Fossati

Sébastien

Gitahy Falcao

Llorca Pm

Psychotropics and COVID-19: An analysis of safety and prophylaxis

Keywords: COVID-19, SARS-CoV-2, psychotropics, safety, prophylaxis sites COVID-19, SARS-CoV-2, psychotropes, sécurité clinique, prophylaxie J o

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Résumé

L'usage des psychotropes en période de pandémie de COVID-19, liée au SARS-CoV-2, a fait émerger deux grandes interrogations d'importance inégale. Prioritairement, quelles doivent être les éventuelles adaptations de traitements pharmacologiques à mener chez les patients souffrant de troubles psychiques ? Secondairement, certains psychotropes sont-ils susceptibles de présenter un effet bénéfique contre le SARS-CoV-2 ? L'objectif de la présente revue est d'investiguer ces deux interrogations sur la base des informations données par la littérature. La recherche bibliographique a appliqué une méthode mixte avec une revue systématique des données liées au COVID-19 / SRAS-CoV-2 (jusqu'au 01/12/20) et une revue consensuelle pour d'autres informations (en particulier les risques iatrogènes associés aux psychotropes). Afin d'envisager la sécurité clinique des psychotropes nous aborderons successivement : (i) les risques de complications symptomatologiques de la COVID-19 liés aux psychotropes avec les impacts en termes de dépression de l'activité centrale, de risque d'allongement de l'intervalle QT, de complications infectieuses et thromboemboliques, puis (ii) les risques de confusion diagnostique entre l'impact iatrogène lié aux psychotropes et les symptômes de la COVID-19. Une synthèse est ensuite proposée sur les différentes informations disponibles à ce jour par psychopathologies, en lien avec leurs traitements psychopharmacologiques, dans le contexte de la COVID-19, dans la schizophrénie, les troubles de l'humeur, les troubles anxieux, le TDAH, mais également les troubles du sommeil et le risque suicidaire. La gestion des traitements de la schizophrénie résistante et de la dépression résistante au temps de la COVID-19 sera traitée. Tandis que les risques spécifiques liés aux traitements de la COVID-19 en termes d'impact psychogène et dépressogène sont également abordés. Les effets dépressogènes, avec de potentielles idées suicidaires, sont ainsi décrits avec les corticoïdes, l'interféron alpha, mais également la chloroquine et l'hydroxychloroquine. Les effets psychotiques aigus sont quant à eux rapportés avec les corticoïdes, la chloroquine et l'hydroxycloroquine. L'anakinra, anti-IL-1 et le tocilizumab, anti-IL-6, pour leur action de régulation des cytokines pro-inflammatoires, impliquées dans l'immunopathologie du COVID-19, pourraient présenter un intérêt pour lutter contre les complications neuropsychiatriques de la COVID-19. La problématique spécifique des substances psychoactives au temps de la COVID est également décrite. En cas de COVID-19 avec une symptomatologie respiratoire importante, l'impact de l'arrêt du tabac sur le métabolisme des psychotropes peut être conséquent et nécessiter des adaptations posologiques pour les traitements pris en charge par le CYP1A2. Les publications et sites web de référence pour s'informer sur les psychotropes dans le contexte de la COVID-19 sont référencés afin de faire le point sur les adaptations de prescriptions proposées, ainsi que les interactions médicamenteuses entre psychotropes et les traitements de la COVID-19. Ces données s'appuient notamment sur les informations proposées: (i) par une revue de la littérature établissant des recommandations pratiques fondées sur des preuves (structurée par le centre de référence de l'OMS en santé mentale de l'Université de Vérone), (ii) par les

Introduction

The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic raised great uncertainty regarding psychotropic drugs. Their potential dangerousness as a risk factor for the development of infections or complications comparable to those of COVID-19 (coronavirus disease 2019) has been established [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF], however the possibility of some of them being proposed as a prevention strategy for SARS-CoV-2 is emerging [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Javelot | Psychoactive compounds as multifactorial protection factors against COVID-19[END_REF][START_REF] Plaze | Repurposing chlorpromazine to treat COVID-19: The reCoVery study[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF]. A large number of recommendations have been proposed worldwide, particularly in the field of pharmacotherapy. These concern both therapeutic strategies to combat COVID-19 and proposals for adapting patients' current prescriptions in diverse medical specialties (emergency medicine, infectiology, cardiology, oncology, etc.). In Psychiatry, the first recommendations addressing medications were very general, simply proposing to weight the risks associated with psychotropic drugs [START_REF] Carvalho | The psychiatric impact of the novel coronavirus outbreak[END_REF]. Since then, more targeted recommendations have been proposed for certain drugs such as clozapine [START_REF] Siskind | Consensus statement on the use of clozapine during the COVID-19 pandemic[END_REF] and long-action antipsychotics [START_REF] Ifteni | Long-acting injectable antipsychotics treatment during COVID-19 pandemic -A new challenge[END_REF]. The first more assertive recommendations on psychotropic treatments were formalized (i) in France by the AFPBN (Association Française de Psychiatrie Biologique et de Neuropsychopharmacologie) -in their consensus-based guidelines [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF] (ii) in England by the University of Oxford with broad recommendations for mental health and more targeted ones for several classes of psychotropic drugsevidence-based guidelines [START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF][START_REF] Smith | Covid-19 and mental health: a transformational opportunity to apply an evidence-based approach to clinical practice and research[END_REF]. These different guidelines address: (i) the potential difficulty to adapt to a very dynamic, ever changing scenario [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF][START_REF] Smith | Covid-19 and mental health: a transformational opportunity to apply an evidence-based approach to clinical practice and research[END_REF][START_REF] Javelot | Challenges for psychotropics in the context of the SARS-Cov-2 pandemic[END_REF][START_REF] Javelot | Psychopharmacotherapeutic guidelines : a challenge during health crisis[END_REF], (ii) the complexity for having to fully articulate these recommendations with somatic concerns and their treatments [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]. At the very least, the consensus idea that certain common treatments which do not require excessive monitoring, such as Selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics or sodium valproate could continue to be administered normally, while other treatments such as lithium, clozapine and benzodiazepines, because of their specific risks, require the elaboration of adapted recommendations [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF][START_REF] Smith | Covid-19 and mental health: a transformational opportunity to apply an evidence-based approach to clinical practice and research[END_REF][START_REF] Chatterjee | Impact of COVID-19 pandemic on pre-existing mental health problems[END_REF]. More recently, a structured literature review (WHO RAGs -World Health Organization and Rapid Advice Guidelines), which notably followed the AGREE and AMSTAR-2 methodologies (Appraisal of Guidelines for REsearch & Evaluation and A Measurement Tool to Assess Systematic Reviews, in order to assess the methodological rigour of guidelines and reviews) has been proposed to assess the safety of psychotropics in people with COVID-19 [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF]. In parallel with these recommendations, which essentially address the clinical safety of psychotropics, information on the potential prophylactic or curative nature of some of these molecules has rapidly spread. Thus, in April 2020, the anti-SARS-CoV-2 potential of haloperidol [START_REF] Gordon | A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing[END_REF] and chlorpromazine [START_REF] Plaze | Repurposing chlorpromazine to treat COVID-19: The reCoVery study[END_REF] was discussed in the literature. These data have since been supplemented by expanded lists of psychotropic drugs potentially relevant for SARS-CoV-2 prophylaxis based on the low initial prevalence of COVID-19 in mental health settings [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] El-Khoury | Low prevalence of SARS-CoV-2 among patients presenting at a Parisian psychiatry University Hospital Group[END_REF].

Central Nervous System Depression

Sedation and confusion

Fatigue and confusion can be found in 23% and 9%, respectively, of COVID-19 patients [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]. While their frequency and intensity don't represent cause for alarm, when associated with sedative psychotropic drugs, there might be a cause for concern in mental health patients. Because of the risk of potentializing sedation, the impact of the following treatments is relevant, especially when using high doses and/or combinations of these medications: opiates (analgesics, antitussives and substitution treatments), antipsychotics -1 st and 2 nd generation -, mood stabilizers and/or antiepileptics (e.g. lithium, valproate, carbamazepine, gabapentinoids), barbiturates, benzodiazepines and z-drugs, non-benzodiazepine anxiolytics (e.g. meprobamate), sedative antidepressants (agomelatine, tricyclics -especially those with strong antihistamine effects: doxepin and trimipramine -, mianserin and mirtazapine, trazodone, esketamine), sedative H1 antihistamines, centrally acting antiemetics (e.g. metoclopramide, metopimazine), antimigraine medications, central antihypertensives and other drugs such as baclofene, thalidomide and lenalidomide, sodium oxybate, ropinirole, tetrabenazine [START_REF] Javelot | Psychoactive compounds as multifactorial protection factors against COVID-19[END_REF]. Confusion may be precipitated or accentuated by the sedative treatments mentioned above and the use of benzodiazepines and all treatments known to have anticholinergic effects should be carefully monitored. These effects should mostly be accounted for in elderly patients due to their greater sensitivity to these treatments and their adverse effects, which may be accentuated in cases of SARS-CoV-2 infection. For benzodiazepines, the risks of sedation, confusion and falls (excessive sedation/myorelaxation) must be weighted. For anticholinergic effects, there is an increased risk of confusion, but also peripheral side effects such as dry mouth and eyes, constipation, urinary retention. When addressing these effects, the use of anticholinergic impregnation scales is wise [START_REF] Ifteni | Long-acting injectable antipsychotics treatment during COVID-19 pandemic -A new challenge[END_REF][START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF].

Respiratory Symptoms

Symptoms such as dyspnea and cough are significant in patients affected by COVID-19 (59-82% and 31-55%, respectively) [START_REF] Javelot | Psychoactive compounds as multifactorial protection factors against COVID-19[END_REF]. These elements, associated with other, less frequent symptoms (sore throat, chest pain), also related to the respiratory sphere, lead to a reassessment of the relevance of psychotropic drugs, as well as other treatments, which may contribute to respiratory distress. The latter is indeed aggravated by drugs with sedative properties in conjunction with the combined effects of respiratory muscle weakness and a decrease in spontaneous respiratory effort. This well-known double impact caused by benzodiazepines (sedation and myorelaxation) can be problematic when combined with other treatments with central nervous system depressant effects (see above). Ostuzzi et al [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF] also warn against highly sedating antipsychotics (typically first generation antipsychotics, e.g. phenothiazines and their derivatives), in addition to benzodiazepines, with associated risk factors such as high doses, polypharmacy and preexisting respiratory disturbances. In addition to the respiratory depression risk that has been established, the use of treatments that may contribute to the following should be monitored: (i) dyspnea; this adverse effect is reported in particular with all antipsychotics, but also with other substances used in the mental health setting, such as pramipexole, prazosin, beta-blockers such as propranolol and non-steroidal anti-inflammatory drugs (NSAIDs) [START_REF] Javelot | Psychoactive compounds as multifactorial protection factors against COVID-19[END_REF], (ii) nasal obstruction/congestion; such as with amitriptyline, phenothiazines and alprazolam, or rhinopharyngite-like infections with methylphenidate [START_REF] Javelot | Psychoactive compounds as multifactorial protection factors against COVID-19[END_REF][START_REF] Smith | Covid-19 and mental health: a transformational opportunity to apply an evidence-based approach to clinical practice and research[END_REF]. The risk of respiratory depression is well known for all opiates; in particular : alfentanil, buprenorphine, codeine, dextromethorphan, dihydrocodeine, ethyl morphine (codethyline), fentanyl, hydromorphone, methadone, morphine, nalbuphine, nalmefen, naloxone, naltrexone, noscapine, oxycodone, pethidine, pholcodine, remifentanil, sufentanil, tapentadol, tramadol. These include treatments that may be prescribed in COVID-19: (i) for pain management in the most severe cases (ii) as antitussive treatment (codeine, ethylmorphine (codethyline), dextromethorphan, noscapine, pholcodine are used as antitussive agents). Furthermore, these same treatments might be overused prior to COVID-19 by patients with addiction. All of these opium derivatives increase the risk of respiratory depression when associated with certain psychotropic drugs, in particular: benzodiazepines, barbiturates and sodium oxybate (used for narcolepsy, anesthesia and alcohol addiction).

These precautions appear to be particularly important for patients suffering from multiple drug addiction and likely to associate the substances, which poses more risk; benzodiazepines and morphine in particular and substitution treatments (buprenorphine and methadone). This problem can be of particular importance in North America and other countries affected by the opioid epidemic crisis [START_REF] Boyer | Medication-Assisted Treatment, and Increased Risk for Further Respiratory Depression[END_REF][START_REF] Lambert | Opioids and the COVID-19 pandemic: does chronic opioid use or misuse increase clinical vulnerability[END_REF]. It is also worth highlighting that benzodiazepines and depot antipsychotics should be prescribed with caution for elderly patients at higher risk of respiratory depression [START_REF] Vedavanam | Old age psychiatry services in the UK responding to COVID-19[END_REF].

The impact of sedation may also be mitigated when drugs are used as monotherapy and at standard dosages. For example, mirtazapine appears to be a potentially promising treatment for chronic breathlessness, while the use of benzodiazepines may be a good option to relieve the anxiety associated with dyspnea [START_REF] Javelot | Challenges for psychotropics in the context of the SARS-Cov-2 pandemic[END_REF][START_REF] Guina | Benzodiazepines I: Upping the Care on Downers: The Evidence of Risks, Benefits and Alternatives[END_REF][START_REF] Lowell | Mirtazapine for Chronic Breathlessness? A Review of Mechanistic Insights and Therapeutic Potential[END_REF]. Data recently proposed by Ostuzzi et al [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF] is reassuring about the use of antidepressants in people affected by COVID-19; they performed a study with a high AMSTAR-2 score and described the safety of these treatments in patients with chronic obstructive pulmonary disease (COPD) [START_REF] Ostuzzi | Efficacy and acceptability of antidepressants in patients with ischemic heart disease: systematic review and meta-analysis[END_REF][START_REF] Pollok | Pharmacological interventions for the treatment of depression in chronic obstructive pulmonary disease[END_REF]. However, more recent data regarding respiratory tolerance of antidepressants in COPD contradicted the latter results [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF]. Finally, it is worth noting the extra caution needed for psychotropic drugs with inhalant dosage forms. Inhaled loxapine is contraindicated (i) for patients with acute respiratory signs or symptoms, including dyspnea, and thus by extension any suspected or proven situation of COVID-19, (ii) for patients with active airway diseases, such as patients with asthma or chronic obstructive pulmonary disease, thus this precaution may also extend to COVID-19. About esketamine, in the presence of clinically significant or unstable respiratory disease, such as suspected or confirmed COVID-19, this treatment should be administered in an environment with appropriate equipment and personnel for cardiopulmonary resuscitation; careful weighing of the benefits and risks is therefore also essential in this context. The risk of sedation may be increased by the concomitant use of nasal esketamine and other central nervous system depressants. Such combined prescriptions require close monitoring of sedation and respiratory depression and are highly risky in a suspected or confirmed situation of COVID-19.

Headaches, sweating and hyperthermia

Headaches are particularly common side effects of medications in general and of psychotropic drugs in particular. They occur often to very frequently with most psychotropic drugs classes: antidepressants, antipsychotics, mood stabilizers, benzodiazepines and methylphenidate. These effects can be interpreted as potentially complicating viral symptomatology and as a possible source of confounding factors (see below). Hyperthermia and hyperhidrosis as psychotropic drugs side effects are intuitively associated with serotonergic syndromes, discontinuation syndromes under antidepressants and antipsychotics, and neuroleptic malignant syndrome; which we will discuss later. Nevertheless, regardless of these syndromes, antipsychotics can induce a wide variety of symptoms ranging from benign hyperthermia under clozapine, to hypothermia, while hyperhidrosis is observed with antidepressants (paroxetine, escitalopram, venlafaxine and duloxetine, in particular) and antipsychotics (clozapine, aripiprazole). Finally, hyperthermia related to anticholinergic effects is also well known and is associated with perspiration blockade [START_REF] Javelot | Psychoactive compounds as multifactorial protection factors against COVID-19[END_REF][START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF]. The deleterious aspect of these effects to a COVID-19 setting must be anticipated, particularly in the elderly population, in which these effects are more dangerous [START_REF] Javelot | Psychoactive compounds as multifactorial protection factors against COVID-19[END_REF][START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF].

Treatments with risk of QTc prolongation

Overall, the American reference site CredibleMeds (https://crediblemeds.org; [START_REF] Woosley | CredibleMeds.org: What does it offer?[END_REF] -from the Arizona Center for Education and Research on Therapeutics (AZCERT)) is a great consultation resource to obtain an exhaustive list of substances which may cause QTc prolongation; this ranking should nevertheless be considered within each countryspecific recommendations in this field [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]. Crediblemeds offers a classification in 4 categories: drugs with known risk of torsade de pointe (TdP), possible risk of TdP, conditional risk of TdP and drugs to be avoided by patients with congenital long QT. The problem of QTc prolongation in the context of COVID-19 for mental health patients is multi-level. There is an established interaction of SARS-CoV-2 with the renin-angiotensin-aldosterone system which can cause sometimes severe hypokalemia and is an important risk factor for the occurrence of TdP [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Bansal | Cardiovascular disease and COVID-19[END_REF][START_REF] Chen | Hypokalemia and clinical implications in patients with coronavirus disease[END_REF][START_REF] Vandael | Risk factors for QTc prolongation: systematic review of the evidence[END_REF]. This is even more relevant because many psychotropic drugs, as well as drugs proposed for the treatment of COVID-19, have been shown to increase the QT interval [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Javelot | COVID-19 and (hydroxy)chloroquine-azithromycin combination: Should we take the risk for our patients?[END_REF]. Thus, patients suffering from mental health disorders, infected with CoV-2-SARS and treated with, for example, hydroxychloroquine or chloroquine and/or azithromycin -and particularly if these treatments are combined -should be carefully evaluated for the benefit/risk ratio of these medications, particularly regarding the risk of their psychotropic treatments to cause QTc prolongation [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Javelot | COVID-19 and (hydroxy)chloroquine-azithromycin combination: Should we take the risk for our patients?[END_REF][START_REF] Mansuri | Risk of QTc prolongation with Chloroquine/Hyroxychloroquine and Azithromycin treatment for COVID-19: Quantification and precautions for a busy clinician[END_REF][START_REF] Sciaccaluga | COVID-19 and the burning issue of drug interaction: never forget the ECG[END_REF]. Monitoring the QTc, but also of potassium levels is essential in these high risk situations. Indeed, multiple risk factors are presented in the literature for QTc prolongation: female sex, age over 65 years, personal or family cardiovascular history, liver and/or kidney failure, electrolyte disorders, and a recent study has particularly highlighted the specific risks of hypokalemia, antiarrhythmic drugs and drugs with a known risk of torsade de pointe in the CredibleMeds classification [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Vandael | Risk factors for QTc prolongation: systematic review of the evidence[END_REF]. These elements thus imply a constant re-evaluation of the benefit/risk ratio of those treatments. Vomiting and diarrhea potentially induced by COVID-19 are also sources of digestive potassium loss that can induce hypokalemia, which should also be monitored and treated.

In addition to these situations, there are also potentially risky associations with treatments that may alleviate the symptoms of COVID-19, particularly digestive symptoms, and which may be dangerous, particularly for patients suffering from mental health disorders [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]. For example, the use of drugs such as metoclopramide and metopimazine can generate extrapyramidal syndrome and increase the risk of its occurrence when combined with neuroleptics [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]. Metoclopramide may also induce neuroleptic malignant syndrome or serotonin syndrome [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]. Moreover, domperidone and metoclopramide pose risks for QTc prolongation and are classified with "known risk" and "conditional risk" respectively, in the Crediblemeds classification (https://crediblemeds.org). Recent pharmacovigilance data seem to validate the safety of metopimazine for QTc [START_REF] Rochoy | Réseau français des centres régionaux de pharmacovigilance. Antiemetics and cardiac effects potentially linked to prolongation of the QT interval: Case/non-case analysis in the national pharmacovigilance database[END_REF]. For the respiratory system, the danger may come from short-acting inhaled β2-mimetics, such as salbutamol (or albuterol), in the case of dyspnea, which are quickly identified by patients as some soothing treatments and may induce drug overuse [START_REF] Javelot | Panic and pandemic: Narrative review of the literature on the links and risks of panic disorder as a consequence of the SARS-CoV-2 pandemic[END_REF]. Hypokalemia is also a well-known risk with β2-agonist treatments, particularly at high doses, in combination with other hypokalemic drugs and/or in hypokalemia-inducing situations [START_REF] Javelot | Panic and pandemic: Narrative review of the literature on the links and risks of panic disorder as a consequence of the SARS-CoV-2 pandemic[END_REF]. These elements therefore call for caution with the use of these anti-asthmatic treatments which, when combined with risky psychotropic drugs and with the hypokalemia induced by COVID-19, could contribute to the occurrence of torsades de pointes. The recommendations provided so far in the literature on anti-psychotics are generally consensual regarding the risk on QT [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF][START_REF] Chatterjee | Impact of COVID-19 pandemic on pre-existing mental health problems[END_REF][START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF][START_REF] Bishara | Emerging and experimental treatments for COVID-19 and drug interactions with psychotropic agents[END_REF]. Regarding antidepressants, a recent update on QTc prolongation risks unsurprisingly identified citalopram and, by extrapolation, escitalopram as the drug which carries the biggest risk of QTc prolongation [START_REF] Beach | QT prolongation, Torsades de Pointes, and Psychotropic Medication: a 5-Year update[END_REF]. For this reason, the initial orientation (acute phase) towards citalopram and escitalopram in a SARS-CoV-2 pandemic situation, for reasons of tolerance and minimal interactions with CYP450, may appear questionable especially in the at-risk populations mentioned above [START_REF] Zhang | Treatment concerns for psychiatric symptoms in patients with COVID-19 with or without psychiatric disorders[END_REF]. Overall, it is recommended that patients taking medications which increase risk for QTc prolongation and have COVID-19 should have regular potassium measurements and ECG monitoring. Reevaluation of combined treatments which increase risk of QTc prolongation (associations between psychotropic drugs at risk or psychotropic drugs at risk + antiarrhythmic drugs) should be done in all cases. Beyond QTc, antipsychotics usage has been associated with serious cardiovascular events like stroke, sudden cardiac death and myocardial infarction and this risk could be higher in the elderly [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF][START_REF] Papola | Antipsychotic use and risk of life-threatening medical events: umbrella review of observational studies[END_REF], whereas antidepressants appears safe in patients with ischemic heart disease and depression in a meta-analysis mainly concerning SSRIs [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF][START_REF] Ostuzzi | Efficacy and acceptability of antidepressants in patients with ischemic heart disease: systematic review and meta-analysis[END_REF].

Risks of infectious complications

The links between infectious complications and the use of psychotropic drugs are complex. There are contradictory theories regarding antipsychotic use and its effect on immunity [START_REF] Baumeister | Effects of psychotropic drugs on inflammation: consequence or mediator of therapeutic effects in psychiatric treatment?[END_REF], without calling into question the relevance of the global approach to immunopsychiatry, particularly in psychotic disorders [START_REF] Leboyer | Is it time for immunopsychiatry in psychotic disorders?[END_REF]. If, for example, schizophrenic patients appear to be more susceptible to infections, the involvement of antipsychotics in this phenomenon is not clearly defined [START_REF] May | The antipsychotic medication, risperidone, causes global immunosuppression in healthy mice[END_REF]. Nevertheless, recent data have made it possible to affirm that in patients aged 65 or over, hospitalized for pneumonia, an association was found between the use of second-generation antipsychotics and increased mortality, particularly in those suffering from previous mental or cardiac disorders [START_REF] Boivin | Association of atypical antipsychotics and mortality for patients hospitalised with pneumonia[END_REF]. Rajamaki et al [START_REF] Rajamaki | Psychotropic Drug-Associated Pneumonia in Older Adults[END_REF] recently showed that the use of antipsychotics, benzodiazepines and z-substances is associated with an increased risk of pneumonia in the elderly, while there was insufficient data for antidepressants and antiepileptics. Regarding antipsychotics, Dzahini et al [START_REF] Dzahini | Antipsychotic drug use and pneumonia: Systematic review and metaanalysis[END_REF] observed that those with sufficient data in the literature are all associated with an increased risk of pneumonia: haloperidol, olanzapine, clozapine, risperidone, quetiapine and zotepine. The authors urge caution in patients initiating antipsychotic therapy and particularly in those with other risk factors for pneumonia (older age, chronic respiratory disease, smoking, dysphagia and cerebrovascular disease) [START_REF] Dzahini | Antipsychotic drug use and pneumonia: Systematic review and metaanalysis[END_REF]. Pneumonia is also reported to occur more frequently and with more fatal consequences with clozapine than with other second-generation antipsychotics [START_REF] De Leon | Pneumonia may be more frequent and have more fatal outcomes with clozapine than with other second-generation antipsychotics[END_REF]. In addition, data from Yang et al. [START_REF] Yang | Antipsychotic drugs, mood stabilizers, and risk of pneumonia in bipolar disorder: a nationwide case-control study[END_REF] had revealed that certain mood stabilizing combinations may be at greater risk of inducing pneumonia -olanzapine + carbamazepine and clozapine + valproic acid -contributing to an overall caution about the dangers of polypharmacy in general and with psychotropic drugs [START_REF] Rajamaki | Psychotropic Drug-Associated Pneumonia in Older Adults[END_REF]. While the mechanism behind antipsychotic-induced pneumonia remains poorly understood, different neurotransmitters seem to be involved: dopaminergic, serotonergic, cholinergic, histaminergic, but also actions linked to the receptors of the thromboxane A2 (TBXA2R) and the platelet activating factor (PTAFR) [START_REF] Sultana | Biological substantiation of antipsychotic-associated pneumonia: Systematic literature review and computational analyses[END_REF]. Among all these transmitters, anticholinergic effects are well-known to increase the risk of aspiration pneumonia by contributing to a succession of deleterious effects including dry mouth, swallowing disorders and decreased cough reflex [START_REF] Trifirò | Antipsychotic drug use and community-acquired pneumonia[END_REF]. The contribution of these effects in pneumonia in elderly subjects may be particularly important [START_REF] Paul | Anticholinergic medications and risk of community-acquired pneumonia in elderly adults: a population-based case-control study[END_REF][START_REF] Chatterjee | Anticholinergic Medication Use and Risk of Pneumonia in Elderly Adults: A Nested Case-Control Study[END_REF]. Although the specific risk of aggravation of COVID-19 pneumonia by antipsychotic drugs has not been established, overall, the above data suggest caution. Elements of specific vigilance include: (i) the introduction and use of clozapine (see recommendations below), (ii) the use of antipsychotic drugs in the elderly, with specific consideration of: their risk of complications and death related to COVID-19, sensitivity to polypharmacy and to anticholinergic effects in particular, the need to re-evaluate these treatments and to adopt, whenever possible, the shortest possible treatment duration. Finally, it should be noted that the risk of infectious complications is increased during neutropenia/agranulocytosis and that certain psychotropic drugs are at high risk of causing this effect. Among the antipsychotic drugs, clozapine is the most known to cause this adverse effect, but phenothiazines and to a lesser extent olanzapine and quetiapine also can cause, yet very rarely, this adverse effect and the other antipsychotic drugs are not without danger [START_REF] Flanagan | Haematological toxicity of drugs used in psychiatry[END_REF]. Regarding mood stabilizers, although less risky than clozapine, carbamazepine, oxcarbazepine and to a lesser extent valproate and its derivatives can also lead to neutropenia/agranulocytosis [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF][START_REF] Flanagan | Haematological toxicity of drugs used in psychiatry[END_REF][START_REF] Murru | Management of adverse effects of mood stabilizers[END_REF]. To sum up, the amount of influence of psychotropic drugs in the risk of infection remains uncertain, except for the objective situations of neutropenia/agranulocytosis. The systematic review data in this field appear particularly weak (see [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF]: the only review selected by the working group on the side of infectiology is that of [START_REF] Dzahini | Antipsychotic drug use and pneumonia: Systematic review and metaanalysis[END_REF] with an AMSTAR-2 score classified as "critically low").

Risks of thromboembolic events

The link between infections and thromboembolic events is well known [START_REF] Beristain-Covarrubias | Understanding Infection-Induced Thrombosis: Lessons Learned From Animal Models[END_REF][START_REF] Yu | Viral infection related venous thromboembolism: potential mechanism and therapeutic targets[END_REF], while the specific link between COVID-19 and such complications is now widely established [START_REF] Barnes | Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum[END_REF][START_REF] Boccia | COVID-19 and coagulative axis: review of emerging aspects in a novel disease[END_REF][START_REF] Stoneham | Thrombotic risk in COVID-19: a case series and case-control study[END_REF]. Data from China, the Netherlands and Italy early described the significant risks of global thromboembolic events (venous and arterial), venous thromboembolism and pulmonary embolism during COVID-19 [START_REF] Barnes | Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum[END_REF]. The risk factors of venous thromboembolism are known and include: age, acute infection, cancer, previous venous thromboembolism, prolonged immobility, recent major surgery, obesity, and chronic heart or respiratory failure [START_REF] Samama | A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group[END_REF].

The presence of two risk factors can be considered as a clinical situation close to that of hospitalized patients, for whom thromboprophylaxis is recommended. COVID-19, thus induces many high-risk situations for patients with acute infection and for whom the risk of immobilization is increased: by the disease itself, particularly in the case of active viral pneumopathy, but also by recommendations for confinement and/or social distancing (reduction in the number of discharges, visits). The first risk linked to psychotropic drugs is the contribution to immobility through excessive sedation. This effect can appear mainly at the initiation of a new treatment and with a drug recognized for having sedative effects (see previous chapter: Risk of depression of central activity -Sedation and confusion). Many factors must be considered in order to explain the increased risk of venous thromboembolism under antipsychotic drugs. Sedation and weight gain appear to be the most reliable and constant ones by increasing immobility and venous stasis in the lower extremities [START_REF] Jönsson | Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence[END_REF]. Nevertheless, hyperprolactinemia, antiphospholipid antibodies, acute phase of a psychotic illness with physical restraint or situations with catatonic syndromes, highsensitive C-reactive protein (CRP) and other inflammatory markers or hyperhomocysteinemia represent other factors likely to increase the risk of venous thromboembolism [START_REF] Jönsson | Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence[END_REF]. In a large retrospective study, a statistically significant increase in risk of pulmonary embolism was observed in antipsychotics users compared with non-users, while clozapine users had the highest risk, a smaller risk was also noted for users of chlorpromazine, haloperidol, olanzapine, risperidone and ziprasidone and the risk is dose dependent [START_REF] Allenet | Antipsychotic drugs and risk of pulmonary embolism[END_REF]. Antidepressants, as well as depression itself, have been cited as risk factors for venous thromboembolism, but conflicting data exists in the literature [START_REF] Kunutsor | Depression, antidepressant use, and risk of venous thromboembolism: systematic review and meta-analysis of published observational evidence[END_REF][START_REF] Wang | Antidepressant Use and Risk of Venous Thromboembolism: A Systematic Review and Meta-Analysis[END_REF]. Despite the lack of data available concerning this risk with other psychotropic drugs, the contribution to an overall sedation increase, for example with benzodiazepines and mood stabilizers cannot be excluded [START_REF] Van Neste | Deep venous thrombosis and pulmonary embolism in psychiatric setting[END_REF], especially in the context of polypharmacy by psychotropics in elderly people.

The baseline risk of venous and pulmonary thromboembolism is known in COVID-19 and this risk increases in association with mainly antipsychotic drugs. These elements encourage caution, in a similar manner to what has been suggested for the risk of infection: (i) to know and anticipate the potentially negative vascular consequences of antipsychotics, particularly clozapine (see recommendations below), (ii) to take into account the overall sedative impact of psychotropic drugs, especially in case of sedative polypharmacy and this particularly in situations when other risk factors are present, including, as a priority, age.

Psychotropic drugs and the risk of diagnostic confusion with COVID-19

Please see Table 3 for information about psychotropic drugs' effects on symptoms of COVID-19 (adapted from Javelot et al. [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]).

Drug Withdrawal and Abstinence Syndrome

The SARS-CoV-2 pandemic is proving to be particularly anxiety-inducing for the general population and thus potentially a trigger of decompensation for patients suffering from mental health disorders. For one side, in the absence of a clear link between the dangerousness of psychotropic drugs and the evolution of COVID-19, the maintenance of the standard therapies for the mental wellbeing of patients must be a priority [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF][START_REF] Javelot | Psychoactive compounds as multifactorial protection factors against COVID-19[END_REF]. On the other hand, changes in current treatments that are not justified by the clinical evolution of the patient may expose patients to the following risks: (i) to decompensations of their mental health balance, potentially with all psychotropic drugs, and/or (ii) to withdrawal syndromes with benzodiazepines [START_REF] Guina | Benzodiazepines I: Upping the Care on Downers: The Evidence of Risks, Benefits and Alternatives[END_REF], antidepressants [START_REF] Wilson | A review of the management of antidepressant discontinuation symptoms[END_REF], antipsychotics [START_REF] Keks | Stopping and switching antipsychotic drugs[END_REF] or methylphenidate [START_REF] Ferreira | Withdrawal from methylphenidate increases neural reactivity of dorsal midbrain[END_REF].

It is important to note that the antidepressant discontinuation/withdrawal syndrome, mainly related to SSRIs and to a lesser extent to serotonin-norepinephrine reuptake inhibitors, may represent a major risk factor for differential diagnosis with COVID-19 and may include: influenza-like illness, headache, fatigue, dyspnea, myalgia, nausea, vomiting, diarrhea and confusion [START_REF] Fava | Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review[END_REF][START_REF] Fava | Withdrawal Symptoms after Serotonin-Noradrenaline Reuptake Inhibitor Discontinuation: Systematic Review[END_REF]. Benzodiazepine withdrawal syndrome may also induce some of these

Other iatrogenic syndromes causing diagnostic confusion

Among the iatrogenic situations that can cause diagnostic confusion with COVID-19, two should be highlighted: serotonin syndrome and neuroleptic malignant syndrome. The two syndromes have common symptoms, which can be seen in SARS-CoV-2 infection such as: sweat, hyperthermia, tachycardia, tachypnea, myalgia and confusion [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]. In serotonin syndrome, digestive symptoms -nausea and diarrhea -can also resemble COVID-19 symptoms. A long-term exposure to an excess of drugs with anticholinergic effects, which can also be qualified as a strong anticholinergic load, can contribute to confusion and increased body temperature. This situation should be acknowledged in elderly subjects in particular who are more sensitive to these effects. One of the relevant strategies is to re-evaluate current treatments using anticholinergic rating scales (for reviews see: [START_REF] Durán | Systematic review of anticholinergic risk scales in older adults[END_REF][START_REF] Salahudeen | Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review[END_REF]). Other iatrogenic scenarios which can lead to potential clinical confusion with COVID-19 are: the sympathomimetic toxidrome, often related to substances as cocaine, amphetamine and derivatives, but also albuterol [START_REF] Horowitz | Sympathomimetics[END_REF], and some hypersensitivity reactions as the drug reaction with eosinophilia and systemic symptoms (DRESS), notably observed with anticonvulsants and previously named "anticonvulsant hypersensitivity syndrome". Moreover, three situations may induce headaches usually linked to some psychotropic drugs: those occurring with lithium, associated with visual disturbances and that can be linked to a papilledema, those occurring with methylphenidate, which may suggest cerebrovascular disorders with cerebral vasculitis and those occurring with monoamine oxidase inhibitors, since it is known that occipital headaches can be associated with hypertensive crisis.

We will not discuss here the neuropsychiatric effects induced by treatments for COVID-19. We discuss it below with a specific focus on psychopathology. Note that the review of the literature by Bilbul et al. [START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF] exhaustively describes the issue of psychiatric adverse effects induced by COVID-19 treatments.

Index by mental health disorders

The stressful environment generated by the COVID-19 pandemic is likely to affect the psychological wellbeing of patients, in particular through a decrease in response to psychotropic treatments [START_REF] Amanzio | How Do Nocebo Phenomena Provide a Theoretical Framework for the COVID-19 Pandemic?[END_REF]. While anti-SARS-CoV-2 antibodies have been identified in the cerebrospinal fluid, the neurotropism of SARS-CoV-2 has also been established, with potentially significant impacts on the dopaminergic and serotonergic systems, leading to the aggravation, or even emergence, of psychotic manifestations or mood disorders [START_REF] Attademo | Are dopamine and serotonin involved in COVID-19 pathophysiology?[END_REF][START_REF] Butler | Neuropsychiatric complications of covid-19[END_REF][START_REF] Diaz | The role of neurotropism in psychiatric patients with COVID-19[END_REF]. Other acute neuropsychiatric symptoms have already been observed in patients infected with CoV-2-SARS notably, post-traumatic stress disorder, catatonia, suicidal ideation, seizures, cerebrovascular complications, encephalopathy, encephalitis, neuromuscular disorders, anosmia, ageusia, headache, sleep disorders and disabling fatigue [START_REF] Nalleballe | Spectrum of neuropsychiatric manifestations in COVID-19[END_REF][START_REF] De Sousa Moreira | The psychiatric and neuropsychiatric repercussions associated with severe infections of COVID-19 and other coronaviruses[END_REF] or cognitive difficulties, after discharge, in the context of « long covid » (or chronic covid syndrome or CCS) [START_REF] Butler | Neuropsychiatric complications of covid-19[END_REF]. In this regard, the contribution of anakinra, anti-IL-1 and tocilizumab, anti-IL-6, to decrease the action of proinflammatory cytokines, involved in the immunopathology of COVID-19 (cytokine storm involves release of IL-1β and IL-6), could be of interest in order to study the therapeutic effect of cytokine-blocking agents on the neuropsychiatric complications in survivors of severe form of COVID-19 [START_REF] Benedetti | Can Cytokine Blocking Prevent Depression in COVID-19 Survivors?[END_REF].

Schizophrenia

Psychosis and COVID-19

The SARS-CoV-2 pandemic caused both decompensation of stabilized patients [START_REF] Palomar-Ciria | Schizophrenia and COVID-19 delirium[END_REF][START_REF] Ovejero | Coronovirus infection as a novel delusional topic[END_REF], as well as the emergence of psychotic episodes in individuals with no psychiatric history but presumably affected by the global fear context raised by the pandemic [START_REF] Huarcaya-Victoria | Psychosis in a patient with anxiety related to COVID-19: A case report[END_REF][START_REF] Majadas | A case with psychotic disorder as a clinical presentation of COVID-19[END_REF][START_REF] Parra | Psychotic symptoms in COVID-19 patients. A retrospective descriptive study[END_REF][START_REF] Rentero | New-onset psychosis in COVID-19 pandemic: a case series in Madrid[END_REF] and the context of the quarantine [START_REF] Finatti | Psychosis in Patients in COVID-19-Related Quarantine: A Case Series[END_REF]. Beyond these data, the emergence of psychotic symptoms in patients affected by COVID-19 seems to be associated with age, with the appearance of acute delirium in patients already showing cognitive decline [START_REF] Beach | Delirium in COVID-19: A case series and exploration of potential mechanisms for central nervous system involvement[END_REF][START_REF] Varatharaj | Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study[END_REF]. In a follow-up of neurological and neuropsychiatric symptoms of 153 patients, with an average age of 71 years, affected by COVID-19, 10 of 23 patients with neuropsychiatric disorders experienced new-onset psychosis. While other data from the literature estimate that 0.9 to 4% of infected individuals by the SARS-CoV-2 could develop psychotic spectrum disorders [START_REF] Dinakaran | Neuropsychiatric aspects of COVID-19 pandemic: A selective review[END_REF]. More recently Watson et al. [START_REF] Watson | COVID-19 and psychosis risk: Real or delusional concern?[END_REF] reported 42 cases of psychosis in patients infected with SARS-CoV-2 and discussed the potential neurodevelopmental implications of in utero infection and subsequent psychiatric risks.

Multiple causes can be identified for the onset of an acute psychotic episode, but it is clear that their emergence associated with an SARS-CoV-2 infection prompts both (i) to conceive the immunological and neuroinflammatory pathway as a likely cause of these disorders, by following central and peripheral markers of inflammation, (ii) to consider that beyond antipsychotics, infection-fighting treatments, and in particular immunomodulators, may be effective in combating the psychotic episodes observed [START_REF] Ferrando | COVID-19 Psychosis: A Potential New Neuropsychiatric Condition Triggered by Novel Coronavirus Infection and the Inflammatory Response?[END_REF]. Such results could be observed with tocilizumab, which leads to IL-6 inhibition and could improve cognition in schizophrenia [START_REF] García | Covid-19 treatment-induced neuropsychiatric adverse effects[END_REF][START_REF] Miller | An open-label, pilot trial of adjunctive tocilizumab in schizophrenia[END_REF]. Aware of the potential vulnerability of schizophrenic patients in the pandemic, the risk of interrupting medication should be anticipated and the role of professionals and families is crucial for adherence to antipsychotic treatment and sometimes to ensure access to prescriptions and to the drugs delivery [START_REF] Maguire | Vulnerability of people with schizophrenia to COVID-19[END_REF][START_REF] Fonseca | Schizophrenia and COVID-19: risks and recommendations[END_REF]. Regardless of its origin, the emergence of an acute psychotic episode in cases of SARS CoV-2 infection provides an incentive to build on the information available in the literature on managing agitation in individuals affected by COVID-19 [START_REF] Baller | Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19[END_REF][START_REF] Ostuzzi | Pharmacological treatment of hyperactive delirium in people with COVID-19: rethinking conventional approaches[END_REF][START_REF] Meagher | Developing a guidance resource for managing delirium in patients with Covid-19[END_REF][START_REF] Ojeahere | Management of psychiatric conditions and delirium during the COVID-19 pandemic across continents: lessons learned and recommendations[END_REF][START_REF] Wong | Management of Agitation During the COVID-19 Pandemic[END_REF]. As a preamble, it should be recalled that the risk of delirium, regardless of infectious causes, may be occasionally increased by benzodiazepines, antipsychotics and tricyclic antidepressants, with the latter two classes also having potentially anticholinergic effects, particularly in the elderly [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Ostuzzi | Pharmacological treatment of hyperactive delirium in people with COVID-19: rethinking conventional approaches[END_REF][START_REF] Clegg | Which medications to avoid in people at risk of delirium: a systematic review[END_REF].

In a more structured approach, quetiapine and dexmedetomidine compared with placebo in intensive care units and aripiprazole, quetiapine and risperidone in patients with acute psychosis or dementia, showed some potential benefits for agitation [START_REF] Ostuzzi | Pharmacological treatment of hyperactive delirium in people with COVID-19: rethinking conventional approaches[END_REF]. Haloperidol and other conventional neuroleptics appear to be less relevant because of their adverse effects, including impact on QT and the risk of extrapyramidal symptoms [START_REF] Ostuzzi | Pharmacological treatment of hyperactive delirium in people with COVID-19: rethinking conventional approaches[END_REF][START_REF] Wong | Management of Agitation During the COVID-19 Pandemic[END_REF], while olanzapine and benzodiazepines may appear to be at greater risk of sedation and/or contribute more to respiratory depression [START_REF] Meagher | Developing a guidance resource for managing delirium in patients with Covid-19[END_REF][START_REF] Wong | Management of Agitation During the COVID-19 Pandemic[END_REF]. A recent network meta-analysis, however, showed that the best strategies for delirium treatment and prevention were haloperidol plus lorazepam and ramelteon, olanzapine, risperidone, and dexmedetomidine, respectively, in placebo/control comparative data [START_REF] Wu | Association of Delirium Response and Safety of Pharmacological Interventions for the Management and Prevention of Delirium: A Network Meta-analysis[END_REF]. Interestingly, Baller et al. [START_REF] Baller | Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19[END_REF], highlight the use of alpha-2 agonist, dexmedetomidine and clonidine, before resorting to antipsychotics, for delirium with cases with COVID-19. These strategies could prove particularly interesting from the perspective of acute delirium situations associated with the COVID-19 cytokine storm, since catecholamines, including norepinephrine (NE), play a role in this potentially lethal evolution and the alpha-2 agonists such as clonidine, guanfacine, dexmedetomidine, with other NE modulators (e.g. propranolol, prazosin), could be useful therapeutic choices [START_REF] Fitzgerald | Noradrenergic and serotonergic drugs may have opposing effects on COVID-19 cytokine storm and associated psychological effects[END_REF]. Recommendations on the use of psychotropic drugs in acute agitation in patients with COVID-19 may also change. Various elements encourage us to anticipate the deleterious impact that SARS-CoV-2 can have on the dopaminergic system and to reflect on the consequences of a subsequent blockage through the use of an antipsychotic. The SARS-CoV, related to the SARS-CoV-2, induces an angiotensin-converting enzyme (ACE) 2 receptors down-regulation which are significantly co-expressed with dopa decarboxylase (DDC) and could in turn induce a dopamine synthesis alteration [START_REF] Yavarpour-Bali | Update on neurological manifestations of COVID-19[END_REF]. Preliminary data also indicates that patients with Parkinson's are mostly requiring additional levodopa dosage following infection by the SARS-CoV-2 [START_REF] Nataf | An alteration of the dopamine synthetic pathway is possibly involved in the pathophysiology of COVID-19[END_REF], while cases of catatonia syndromes have also been reported in COVID-19 delirium [e.g. [START_REF] Baller | Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19[END_REF][START_REF] Caan | A Case of Catatonia in a Man With COVID-19[END_REF][START_REF] De Araujo | Life-Threatening Catatonia Associated With Coronavirus Disease[END_REF][START_REF] Zandifar | Exacerbation of psychosis accompanied by seizure and catatonia in a patient with COVID-19: A case report[END_REF]. This information notably guided the cautious recommendations of neurologists in the face of delirium in a COVID-19 situation by encouraging the use of melatonin in first intention, then alpha-2 agonists, before considering a partial dopaminergic agonist antipsychotic as aripiprazole specifically for hypoactive delirium with perceptual disturbance [START_REF] Baller | Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19[END_REF]. The possible impact of the anticholinergic effects of some antipsychotics in the aggravation of the COVID-19 cytokine storm must also be evaluated. These elements may guide the choice of antipsychotic treatments in the elderly, for which COVID-19 occurs in a context of immunosenescence and may lead to the disruption of the cholinergic anti-inflammatory pathway [START_REF] Pomara | Impairment of the cholinergic anti-inflammatory pathway in older subjects with severe COVID-19[END_REF].

COVID-19 treatments and psychotic episodes

Among the COVID-19 treatments likely to induce an acute psychotic episode, chloroquine and hydroxychloroquine have so far been the most reported treatments and indeed, there is a neuropsychiatric effect both severe and known with these substances [START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF][START_REF] Akkaoui | Chloroquine-Induced First-Episode Psychosis in a Patient Selfmedicated for COVID-19[END_REF][START_REF] Biswas | Hydroxychloroquine and chloroquine for COVID-19: psychiatric aspects of patient safety considerations[END_REF][START_REF] Garcia | Psychiatric Disorders and Hydroxychloroquine for Coronavirus Disease 2019 (COVID-19): A VigiBase Study[END_REF][START_REF] Gressier | Psychiatric Side Effects of Chloroquine[END_REF][START_REF] Hamm | Psychiatric Aspects of Chloroquine and Hydroxychloroquine Treatment in the Wake of Coronavirus Disease-2019: Psychopharmacological Interactions and Neuropsychiatric Sequelae[END_REF][START_REF] Stip | Psychiatric adverse events with hydroxychloroquine during COVID-19 pandemic[END_REF][START_REF] Uvais | The Risks of Prescribing Hydroxychloroquine in COVID-19-Infected Patients With Schizophrenia[END_REF]. Moreover, corticosteroids can induce cognitive impairment, psychosis and mood J o u r n a l P r e -p r o o f changes and the significant predictive factors are notably prednisone use more than 40 mg/day and a history of psychiatric disorders [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF][START_REF] García | Covid-19 treatment-induced neuropsychiatric adverse effects[END_REF][START_REF] Ricoux | Troubles psychiatriques induits par la corticothérapie orale : mise au point sur la nature, l'incidence, les facteurs de risque et le traitement[END_REF]. Delirium has also been rarely reported with azithromycin and colchicine [START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF][START_REF] García | Covid-19 treatment-induced neuropsychiatric adverse effects[END_REF]. Furthermore, as we mentioned previously, tocilizumab could appear as a cognitive protection agent in the event of a psychotic episode [START_REF] García | Covid-19 treatment-induced neuropsychiatric adverse effects[END_REF][START_REF] Miller | An open-label, pilot trial of adjunctive tocilizumab in schizophrenia[END_REF]. Psychotic symptoms in ten patients infected by the SARS-CoV-2 with no previous history of psychosis were characterized in all cases by delusions (50% described as highly structured), orientation/attention disturbances (60%), auditory and visual hallucinations (40% and 10%), but nine patients had been also previously treated with hydroxychloroquine and antibiotics (all), lopinavir/ritonavir (n=6), tocilizumab (n=6), corticosteroids (n=7) [START_REF] Parra | Psychotic symptoms in COVID-19 patients. A retrospective descriptive study[END_REF]. Such data also show the complex imputability of COVID-19 related psychosis between the infection and iatrogenic origin. Finally, it should be noted that in May, the Spanish Pharmacology Agency reported the occurrence of neuropsychiatric disorders, including acute symptoms of psychosis, but also suicide attempts or suicides, in COVID-19 patients treated with hydroxychloroquine [116].

Management of treatment resistant schizophrenia in COVID-19

Among the new pharmacotherapeutic recommendations in the context of SARS-CoV-2 pandemic, those regarding clozapine were established very quickly [START_REF] Siskind | Consensus statement on the use of clozapine during the COVID-19 pandemic[END_REF]. These were guided by the known hematological adverse effects this medication may cause, the potential difficulty in maintaining the necessary monitoring during a pandemic, the recently objectified increased risk of pulmonary infections and finally by the risk of clozapine toxicity related to infection due to inhibition of cytochrome P450 1A2 by cytokines [START_REF] Siskind | Consensus statement on the use of clozapine during the COVID-19 pandemic[END_REF][START_REF] De Leon | Pneumonia may be more frequent and have more fatal outcomes with clozapine than with other second-generation antipsychotics[END_REF][START_REF] Clark | Elevated clozapine levels associated with infection: A systematic review[END_REF]. These recommendations of Siskind et al. [START_REF] Siskind | Consensus statement on the use of clozapine during the COVID-19 pandemic[END_REF] propose: (i) that the frequency of CBC (Complete Blood Count during blood test) can be reduced to once every 3 months, with dispensation of treatment for up to 90 days (provided that the treatment can be safely stored) for persons meeting all of the following criteria : -receiving continuous clozapine treatment for more than one year, -never had a neutrophil count of <2000/µL (or <1500/µL if there is a history of benign ethnic neutropenia), -not having safe or convenient access to biological/blood tests. (ii) for patients on clozapine with symptoms of infection, an urgent medical evaluation is required, including the performance of a CBC, (iii) for patients on clozapine who become symptomatic (fever and flu-like symptoms); the emergence of symptoms of clozapine-related toxicity may prompt clinicians to reduce the dose of clozapine by half. It is then recommended that this reduced dose be maintained for up to 3 days after the fever has subsided, then gradually return to the previous dose. It should be noted that the fever observed during clozapine therapy, particularly at initiation, although it may be a warning sign of neutropenia, is frequently benign and does not always require discontinuation of therapy [START_REF] Verdoux | Clinical determinants of fever in clozapine users and implications for treatment management: A narrative review[END_REF]. Regarding dose adjustment, recent cases of elevated clozapine plasma levels in patients with COVID-19 and presenting granulocytopenia with catatonia and delirium, have been described [START_REF] Dotson | Clozapine Toxicity in the Setting of COVID-19[END_REF]. Toxic increases in clozapine concentrations may also occur in smoking patients who reduce their tobacco consumption, especially in respiratory infections, and/or increase their caffeine consumption to combat asthenia [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Silva | Clozapine and COVID-19[END_REF]. Thus, regarding enzymatic impacts, one of the priority adaptations in the case of fever may be to limit the doses (and/or use) of CYP1A2 inhibitors: fluvoxamine, caffeine and ciprofloxacin [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF].

In the event of a potentially abrupt decrease in dosage on clozapine, the possibility of withdrawal syndrome should be taken into consideration, the manifestations of which may be multiple: psychotic decompensation (hypersensitivity psychosis), cholinergic rebound (which may aggravate pre-existing viral symptoms, including: confusion, nausea, vomiting, diarrhea, headaches, hyperhidrosis), histaminergic rebound with anxiety and potentially motor symptoms such as dystonia, dyskinesia or catatonia [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Chiappini | Focus on Clozapine Withdrawal-and Misuse-Related Cases as Reported to the European Medicines Agency (EMA) Pharmacovigilance Database[END_REF]. Anticholinergics and olanzapine can be used in clozapine withdrawal syndrome [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Chiappini | Focus on Clozapine Withdrawal-and Misuse-Related Cases as Reported to the European Medicines Agency (EMA) Pharmacovigilance Database[END_REF]. Furthermore, the strategy of clozapine dosage reduction must also be adapted with the possible need to implement combinations of antipsychotic drugs in the face of treatment efficacy reduction. While such combinations may be considered, it should be remembered that the use of clozapine in combination with amisulpride, olanzapine, quetiapine, risperidone and zotepine is also associated with an increased risk of pneumonia [START_REF] Kuo | Second-generation antipsychotic medications and risk of pneumonia in schizophrenia[END_REF]. The excess risk of pneumonia with clozapine compared to other antipsychotic drugs is also well identified [START_REF] Siskind | Consensus statement on the use of clozapine during the COVID-19 pandemic[END_REF][START_REF] De Leon | Pneumonia may be more frequent and have more fatal outcomes with clozapine than with other second-generation antipsychotics[END_REF] and leads to a cautious anticipation of its use at the time of COVID-19, with constant re-evaluation in the light of the most recent data [START_REF] Boland | Clozapine in the Time of COVID-19[END_REF][START_REF] Butler | Clozapine prescribing in COVID-19 positive medical inpatients: a case series[END_REF][START_REF] Dragoi | Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety-Particularities in the Context of COVID-19[END_REF][START_REF] Gee | The effect of COVID-19 on absolute neutrophil counts in patients taking clozapine[END_REF][START_REF] Govind | Clozapine treatment and risk of COVID-19 infection: retrospective cohort study[END_REF][START_REF] Llesuy | Death From COVID-19 in a Patient Receiving Clozapine: Factors Involved and Prevention Strategies to Consider[END_REF]. Gowing et al. [START_REF] Govind | Clozapine treatment and risk of COVID-19 infection: retrospective cohort study[END_REF] identified 6309 individuals using antipsychotics, with schizophrenia-spectrum disorders and 102 tested positive for COVID-19; patients who take clozapine exhibited an increased risk of COVID-19 infection compared with those who take other antipsychotic medication. Besides, the challenge of using ECT in a pandemic may also represent a barrier in access to care for patients with resistant schizophrenia (we discuss the literature on this subject in the chapter on resistant depression; see below) [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF].

Long-acting neuroleptics

The prescription of long-acting neuroleptics may be a difficult decision to make in a pandemic. For one side, these treatments contribute to an improvement in patient compliance and can therefore be assets for maintaining psychological stability. On the other hand, they require regular injections, exposing both patients (potentially among themselves, in waiting rooms) and caregivers to a risk of SARS-CoV-2 contamination. This latter aspect, combined with periods of confinement and the closure of some care sites, may have led to a consequent decrease in the use of longacting neuroleptics in some locations. For example, a Romanian university psychiatric department saw its prescription of long-acting risperidone halved and long-acting olanzapine reduced by 90% between December 2019 and March 2020, with likely consequences on patient's wellbeing [START_REF] Ifteni | Long-acting injectable antipsychotics treatment during COVID-19 pandemic -A new challenge[END_REF]. On the other hand, a psychiatric service in the USA was able to maintain physical appointments to administer long-acting injectable neuroleptics during confinement by applying barrier measures [START_REF] Gannon | Long acting injectable antipsychotic medications: Ensuring care continuity during the COVID-19 pandemic restrictions[END_REF]. This service also offered the option of switching to the oral form for patients who did not wish to visit the site, despite the lack of clear recommendations for switching in this context [START_REF] Gannon | Long acting injectable antipsychotic medications: Ensuring care continuity during the COVID-19 pandemic restrictions[END_REF]. Furthermore, in order to prevent the risk of respiratory depression in the elderly, some hospitals proposed to reduce prescription of depot antipsychotics and to switch to oral form to gain greater flexibility regarding dosage and reversibility [START_REF] Vedavanam | Old age psychiatry services in the UK responding to COVID-19[END_REF]. More specifically, olanzapine long-acting injectable (LAI) is associated with risk of post-injection delirium/sedation syndrome (PDSS), but it remains a rare effect. Recommendations have been made to highlight the importance of this long-acting treatment modality [START_REF] Siskind | Monitoring for post-injection delirium/sedation syndrome with long-acting olanzapine during the COVID-19 pandemic[END_REF]. In probabilistic terms, the risk of exposure to SARS CoV-2 outweighs the risk of developing PDSS. In situations where 2 or 3 hours of monitoring (time frame varies from country to country) proves impractical or dangerous, it is proposed to consider a monitoring period of 30 minutes to one hour, or even to temporarily remove it if a responsible person can perform the monitoring [START_REF] Siskind | Monitoring for post-injection delirium/sedation syndrome with long-acting olanzapine during the COVID-19 pandemic[END_REF]. Moreover, the switch from paliperidone palmitate once-monthly injection to paliperidone palmitate 3-monthly injection is also a suitable modification in order to prevent exposure to SARS-CoV-2 associated with the maintenance of monthly consultations, which can be conceived in the form of telemedicine. Guidelines from the University of Oxford state that initiation of treatment with extended-release injectable neuroleptics is possible for patients who would benefit from them [START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF]. In the event of suspicion or confirmation of COVID-19, it is advisable to perform the injection at home with appropriate protective equipment for caregivers.

Depression Depression and COVID-19

Since the beginning of the COVID-19 pandemic most studies of mental health in the general population have described an increase in symptoms such as depression and anxiety [START_REF] Moreno | How mental health care should change as a consequence of the COVID-19 pandemic[END_REF]. The rising rates of depression during the pandemic can be an environmental consequence, but also a consequence of COVID itself. In a large study on health-care workers in China, 50% of people reported symptoms of depression, ranked ahead of symptoms of anxiety or insomnia [START_REF] Lai | Factors Associated With Mental Health Outcomes Among Health Care Workers Exposed to Coronavirus Disease 2019[END_REF]. Moreover, the possibility of an increase in the proportion of depressed patients as a result of CoV-2-SARS infection has been raised in the literature (see e.g.: [START_REF] Moreno | How mental health care should change as a consequence of the COVID-19 pandemic[END_REF][START_REF] Lyons | Fallout from the Covid-19 pandemic-should we prepare for a tsunami of post viral depression?[END_REF]134]), while meta-analytic data from 10 studies recently reported a pooled prevalence of 22.8% of depression among healthcare workers [START_REF] Pappa | Prevalence of depression, anxiety, and insomnia among healthcare workers during the COVID-19 pandemic: A systematic review and meta-analysis[END_REF]. Other viruses have been linked to psychological impacts such as depression, for example Epstein-Barr virus, varicellazoster virus, human immunodeficiency virus or influenza A (H1N1). Survivors of the Spanish flu seem to have exhibited symptoms including depression, sleep disturbances, difficulty coping at work and increased suicide rates in the United States [START_REF] Lyons | Fallout from the Covid-19 pandemic-should we prepare for a tsunami of post viral depression?[END_REF]. Such a tsunami of post viral depression appears all the more important to anticipate if people might suffer from clinical recurrences of COVID-19 symptoms after recovery by re-infection or reactivation (CCS) [START_REF] Lyons | Fallout from the Covid-19 pandemic-should we prepare for a tsunami of post viral depression?[END_REF][START_REF] Batisse | Clinical recurrences of COVID-19 symptoms after recovery: viral relapse, reinfection or inflammatory rebound?[END_REF]. As previously explained, DDC is a major enzyme involved in dopamine but also serotonin synthesis and is co-expressed with ACE2 receptor and the SARS-CoV-2, as SARS-CoV, could induce ACE2 down-regulation and thus a dopamine and serotonin disturbance and consequently an impact on mood [START_REF] Yavarpour-Bali | Update on neurological manifestations of COVID-19[END_REF]. These elements could prove to be essential in understanding the best way to treat patients with possible post-COVID-19 depression.

Treatments for COVID-19 and depression

Among the treatments for COVID, those associated with the highest risk of mood depressant effects, with potential suicidal ideation are corticosteroids and mostly interferon alpha [START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF][START_REF] Brown | Mood and Cognitive Changes During Systemic Corticosteroid Therapy[END_REF][START_REF] Shader | COVID-19, interferons, and depression: A commentary[END_REF]. The possible consequences on mood must be acknowledged, especially since the adoption of SSRIs is described as effective in combating this iatrogenic depression [START_REF] Kenna | Psychiatric complications of treatment with corticosteroids: review with case report[END_REF][START_REF] Pinto | Interferon-Related Depression: A Primer on Mechanisms, Treatment, and Prevention of a Common Clinical Problem[END_REF]. For chloroquine and hydroxychloroquine, although identified as being less at risk than corticosteroids, there are case reports (essentially for chloroquine) and data from few studies or from pharmacovigilance (for hydroxychloroquine); these elements lead to caution about the possibility of mood depression or even suicidal effects [START_REF] Hamm | Psychiatric Aspects of Chloroquine and Hydroxychloroquine Treatment in the Wake of Coronavirus Disease-2019: Psychopharmacological Interactions and Neuropsychiatric Sequelae[END_REF]116]. Tocilizumab is associated with conflicting data regarding its mood depressor risk [START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF] and remains more known by its status as a cytokine regulatory agent [START_REF] Kappelmann | Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions[END_REF].

Management of resistant depression with COVID-19

Among the strategies for resistant depression, two available options are facing barriers to access, for different reasons, elucidated below. First, electroconvulsive therapy (ECT) has been the subject of extensive literature since the beginning of the pandemic, herein we highlight in particular the difficulty of sustaining this care due to several challenges; among them the problem of general anesthesia and the need to adapt procedures, while recalling the importance of maintaining access to this strategy in terms of the benefit/risk ratio for patients who require it [START_REF] Boland | ECT and COVID-19 in acute inpatient psychiatry: More than clinical issues alone[END_REF][START_REF] Bryson | A strategy for management of ECT patients during the COVID-19 pandemic[END_REF][START_REF] Burhan | Electroconvulsive therapy for geriatric depression in the COVID-19 era: reflection on the ethics[END_REF][START_REF] Colbert | Images in Clinical ECT: Immediate impact of COVID-19 on ECT Practice[END_REF][START_REF] Daniel | Access barriers to electroconvulsive therapy during COVID-19 pandemic[END_REF][START_REF] Espinoza | Electroconvulsive Therapy During COVID-19: An Essential Medical Procedure-Maintaining Service Viability and Accessibility[END_REF][START_REF] Limoncelli | General Anesthesia Recommendations for Electroconvulsive Therapy During the Coronavirus Disease 2019 Pandemic[END_REF][START_REF] Luccarelli | Modified Anesthesia Protocol for Electroconvulsive Therapy Permits Reduction in Aerosol-Generating Bag-Mask Ventilation during the COVID-19 Pandemic[END_REF][START_REF] Sienaert | Electroconvulsive Therapy During COVID-19-Times: Our Patients Cannot Wait[END_REF][START_REF] Thiruvenkatarajan | Uninterrupted anesthesia support and technique adaptations for patients presenting for electroconvulsive therapy during the COVID-19 era[END_REF]. The non-invasive brain stimulation, transcranial magnetic stimulation and low intensity transcranial electrical stimulation (transcranial direct current stimulation and transcranial alternating current stimulation), could also be an adaptive choice for extending the benefit of ECT in related-COVID-19 settings with compromised access to anesthesia [START_REF] Bikson | Guidelines for TMS/tES clinical services and research through the COVID-19 pandemic[END_REF]. Regarding esketamine, its use may be limited during COVID-19 because of the risk associated with the inhalant form and a contraindication in the event of significant pulmonary insufficiency (see previously). Its use has been described, with intranasal esketamine self-administered under clinical supervision via telemedicine [START_REF] Longpré-Poirier | Remote Monitoring of Intranasal Ketamine Self-Administration as Maintenance Therapy in Treatment-Resistant Depression (TRD): A Novel Strategy for Vulnerable and At-Risk Populations to COVID-19?[END_REF]. The use of ketamine/ intravenous/intranasal esketamine in depressive episodes related to neuropsychiatric complications of COVID-19 should not be overlooked [START_REF] Akinosoglou | Ketamine in COVID-19 patients: Thinking out of the box[END_REF]. Ketamine seems to derive its therapeutic action, at least in part, from a decrease in the production of pro-inflammatory cytokines, including IL-6, involved in the immunopathology of COVID-19 [START_REF] Akinosoglou | Ketamine in COVID-19 patients: Thinking out of the box[END_REF]. Thus, just as patients with an active inflammatory state seem to require the use of pro-dopaminergic or glutaminergic drugs, such as ketamine, to avoid an alteration of the neurotransmission systems affecting the response to first-line antidepressant drugs, post-COVID-19 depressions could also require this type of drug strategy [START_REF] Akinosoglou | Ketamine in COVID-19 patients: Thinking out of the box[END_REF].

Anxiety disorders

The concept of "stress" generated by the COVID-19 pandemic has been one of the most common expressions used to describe the psychological impact of this unique situation. The pandemic generated moderate to severe levels of stress-or anxiety-related symptoms in 25% of the general population in China [START_REF] Taylor | COVID stress syndrome: Concept, structure, and correlates[END_REF]. COVID-stress syndrome has been proposed as five components of COVID-19-related distress which notably include fear of the dangerousness of COVID-19 and direct or indirect traumatic exposure to COVID-19 [START_REF] Taylor | COVID stress syndrome: Concept, structure, and correlates[END_REF]. Available data about SARS-CoV-1 survivors showed a dramatic increase in the prevalence of all psychiatric diagnoses and exhibited high levels of anxiety disorders, predominantly PTSD, panic disorder and obsessive compulsive disorder (54.5%, 32.5% and 15.6%, respectively) [134,[START_REF] Lam | Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term follow-up[END_REF]. The consequences of an explosion of anxiety disorders should encourage the use of structured recommendations by the World Federation of Biological Psychiatry, recalling that the chronic treatment of these disorders is based on SSRIs or venlafaxine, while benzodiazepines are to be used during the first weeks, in the treatment of short-term distress and p.r.n. (pro re nata medication or "as needed") [START_REF] Bandelow | Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care[END_REF]. Monitoring the consumption of benzodiazepines in such a context is important in order also to avoid the respiratory side effects these treatments may have. A crisis of tranquilizers, including benzodiazepines, in addition to the opioid crisis, at the time of COVID-19 could have dramatic consequences in this sense. More specifically, the legitimate concern about the emergence of post-COVID PTSD cases must prompt us to reexamine the validity of the pharmacological tools available to us in this context [START_REF] Liu | Prevalence and predictors of PTSS during COVID-19 outbreak in China hardest-hit areas: Gender differences matter[END_REF]. In this respect, if hydrocortisone cannot be considered as a routine treatment for PTSD, it will be interesting to follow the possible results of studies, in post-COVID-19 PTSD, since this therapeutic strategy has already demonstrated its efficacy versus placebo in 3 studies [START_REF] Wright | Pharmacological prevention and early treatment of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis[END_REF].

Pandemic and the fear of contamination can generate an intuitive increase in obsession and compulsion severity for patients with OCD, with a potential aggravation during the quarantine [START_REF] Davide | The impact of the COVID-19 pandemic on patients with OCD: Effects of contamination symptoms and remission state before the quarantine in a preliminary naturalistic study[END_REF]. Such consequences can also lead to the inappropriate use of certain treatments, such as chloroquine or hydroxychloroquine, which can lead to cardiac toxicity, or even death, in some people [START_REF] Banerjee | The other side of COVID-19: Impact on obsessive compulsive disorder (OCD) and hoarding[END_REF]. The recommendations regarding OCD during COVID-19 pandemic recall that most patients can be treated with SSRI for the two first choices and clomipramine could be an alternative (after an ECG) [START_REF] Fineberg | How to manage obsessive-compulsive disorder (OCD) under COVID-19: A clinician's guide from the International College of Obsessive Compulsive Spectrum Disorders (ICOCS) and the Obsessive-Compulsive and Related Disorders Research Network (OCRN) of the European College of Neuropsychopharmacology[END_REF]. An important warning from the sanitary authorities concerns the increased risk in young people and other vulnerable patients about "activation", agitation, dysphoric states or newly emergent or increased suicidal ideations, which lead to the recommendation "start low and go slow" for treating children and adolescents with antidepressants [START_REF] Fineberg | How to manage obsessive-compulsive disorder (OCD) under COVID-19: A clinician's guide from the International College of Obsessive Compulsive Spectrum Disorders (ICOCS) and the Obsessive-Compulsive and Related Disorders Research Network (OCRN) of the European College of Neuropsychopharmacology[END_REF]. Finally, concerning panic disorder and the COVID-19 pandemic, it would be interesting to follow both the overall evolution of this disorder, but also the specific prevalence rate of the respiratory subtype. While several studies have investigated the psychological consequences of the current pandemic, to date very few studies have focused on panic disorder specifically [START_REF] Javelot | Panic and pandemic: Narrative review of the literature on the links and risks of panic disorder as a consequence of the SARS-CoV-2 pandemic[END_REF][START_REF] Javelot | COVID-19 and its psychological consequences: Beware of the respiratory subtype of panic disorder[END_REF]. This might seem surprising given the predominance of respiratory symptoms in both COVID-19 and panic disorder, on the one hand, and the generalized fear of contamination and fear of suffocation heightened by the pandemic, on the other hand [START_REF] Javelot | Panic and pandemic: Narrative review of the literature on the links and risks of panic disorder as a consequence of the SARS-CoV-2 pandemic[END_REF][START_REF] Javelot | COVID-19 and its psychological consequences: Beware of the respiratory subtype of panic disorder[END_REF]. Salbutamol, a short-acting β-stimulant can be overused in many situations; in patients with asthma, in comorbid situations with asthma and panic disorder (or the latter disorder alone misdiagnosed as asthma) or in the respiratory subtype of panic disorder [START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF]. As previously explained this overuse could represent a particular danger for patients with diarrhea and vomiting during COVID-19 due to the digestive potassium leakage, leading to augmenting the risk of severe hypokalemia in patients taking psychotropics and thus possibly causing QTc prolongation (see previously; [START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF]).

Bipolar Disorder

It is well-known that bipolar patients are sensitive to numerous factors which can trigger manic or depressive states such as: stress environment and or disturbances in circadian rhythm and overuse of toxic substances, mainly alcohol consumption [START_REF] Rajkumar | Bipolar disorder, COVID-19, and the risk of relapse[END_REF]. In the literature, two cases of manic episodes are described in the context of the pandemic; one without infection by SARS-CoV-2, but precipitated by the stress due to the virus, after more than 15 years of stability, the other linked to the infection and without a history of mental disorders [START_REF] Uvais | Mania Precipitated by COVID-19 Pandemic-Related Stress[END_REF][START_REF] Lu | First report of maniclike symptoms in a COVID-19 patient with no previous history of a psychiatric disorder[END_REF].

The link between seropositivity for coronaviruses and the risk of mood disorders and suicide has also been established [START_REF] Rajkumar | Bipolar disorder, COVID-19, and the risk of relapse[END_REF][START_REF] Okusaga | Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts[END_REF]. Among the treatments for bipolar disorder, lithium remains the gold standard. However, the need for regular blood tests may interfere with its safe use during a pandemic. As proposed by NICE (National Institute for Health and Care Excellence), measurement of plasma levels is recommended every 3 months for the first year, then every 6 months [168]. After the first year, plasma lithium levels measurements are maintained every 3 months only for older people and people taking drugs that interact with lithium, who are at risk of impaired renal or thyroid function, raised calcium levels or other complications, who have poor symptom control, with poor adherence, whose last plasma lithium level was 0.8 mmol per litre or higher. In every other case plasma lithium levels can be measured every 6 months. During COVID-19 due to the pandemic and restricted access to biological monitoring, these blood tests can be spaced out, with a decision on a case-by-case basis, but especially for patients who are stable and do not present any risk factors [START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF]. Factors that alter the salt/water balance, infections with fever, dehydration, initiation of drugs that alter lithium excretion, can all induce lithium intoxication [169]. These elements should therefore be taken into consideration during a SARS-CoV-2 infection, even though up to 60% of patients affected by COVID-19 would be apyretic [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]. Some drugs interact with lithium and may increase its plasma concentration, mainly: non-steroidal anti-inflammatory drugs, converting enzyme inhibitors, angiotensin receptor blockers, loop and thiazide diuretics and corticosteroids [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]. In combination with lithium, antipsychotics may induce neurological signs suggestive of neuroleptic malignant syndrome or lithium intoxication, whereas with SSRIs the risk of serotonin syndrome is increased. These dangerous syndromes may be misdiagnosed by COVID-19 (see above) [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]. Besides drug interactions, dehydration and/or infections with fever may also cause an increase in lithemia [169]. Two recently reported cases of COVID-19 with lithium toxicity remind us of this [START_REF] Suwanwongse | Lithium Toxicity in Two Coronavirus Disease 2019 (COVID-19) Patients[END_REF]. Overall, patients should be informed of the signs suggestive of lithium intoxication, including: nausea, tremor, thirst and balance disorders. The appearance of these signs requires rapid control of lithemia, with the necessary safety conditions in relation to patient/caregiver contact, and adaptation of treatment.

Suicide risk

The massive stress induced by the pandemic has quickly raised concerns of an increase in suicides [START_REF] Gunnell | COVID-19 Suicide Prevention Research Collaboration. Suicide risk and prevention during the COVID-19 pandemic[END_REF][START_REF] Kawohl | COVID-19, unemployment, and suicide[END_REF][START_REF] Klomek | Suicide prevention during the COVID-19 outbreak[END_REF][START_REF] Mirza | Command Suicidal Hallucination as Initial Presentation of Coronavirus Disease 2019 (COVID-19): A Case Report[END_REF][START_REF] Sher | Individuals with untreated psychiatric disorders and suicide in the COVID-19 era[END_REF][START_REF] Sher | Are COVID-19 survivors at increased risk for suicide?[END_REF][START_REF] Wand | COVID-19: the implications for suicide in older adults[END_REF]. This fear is supported in part by data describing an increase in the number of suicides in the USA during the Spanish Influenza outbreak and in Hong Kong by the elderly in 2003 during the SARS-CoV-1 epidemic [START_REF] Gunnell | COVID-19 Suicide Prevention Research Collaboration. Suicide risk and prevention during the COVID-19 pandemic[END_REF]. The increase in suicide attempts and suicides can be linked to several factors: acute psychic decompensation in people with or without a psychological history in the face of stress directly linked to the pandemic [START_REF] Klomek | Suicide prevention during the COVID-19 outbreak[END_REF][START_REF] Mirza | Command Suicidal Hallucination as Initial Presentation of Coronavirus Disease 2019 (COVID-19): A Case Report[END_REF], in people undergoing indirect psychological suffering: loneliness and social isolation with quarantine, especially in elderly patients, unemployment, job loss [START_REF] Kawohl | COVID-19, unemployment, and suicide[END_REF][START_REF] Wand | COVID-19: the implications for suicide in older adults[END_REF] and for COVID-19 survivors due to psychological and / or neurobiological consequences [START_REF] Sher | Are COVID-19 survivors at increased risk for suicide?[END_REF]. Overall, psychiatric illnesses are associated with suicidal behavior, and it is estimated in the USA that only 42.6% of adults suffering from psychiatric disorders received adequate care in the past year [START_REF] Sher | Individuals with untreated psychiatric disorders and suicide in the COVID-19 era[END_REF]. Moreover, the data from a large international study revealed that more than half of people with major depression, generalized anxiety disorder, and alcohol use disorder were untreated [START_REF] Sher | Individuals with untreated psychiatric disorders and suicide in the COVID-19 era[END_REF]. These data plead not to undertreat patients who require pharmacological treatment but to pursue intensively the detection of people requiring it, without delaying the start of treatment. From this perspective, telemedicine can play a key role in maintaining the continuity of care. Antidepressants, for all steps, initiation, dosing changes and discontinuation (stopping before 2 months) have been associated with significant risk for suicide attempt [START_REF] Valuck | Antidepressant discontinuation and risk of suicide attempt: a retrospective, nested case-control study[END_REF]. Benzodiazepines and antipsychotics use may also increase the risk of suicide [START_REF] Cato | Association between benzodiazepines and suicide risk: a matched case-control study[END_REF][START_REF] Mihanović | Suicidality and side effects of antidepressants and antipsychotics[END_REF]. However, for all these data, indication bias and substantial confounding factors exist [START_REF] Valuck | Antidepressant discontinuation and risk of suicide attempt: a retrospective, nested case-control study[END_REF]. Nevertheless, it is important to recall that most pharmacoepidemiologic studies show a protective effect of antidepressants against suicide [START_REF] Courtet | Antidepressants and suicide risk in depression[END_REF]. In addition, the precautions previously detailed regarding the use of clozapine and lithium during SARS-CoV-2 pandemic should also be reconsidered in light of the prophylactic effects of these treatments on the risk of suicide [START_REF] Müller-Oerlinghausen | The Contributions of Lithium and Clozapine for the Prophylaxis and Treatment of Suicidal Behavior[END_REF][START_REF] Zalsman | Suicide prevention strategies revisited: 10-year systematic review[END_REF]. For these two treatments, a possible dosage reduction in response to signs of infection should ideally be considered, taking into account the clinical response observed to previous dosage reductions, in order to determine the height of this adjustment and whether a treatment of the same class should be implemented, or the dosage adjusted [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF].

Sleep disorders

Global stressful circumstances related to pandemic and mass home confinement can have a dramatic impact on sleepwake rhythms in general and night-time sleep in particular [START_REF] Altena | Dealing with sleep problems during home confinement due to the COVID-19 outbreak: Practical recommendations from a task force of the European CBT-I Academy[END_REF]. In an observational study for assessing subjective neurological symptoms in patients with COVID-19, sleep impairment appeared as the most frequent symptom and was more frequent in patients with more than 7 days of hospitalization [START_REF] Liguori | Subjective neurological symptoms frequently occur in patients with SARS-CoV2 infection[END_REF]. A task force of the European CBT-I (Cognitive Behavioural Therapy for Insomnia) Academy proposed practical recommendations for sleep-disturbances induced by the COVID-19 pandemic [START_REF] Altena | Dealing with sleep problems during home confinement due to the COVID-19 outbreak: Practical recommendations from a task force of the European CBT-I Academy[END_REF]. However, as a second-line of treatment if CBT is ineffective or unavailable, some pharmacological treatments can be considered with benzodiazepines, hypnotic benzodiazepine receptor agonists -also known as z-drugs: zaleplon, zolpidem, and zopiclone -for short-term use, or sedative antidepressants like agomelatine, doxepin, mirtazapine, trazodone, and trimipramine [START_REF] Altena | Dealing with sleep problems during home confinement due to the COVID-19 outbreak: Practical recommendations from a task force of the European CBT-I Academy[END_REF]. Antidepressants can be useful if benzodiazepines and derivatives are deemed inappropriate or if a psychic comorbidity validates their use [START_REF] Altena | Dealing with sleep problems during home confinement due to the COVID-19 outbreak: Practical recommendations from a task force of the European CBT-I Academy[END_REF]. However, as we have explained previously, z-drugs, like benzodiazepines and sedative antidepressants, are at risk of causing or worsening dyspnea, particularly in cases of high doses and/or combinations between them or with other risky treatments. As the elderly are particularly sensitive to the risks of respiratory distress with benzodiazepines and to the respiratory effects associated with SARS-CoV-2, referral to melatonin as a first-line option in these populations may seem relevant. On the other hand, it can be deleterious to modify the treatment of a person suffering from sleep disturbances with a benzodiazepine or a z-drug, especially during an anxiety-provoking period such as a pandemic. Stopping treatment with benzodiazepines or derivatives should not be sudden at the risk of inducing rebound insomnia caused by withdrawal syndrome. In other cases, placing melatonin as the first line option is also supported by the treatment plan proposed by neurologists in the event of delirium (see above; [START_REF] Baller | Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19[END_REF]) and, in part, due to these possible preventive effects on COVID-19 progression (see below: [START_REF] Javelot | Psychoactive compounds as multifactorial protection factors against COVID-19[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] Cardinali | Can Melatonin Be a Potential "Silver Bullet" in Treating COVID-19 Patients?[END_REF][START_REF] Cardinali | Elderly as a High-risk Group during COVID-19 Pandemic: Effect of Circadian Misalignment, Sleep Dysregulation and Melatonin Administration[END_REF]).

Attention-Deficit Hyperactivity Disorder

The COVID-19 pandemic and the lockdown that followed it proved themselves to be a big challenge for parents of children with attention deficit hyperactivity disorder, be it the hyperactive/impulsive form or the predominant inattentive/distractible type. This is a notorious issue that has been publicly discussed during the European confinement -and the European ADHD Guidelines Group (EAGG) has proposed directions for management of ADHD during the COVID-19 pandemic [START_REF] Cortese | ADHD management during the COVID-19 pandemic: guidance from the European ADHD Guidelines Group[END_REF]. Continuity of treatment, mostly with specific legislation and/or therapeutic follow-up, can become an additional burden for patients and their parents. The EAGG advocates for continuity of treatment with constant dosage, hoping for flexibility in access to these treatments, to avoid exacerbation of the disorders and to promote patient acceptance of barrier measures [START_REF] Cortese | ADHD management during the COVID-19 pandemic: guidance from the European ADHD Guidelines Group[END_REF]. It is also necessary to question the usefulness of the weekend therapeutic window, which can be detrimental to family balance in a situation of confinement or withdrawal to a small family nucleus [START_REF] Cortese | ADHD management during the COVID-19 pandemic: guidance from the European ADHD Guidelines Group[END_REF]. Sleep phases may also be staggered during this health crisis, leading to disorganization of routine. Sleep hygiene advice can then judiciously complement the effects of melatonin (5 to 6mg/evening) [START_REF] Cortese | ADHD management during the COVID-19 pandemic: guidance from the European ADHD Guidelines Group[END_REF]; this treatment can also sometimes help to combat iatrogenic insomnia, linked to psychostimulants (off-label use). More recently, this same task force inside the EAGG has proposed new recommendations for starting ADHD medication during the pandemic [START_REF] Cortese | Starting ADHD medications during the COVID-19 pandemic: recommendations from the European ADHD Guidelines Group[END_REF]. We invite the reader to look at the original documents for further details, but in essence, they propose that before the start of the medication: (i) a summary of the clinical history of the patient, including parameters like exercise resistance and cardiological monitoring, (ii) a summary of the family disease history, in particular for identifying cases of sudden death for first-degree relatives aged less than 40, and (iii) baseline monitoring with blood pressure and heart rate on three separate occasions -if needed, this can be done by another person aided by telephone guidance [START_REF] Cortese | Starting ADHD medications during the COVID-19 pandemic: recommendations from the European ADHD Guidelines Group[END_REF]. In addition, Javelot et al. [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF] pointed out that methylphenidate can cause symptoms important for differential diagnosis with COVID-19, such as nasopharyngeal (see previously), and digestive symptoms -the last ones particularly during the beginning of the treatment, with possibility of diarrhea, abdominal pain, nausea, and vomiting. Headaches are also quite common with the use of psychostimulants, and the EAGG reminds that paracetamol should be preferred over ibuprofen for pain management [START_REF] Cortese | ADHD management during the COVID-19 pandemic: guidance from the European ADHD Guidelines Group[END_REF]. Regardless, the use of analgesics should not delay a diagnosis for COVID-19, and in this sense, the availability of SARS-CoV-2 laboratory tests for case tracing becomes even more important.

Psychoactive substances and COVID-19

Inhalants such as tobacco and cannabis are likely to induce coughing, increasing the overall risk of infection and its severity, while many psychoactive substances can contribute to decreased alertness (alcohol, cannabis, synthetic drugs). The symptomatology of COVID-19 can therefore be amplified by the consumption of these products, in its peripheral and central consequences. Alcohol may exacerbate the risk of smoking-related chronic obstructive pulmonary disease, increase the risk of community-acquired pneumonia, but may also contribute to a deterioration in pulmonary function regardless of smoking status [START_REF] Sisson | Alcohol and airways function in health and disease[END_REF][START_REF] Simou | Alcohol and the risk of pneumonia: a systematic review and meta-analysis[END_REF]. For smokers, in particular, polycyclic aromatic hydrocarbons in tobacco smoke strongly induce the CYP1A2 enzyme for smoker patients, meaning that medication is metabolized much faster. When these patients stop smoking, the absence of the hydrocarbons slows the usual rate of metabolization, and thus increases drug concentration in plasma and potential adverse side effects. Increases in plasma concentrations of psychotropic drugs (or psychoactives substances) metabolized mainly by CYP1A2 are expected for: caffeine, clomipramine, clozapine, doxepin, duloxetine, fluvoxamine, mirtazapine, olanzapine, pimozide, propranolol, ramelteon, rasagiline, riluzole, ropinirole, theophylline, thiothixene, trifluoperazine and in a lesser extend for almotriptan, amitriptyline, asenapine, chlorpromazine, desipramine, diazepam, fluphenazine, frovatriptan, haloperidol, imipramine, maprotiline, melatonin, naratriptan, nortriptyline, perphenazine, rivastigmine, selegiline, thioridazine, trazodone, ziprasidone, zolmitriptan and zolpidem [START_REF] Fankhauser | Drug interactions with tobacco smoke: Implications for patient care[END_REF][START_REF] Anderson | Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products[END_REF].

One should be aware of these effects in case of sudden smoking cessation impulsed by COVID-19 respiratory symptoms in smokers. Therefore, in such cases for patients under clozapine or olanzapine, a dosage reduction of 30% to 40% with 10% reduction on daily dose every four days might be proposed, or otherwise a dosage reduction by a factor of 1.5 in two to four weeks [START_REF] De Leon | Atypical antipsychotic dosing: the effect of smoking and caffeine[END_REF][START_REF] Lowe | Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment[END_REF]. However, other stronger or faster dosage adjustments can be necessary if there are infectious COVID-19 symptoms [START_REF] Siskind | Consensus statement on the use of clozapine during the COVID-19 pandemic[END_REF], and also having in mind that there is genetic influence over the level of inducibility of CYP1A2 by smoking [START_REF] Koonrungsesomboon | The impact of genetic polymorphisms on CYP1A2 activity in humans: a systematic review and meta-analysis[END_REF], which encourages doctors to follow prioritarily the clinical evolution of the patient over a standardised reduction scheme. Alcohol can potentiate the effects of sedative drugs (see above) and worsen the risks of dyspnea and respiratory distress in combination with other substances or drugs at risk (especially morphine and benzodiazepines) [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Johnson | Alcohol-medical drug interactions[END_REF].

In general, the pandemic has increased consumption of cannabis products and benzodiazepines, which could be linked to the feeling of stress induced by an anxiogenic environment [START_REF] Trana | Consequences of COVID-19 Lockdown on the Misuse and Marketing of Addictive Substances and New Psychoactive Substances[END_REF] that appeared alongside COVID-19. Moreover, drug misuse could have shifted toward alternative substances and home-made "New Psychoactive Substances" (official terminology of the European Union) and increase the risk of atypical presentations of intoxications [START_REF] Trana | Consequences of COVID-19 Lockdown on the Misuse and Marketing of Addictive Substances and New Psychoactive Substances[END_REF].

Reference websites and publications about psychotropics and COVID-19

The SARS-CoV-2 pandemic has forced the entire medical-scientific community to adapt to an urgent and exceptional health situation. Unlike any time before, the vast production of articles related to this field requires recurrent synthesis efforts to identify relevant and practical information. Several publications and reference websites play an important role in guiding the clinician; articles often make it possible to answer specific questions in targeted literature reviews [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF][START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF][START_REF] Ostuzzi | Pharmacological treatment of hyperactive delirium in people with COVID-19: rethinking conventional approaches[END_REF] and/or to establish local recommendations, adapted to the health system of each country and the treatments available there [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Andrade | Recommendations about the Use of Psychotropic Medications during the COVID-19 Pandemic[END_REF][START_REF] Seifert | Psychopharmacotherapy during the COVID-19 pandemic[END_REF], but can be quickly overlooked in the current scenario, given the expressive number of new articles being published every day. Websites, on the other hand, allow for regular updates, but often offer more generalist content, requiring either the selection of useful information (see below, e.g. the University of Liverpool website) or reference to local practice recommendations (see below, e.g. the University of Oxford website).

Adaptations of psychotropic drugs prescriptions in the COVID-19 pandemic

The Oxford Precision Psychiatry Lab (OxPPL), an international multi-disciplinary working group, has released the platform "COVID-19 & clinical management of mental health disorders" (link: https://oxfordhealthbrc.nihr.ac.uk/ourwork/oxppl/covid-19-and-mental-health-guidance) ( [START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF]; announced in Smith et al [START_REF] Smith | Covid-19 and mental health: a transformational opportunity to apply an evidence-based approach to clinical practice and research[END_REF]). The OxPPL provides evidence-based medical recommendations addressing several themes/issues raised by mental health clinicians during the pandemic [START_REF] Smith | Covid-19 and mental health: a transformational opportunity to apply an evidence-based approach to clinical practice and research[END_REF]. The recommendations propose several sections, 4 of which are directly related to psychopharmacotherapy with information about benzodiazepines, z-drugs, clozapine, lithium and long-acting injectable antipsychotics. Moreover, the section "inpatient wards" contain information on medication for acute episodes and the section "end of life care" provides internet links to useful pharmacotherapeutic recommendations in this area [START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF]. The platform allows the free sharing of scientific information validated by OxPPL members. Although there is no independent reading committee for the validation of the information communicated, each user has the possibility to share queries transmitted to the working group. Translations of the OxPPL guidelines are available in Chinese, French, Italian and Turkish [START_REF]COVID-19 & clinical management of mental health issues. Evidence-based guidance[END_REF]. The impact of COVID-19 on psychotropics safety is discussed in numerous reviews (i.e. in English: [START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF][START_REF] Luykx | Safe and informed prescribing of psychotropic medication during the COVID-19 pandemic[END_REF]). A more structured approach regarding safety of psychotropic medications in people with COVID-19 was made by WHO (World Health Organization) Collaborating Centre for Research and Training in Mental Health and Service Evaluation (University of Verona; [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF]). This review concluded that all classes of psychotropics showed acceptable safety risks for use in patients with COVID-19 and proposed 12 evidence-based recommendations. These recommendations mainly include: (i) the detection of drug interactions between psychotropic drugs and COVID-19 treatments (as proposed by the Liverpool site in a non-selective manner, see below), (ii) monitoring of the risk of respiratory depression with in particular benzodiazepines and antipsychotics with highly sedative profiles, (iii) cardiovascular risk, firstly linked to QTc-prolongation, with psychotropic drugs known to be at risk, as well as treatments for COVID-19, for those identified at risk, and secondly, the thromboembolic risk, with antipsychotics and antidepressants, (iv) the risk of infection which may be increased with psychotropic drugs and particularly with clozapine, carbamazepine and oxcarbazepine, (iv) finally, the risk of contributing to delirium with anticholinergic treatments, benzodiazepines and lithium.

Concerning the management of acute psychopathology in patients with COVID-19, some authors have also proposed cases centered recommendations for acute anxiety [START_REF] Khawam | Treating acute anxiety in patients with COVID-19[END_REF] and delirium in elderly population, severe mental illness in median aged patients with few medical comorbidities and non-severe mental illness with depressive and/or anxiety symptoms [START_REF] Anmella | COVID-19 inpatients with psychiatric disorders: Real-world clinical recommendations from an expert team in consultation-liaison psychiatry[END_REF]. About delirium or acute agitation in patients with COVID-19, the more structured work is also from the WHO team in Verona [START_REF] Ostuzzi | Pharmacological treatment of hyperactive delirium in people with COVID-19: rethinking conventional approaches[END_REF] and complementary data can be found in three other articles [START_REF] Baller | Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19[END_REF][START_REF] Meagher | Developing a guidance resource for managing delirium in patients with Covid-19[END_REF][START_REF] Wong | Management of Agitation During the COVID-19 Pandemic[END_REF]. We have previously proposed a synthesis of all these data. Bilbul et al. [START_REF] Bilbul | Psychopharmacology of COVID-19[END_REF] offer a unique and exhaustive vision, to the best of our knowledge, about the psychiatric safety of COVID-19 treatments.

Drug interactions between psychotropic drugs and COVID-19 treatments

Interactions between psychotropic drugs and COVID-19 treatments have been the subject of several reviews ( [START_REF] Chatterjee | Impact of COVID-19 pandemic on pre-existing mental health problems[END_REF][START_REF] Meagher | Developing a guidance resource for managing delirium in patients with Covid-19[END_REF][START_REF] Anmella | COVID-19 inpatients with psychiatric disorders: Real-world clinical recommendations from an expert team in consultation-liaison psychiatry[END_REF]; this last one for the most commonly used medications in delirium) and sometimes targeted to certain COVID-19 treatments ( [START_REF] Mansuri | Ritonavir/Lopinavir and Its Potential Interactions With Psychiatric Medications: A COVID-19 Perspective[END_REF][START_REF] Mansuri | Remdesivir and Potential Interactions With Psychotropic Medications: A COVID-19 Perspective[END_REF]; with ritonavir/lopinavir combination and remdesivir [START_REF] Mohebbi | Drug Interactions of Psychiatric and COVID-19 Medications[END_REF]; with ritonavir/lopinavir combination and chloroquine/hydroxychloroquine) or certain classes of psychotropic drugs [START_REF] Mansuri | Opioid Use Disorder Treatment and Potential Interactions With Novel COVID-19 Medications: A Clinical Perspective[END_REF][START_REF] Fırat | COVID-19 & antiepileptic drugs: Should we pay attention?[END_REF]. The publications offering the most comprehensive view of these interactions to date are proposed by Bishara et al. [START_REF] Bishara | Emerging and experimental treatments for COVID-19 and drug interactions with psychotropic agents[END_REF] and Ostuzzi et al. 2020 (in article and additional file; [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF]). These data provide a synthetic and targeted overview of the psychotropic medications which interact with COVID-19 treatments, by extracting data from the University of Liverpool website. The Liverpool Drug Interaction Group is a working group made up of members of the Department of Pharmacology of the University of Liverpool extended to other international specialists according to the themes addressed; this group has worked on several databases on drug interactions with anti-HIV and hepatitis antiretrovirals, as well as anti-cancer drugs. This working group now offers a platform to search for drug interactions between experimental drugs used against COVID-19 and other regularly prescribed medications (https://www.covid19-druginteractions.org/checker). Based on pharmacokinetic, pharmacological, toxicological and literature data, the tool allows to identify potential drug interactions between each drugs. This particularly exhaustive tool can both complicate the work of the clinician who would like to extract information relating only to psychotropic drugs in a timely manner, but also allow to find new therapeutic interactions related to the treatment of COVID-19. New treatments have already been referenced in this way in the website since the syntheses of Bishara et al. [START_REF] Bishara | Emerging and experimental treatments for COVID-19 and drug interactions with psychotropic agents[END_REF] and Ostuzzi et al. [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF], which argue for direct use of the University of Liverpool website.

Possible antiviral effects of psychotropics against SARS-CoV-2

Please see Table 4 for synthetic information about the main neurotransmitters modulators (psychotropics) with potential anti-SARS-CoV-2 activities.

Epidemiology

Concerning the role of existing psychoactive drugs amidst the pandemic, both the potential dangerousness of certain psychotropics, like clozapine [START_REF] Siskind | Consensus statement on the use of clozapine during the COVID-19 pandemic[END_REF], and the possible beneficial side effects of others, like haloperidol and chlorpromazine [START_REF] Plaze | Repurposing chlorpromazine to treat COVID-19: The reCoVery study[END_REF][START_REF] Gordon | A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing[END_REF][START_REF] Nobile | Could the antipsychotic chlorpromazine be a potential treatment for SARS-CoV-2?[END_REF], were quickly raised. Regarding the possible benefits, it is important to note that the proportion of patients with COVID-19 or with serious development of the disease was not higher within mental health institutions at the start of the pandemic [START_REF] Plaze | Repurposing chlorpromazine to treat COVID-19: The reCoVery study[END_REF][START_REF] El-Khoury | Low prevalence of SARS-CoV-2 among patients presenting at a Parisian psychiatry University Hospital Group[END_REF][START_REF] Lee | Association between mental illness and COVID-19 susceptibility and clinical outcomes in South Korea: a nationwide cohort study[END_REF], which was originally not expected. During the first lockdown in Europe, it was observed that inside psychiatric facilities , the units which dedicated to COVID-19 patients remained relatively empty [START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF], and that the proportion of medical staff affected by the disease was higher than that of the patients [START_REF] Plaze | Repurposing chlorpromazine to treat COVID-19: The reCoVery study[END_REF]. There are many possible explanations for this phenomenon, including the relative isolated location of some institutions or even the natural social distancing of some psychiatric patients [START_REF] El-Khoury | Low prevalence of SARS-CoV-2 among patients presenting at a Parisian psychiatry University Hospital Group[END_REF]. However, these hypothesis did not consider other factors that should have made these populations more vulnerable to COVID-19, such as the difficulty for certain patients to respect measures to prevent infection and the fact that very often psychiatric patients also suffer from comorbidities which put them at high risk for contracting SARS-CoV-2, like cardiovascular and pulmonary diseases, obesity and diabetes [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF]. Therefore, the lack of a plausible explanation for this initial lower rate of infection among inpatients led the community to investigate the possibility of chemoprotection created by psychotropics [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Plaze | Repurposing chlorpromazine to treat COVID-19: The reCoVery study[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] El-Khoury | Low prevalence of SARS-CoV-2 among patients presenting at a Parisian psychiatry University Hospital Group[END_REF].

In vitro evidence and theoretical basis for antiviral actions

Many pathways are available for explaining the hypothesized antiviral activity of psychotropics. Three main areas should be further studied : (i) the psychotropics' antiviral activity against SARS-CoV-2 itself [START_REF] Gordon | A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing[END_REF][START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF][START_REF] Yang | Identification of SARS-CoV-2 entry inhibitors among already approved drugs[END_REF][START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF], (ii) the psychotropics' antiviral activity against other coronaviruses, such as MERS-CoV, or SARS-CoV-1 [START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF], (iii) the psychotropics' antiviral activity against other types of viruses [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF], (iv) the hypothesis of anti-SARS-CoV-2 activity by drugs with similarities to the ones in items (i) to (iii), in this case defined by structure-activity relationship (SAR) similarities between the drugs [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF]. Also, there is pharmacoepidemiological data connecting the lowest incidence of COVID-19 in psychiatric patients with the use of certain commercial drugs. This was verified in different settings: for a single unit of an institution [START_REF] Plaze | Repurposing chlorpromazine to treat COVID-19: The reCoVery study[END_REF], for a whole mental health establishment [START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF], and for country-wide pharmacoepidemiological data [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF]. Furthermore, the data from [START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF] showed some psychotropic drugs were present in treatment schemes which showed anti-SARS-CoV-1 and/or anti-MERS-CoV activity [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF]. These sources recognized the potential efficacy of many first generation antipsychotics against coronaviruses, and in particular verified the possible benefits of phenothiazines (about half of the substances examined), and other substances from pharmacochemical classes structurally related to them, notably thioxanthene and diphenylbutylpiperidine [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF]. Based on this, chlorpromazine has been put forward for its anti-SARS-CoV-2 potential [START_REF] Plaze | Repurposing chlorpromazine to treat COVID-19: The reCoVery study[END_REF][START_REF] Nobile | Could the antipsychotic chlorpromazine be a potential treatment for SARS-CoV-2?[END_REF][START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF][START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF][START_REF] Han | Advances and challenges in the prevention and treatment of COVID-19[END_REF][START_REF] Nitulescu | Comprehensive analysis of drugs to treat SARS-CoV-2 infection: Mechanistic insights into current COVID-19 therapies (Review)[END_REF][START_REF] De | Psychosis Treatment During COVID-19 Pandemic and the Potential Role of Phenothiazines: A Call for Research Studies[END_REF][START_REF] Sathyamoorthy | Plausible role of combination of Chlorpromazine hydrochloride and Teicoplanin against COVID-19[END_REF]. Chlorpromazine is usually found in high concentrations in the lungs and its antiviral activity could be due to its interference with clathrin-mediated endocytosis and post-entry effects on viral replication [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Plaze | Repurposing chlorpromazine to treat COVID-19: The reCoVery study[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF]. However, because of the large number of phenothiazines that showed some anti-coronavirus activity [START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF], it's likely that this antiviral effect is not restricted to chlorpromazine, and could be instead a drug class effect. This means that certain phenothiazines which are more used than chlorpromazine in some countries (like cyamemazine or alimemazine in France) could also provide comparable anti-coronavirus effects [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] De | Psychosis Treatment During COVID-19 Pandemic and the Potential Role of Phenothiazines: A Call for Research Studies[END_REF][START_REF] Otręba | Antiviral activity of chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine towards RNA-viruses. A review[END_REF][START_REF] Udrea | Laser irradiated phenothiazines: New potential treatment for COVID-19 explored by molecular docking[END_REF]. This hypothesis is supported by the recently published data in [START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF], which demonstrated the anti-SARS-CoV-2 activity of seven psychotropics studied in [START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF]. In this study, five out of the seven psychotropics showing anti-SARS-CoV-2 activity were phenothiazines or derived substances.

Clinical evidence and the locus of potential effects

These results were the starting point for the use of pharmacoepidemiological data associated with antiviral efficacy data as proposed in two recent articles [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF]. They allowed us to identify a list of 20 drugs with chemoprotective potential for mental health patients in France; they are, in alphabetical order: alimemazine, aripiprazole, cetirizine, chlorpromazine, citalopram, clozapine, cyamemazine, escitalopram, haloperidol, hydroxyzine, lithium, levomepromazine, melatonin, nicotine, paroxetine, quetiapine, sertraline, trihexyphenidyl, tropatepine, valproic acid (for details, see Table 4). Moreover, Lithium has been analyzed by a number of different publications, like chlorpromazine, and these articles have described its potential anti-SARS-CoV-2 effects [START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] Khalil | Lithium chloride combination with rapamycin for the treatment of COVID-19 pneumonia[END_REF][START_REF] Murru | International Group for The Study of Lithium Treated Patients (IGSLi). Lithium's antiviral effects: a potential drug for CoViD-19 disease?[END_REF][START_REF] Nowak | Lithium and coronaviral infections. A scoping review[END_REF][START_REF] Rajkumar | Lithium as a candidate treatment for COVID-19: Promises and pitfalls[END_REF][START_REF] Rudd | GSK-3 Inhibition as a Therapeutic Approach Against SARs CoV2: Dual Benefit of Inhibiting Viral Replication While Potentiating the Immune Response[END_REF][START_REF] Santos | A tale of (glycogen synthase kinase) three: Lithium, the kidney and coronavirus disease 19[END_REF][START_REF] Spuch | Does Lithium Deserve a Place in the Treatment Against COVID-19? A Preliminary Observational Study in Six Patients, Case Report[END_REF][START_REF] Viel | Microdose lithium reduces cellular senescence in human astrocytes -a potential pharmacotherapy for COVID-19?[END_REF]. Interestingly as well, a 2013 study on the risk of pneumonia in bipolar patients has also demonstrated a dose-dependent protective effect with lithium, and this effect was not observed with any other antipsychotic or mood stabilizer in this study [START_REF] Yang | Antipsychotic drugs, mood stabilizers, and risk of pneumonia in bipolar disorder: a nationwide case-control study[END_REF]. However, some other substances which are less prescribed, and for which there is therefore less pharmacoepidemiological data available, could also be promising in terms of anti-SARS-CoV-2 effects. Among those, many are also phenothiazines, and we highlight: fluphenazine, promethazine, thiethylperazine and triflupromazine, since they have demonstrated anti-SARS-CoV-1 and/or anti-MERS-CoV efficacy and also effects on other viruses [START_REF] Khalil | Lithium chloride combination with rapamycin for the treatment of COVID-19 pneumonia[END_REF], and propericiazine (periciazine), pipotiazine, metopimazine and mequitazine (3). Thioxanthenes, which are related to phenothiazines, have also showed benefits in some cases, as with thiothixene, demonstrating anti-SARS-CoV-1 and anti-MERS-CoV activity [START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF]. It should be noted that other first generation antipsychotics could also be of interest, such as fluspirilene (anti-SARS-CoV-1 and anti-MERS-CoV efficacy demonstrated; [START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF]), of which pimozide and penfluridol are derivatives (diphenylbutylpiperidine derivatives; [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF]), as well as pipamperone, structurally linked to haloperidol (butyrophenones derivate; [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF]).

Among phenothiazines and their derivatives, 7 of them have recently had their SARS-CoV-2 activity confirmed: alimemazine/trimeprazine, chlorpromazine, flupentixol, fluphenazine, fluspirilene, promethazine and thiethylperazine [START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF][START_REF] Yang | Identification of SARS-CoV-2 entry inhibitors among already approved drugs[END_REF][START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF], while the effect of haloperidol has also been studied [START_REF] Gordon | A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing[END_REF][START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF].

Analyzing antidepressants, imipramines, which also have a structural link to phenothiazines, may be of interest, in particular clomipramine which has demonstrated anti-SARS-CoV1, anti-MERS-CoV activity [START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF][START_REF] Carpinteiro | Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells[END_REF][START_REF] Nobile | Clomipramine Could Be Useful in Preventing Neurological Complications of SARS-CoV-2 Infection[END_REF] and probably anti-SARS-CoV-2 activity according to Weston et al. [START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF], while the potential of imipramine, amitriptyline, desipramine and maprotiline should be considered [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Carpinteiro | Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells[END_REF][START_REF] Glebov | Understanding SARS-CoV-2 endocytosis for COVID-19 drug repurposing[END_REF]. The anti-SARS-CoV-2 efficacy of these four tricyclics was recently confirmed by Carpinteiro et al [START_REF] Carpinteiro | Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells[END_REF]. SSRIs could potentially be of class interest [START_REF] Carpinteiro | Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells[END_REF][START_REF] Glebov | Understanding SARS-CoV-2 endocytosis for COVID-19 drug repurposing[END_REF][START_REF] Hamed | The possible immunoregulatory and anti-inflammatory effects of selective serotonin reuptake inhibitors in coronavirus disease patients[END_REF][START_REF] Schloer | Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine[END_REF]. The first clinical trial demonstrating the possible prophylactic effects of a psychotropic drug was recently published with fluvoxamine. Compared to placebo (n=72), patients treated with fluvoxamine (n=80; increase to 300mg/day) had a lower likelihood of clinical deterioration over 15 days [START_REF] Lenze | Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial[END_REF].

All the above data encourages the study of anti-SARS-CoV-2 properties of psychotropic medications, beyond standard therapeutic usages, so that new drug mechanisms against COVID-19 can be identified. For instance, the antihistaminic effect H1 seems to be involved in anti-coronavirus activity in general and anti-SARS-CoV-2 in particular. The H2 effect, which has also been studied for COVID-19 with famotidine, will not be analyzed here since it is not predominantly associated with psychotropics. Among anti-H1 antihistamines, chlorphenoxamine has shown anti-SARS-CoV-1 and anti-MERS-CoV activity [START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF] and is pharmacologically related to some often prescribed medications --i.e., alimemazine/trimeprazine, hydroxyzine and cetirizine --and with less common onesi.e., pheniramine, brompheniramine, chlorphenamine, dexchlorpheniramine, diphenhydramine, doxylamine, triprolidine,

. Among the above mentioned substances, alimemazine/trimeprazine, azelastine, clemastine, and cloperastine have confirmed anti-SARS-CoV-2 activity [START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF][START_REF] Yang | Identification of SARS-CoV-2 entry inhibitors among already approved drugs[END_REF]. These effects are especially worth noting since, beyond the SAR linking certain substances, the anti-H1 effect appears to be the common denominator of all 11 substances identified as "neurotransmitters inhibitors'' by Dyall et al. [START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF], with anti-coronavirus efficacy. This anti-H1 property is present in treatments qualified as antihistamines, but also in first generation antipsychotics such as phenothiazines and thioxanthene and tricyclic antidepressants. Other substances like astemizole, --a butyrophenone derivative similar to haloperidol --which is classified as an antihistamine, and benztropine --an atropine derivative --which has antihistamine and anticholinergic effects, presented anti-SARS-CoV-2 activity according to Sauvat et al., [START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF] and Weston et al., [START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF]. Citalopram, which was mentioned in Villoutreix et al. [START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF] because of its structural connection to diphenylbutanamines (as was the case with escitalopram and fluoxetine), has shown the strongest anti-H1 properties among SSRIs. Moreover, the antipsychotics proposed by Villoutreix et al. [START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF] i.e., clozapine, olanzapine, and quetiapine -also have strong antihistamine properties. In addition to the beneficial and potentially prophylactic effects of certain antihistamines, i.e., the aforementioned phenothiazines, blocking the H1 histamine receptor could also prevent complications related to SARS-CoV-2 infection. IL-6 secretion from human lung macrophages is positively regulated by histamine, and it is one of the key messengers produced in COVID-19's cytokine-storm [START_REF] Altschuler | Dapsone, colchicine and olanzapine as treatment adjuncts to prevent COVID-19 associated adult respiratory distress syndrome (ARDS)[END_REF][START_REF] Liu | Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?[END_REF]. For this reason, some authors have proposed that the antihistamine effects of molecules like olanzapine or quetiapine could be useful in order to prevent COVID-19-associated adult respiratory distress syndrome (ARDS) [START_REF] Altschuler | Dapsone, colchicine and olanzapine as treatment adjuncts to prevent COVID-19 associated adult respiratory distress syndrome (ARDS)[END_REF]. The cytokine regulatory ability has also been hypothesized with antidepressants as anti-inflammatory agents against COVID-19 and thus it would be possible to prevent cytokinestorm by evoking all SSRIs (and other antidepressants; [START_REF] Fitzgerald | Noradrenergic and serotonergic drugs may have opposing effects on COVID-19 cytokine storm and associated psychological effects[END_REF]) or in a targeted manner with fluoxetine [START_REF] Wang | A longitudinal study on the mental health of general population during the COVID-19 epidemic in China[END_REF]. However, even though cytokine regulation seems to be acquired with the use of antidepressants, the specificity of such a mechanism over IL-6 has been put in question by recent data [START_REF] Almeida | Inflammatory modulation of fluoxetine use in patients with depression: A systematic review and meta-analysis[END_REF][START_REF] Hannestad | The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis[END_REF][START_REF] Liu | Peripheral cytokine levels and response to antidepressant treatment in depression: a systematic review and meta-analysis[END_REF][START_REF] Więdłocha | Effect of antidepressant treatment on peripheral inflammation markers -A meta-analysis[END_REF]. Other pharmacological mechanisms which could be useful against SARS-CoV-2 through psychotropics were also identified and herein we highlight: the modulation of sigma receptor activity [START_REF] Gordon | A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing[END_REF][START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF][START_REF] Yang | Identification of SARS-CoV-2 entry inhibitors among already approved drugs[END_REF][START_REF] Vela | Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?[END_REF][START_REF] Yesilkaya | Reissuing the sigma receptors for SARS-CoV-2[END_REF], modulation of ACE-2 receptor activity [START_REF] Sheikhpour | The Current Recommended Drugs and Strategies for the Treatment of Coronavirus Disease (COVID-19)[END_REF][START_REF] Sinha | In vitro and in vivo identification of clinically approved drugs that modify ACE2 expression[END_REF], and modulation of 5-HT2A receptor activity [START_REF] Zimering | Inverse Association between Serotonin 2A Receptor Antagonist Medication Use and Mortality in Severe COVID-19 Infection[END_REF]. Moreover, nicotine was evoked early on as a substance with anti-SARS-CoV-2 properties because of the low incidence of smokers hospitalised during the beginning of the pandemic in China [START_REF] Farsalinos | Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system[END_REF]. Smoking, however, cannot be seen as a therapeutic strategy against COVID-19, and there is robust evidence pointing to it as a risk factor leading to more severe forms of the disease [START_REF] Takagi | Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option?[END_REF]. Nevertheless, it seems that the halt in smoking (and consequently, in nicotine intake) caused by hospitalization in severe COVID-19 cases can be an aggravating factor for smokers [START_REF] Farsalinos | Current smoking, former smoking, and adverse outcome among hospitalized COVID-19 patients: a systematic review and meta-analysis[END_REF][START_REF] Farsalinos | Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option?[END_REF]. Through its immunomodulatory effects and its complex interactions with renin-angiotensin system, nicotine can offer a potential prophylactic option for COVID-19 and/or a protective factor against cytokine-storm only in current smokers during hospitalization [START_REF] Farsalinos | Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option?[END_REF]. Other data on psychoactive substances such as cannabis, cannabis-derived products [START_REF] Wang | In search of preventive strategies: novel high-CBD Cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues[END_REF] -with oral cannabis/cannabinoids (for example: cannabidiol, dronabinol and nabilone -approved by the FDA), oromucosal sprays (nabiximols -approved in Canada and in many European countries) -, and oxytocin [START_REF] Buemann | Can intravenous oxytocin infusion counteract hyperinflammation in COVID-19 infected patients?[END_REF][START_REF] Diep | Hypothesis: Oxytocin is a direct COVID-19 antiviral[END_REF][START_REF] Thakur | Oxytocin as a Potential Adjuvant against COVID-19 Infection[END_REF], which is available as an injectable treatment in several countries should also be highlighted. However, the possible benefits of cannabis and its derivatives must be carefully evaluated and communicated to avoid that retailers of these products make unsupported medical claims about their products given the risks involved.

A number of favorable chemical properties with anti-SARS-CoV-2 activity have been identified and those are shared by a large number of psychotropic drugs. For instance, cationic amphiphilic drugs (CADs) are a group of compounds that share at least two features: a cationic center, and a lipophilic portion [START_REF] Kornhuber | Functional inhibitors of acid sphingomyelinase (FIASMAs)[END_REF]. CADs have lysosomotropic effects and may disturb endosomal processes for viral entry [START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF][START_REF] Vaugeois | Psychotropics drugs with cationic amphiphilic properties may afford some protection against SARS-CoV-2: A mechanistic hypothesis[END_REF] and thus could have significant anti-SARS-CoV-2 activity. Recently, a new pharmacological group named FIASMA, acronym for Functional Inhibitors of Acid SphingoMyelinase, has been proposed [START_REF] Kornhuber | Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications[END_REF]. Their pharmacological action inhibits Acid SphingoMyelinase (ASM), an enzyme that, when abnormally activated due to higher ceramide levels, could be behind several neuropsychiatric diseases, including depression [START_REF] Kornhuber | Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications[END_REF]. Usually FIASMAs have the following properties: they are CADs, they violate Lipinski's Rule-of-5 (Lo5), a rule for determining the bioavailability of compounds, more often than other non-FIASMA drugs, have the ability to cross the blood-brain barrier, and induce phospholipidosis [START_REF] Kornhuber | Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications[END_REF]. An interesting fact concerns the distribution of FIASMAs in the anatomical therapeutic chemical (ATC) drug classification system, since over 40 % of the known FIASMAs belong to groups N04, N05 and N06 -which are anti-Parkinson drugs, psycholeptics and psychoanaleptics, respectively -, and this supports the great importance of psychotropics in FIASMA and the fact that their clinical effects may be related, at least in part, to their functional inhibition of ASM [START_REF] Kornhuber | Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications[END_REF]. The acid sphingomyelinase/ceramide system seems to play an important role in bacterial and viral infections and Carpinteiro et al. [START_REF] Carpinteiro | Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells[END_REF] demonstrated that SARS-CoV-2 activates and uses this pathway for infection. In this sense, Carpinteiro et al. [START_REF] Carpinteiro | Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells[END_REF] and Schloer et al. [START_REF] Schloer | Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine[END_REF] showed the benefit of amitriptyline, imipramine, desipramine, maprotiline, fluoxetine, fluvoxamine and sertraline, which display properties to inhibit ASM and therefore appear as a potential strategy against SARS-CoV-2.

However, it should be noted that recent data suggest that having a psychiatric disorder could increase the risk of being affected, of developing a severe form or of dying of COVID-19 [START_REF] Lee | Association between mental illness and COVID-19 susceptibility and clinical outcomes in South Korea: a nationwide cohort study[END_REF][START_REF] Taquet | Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA[END_REF][START_REF] Li | Association of a Prior Psychiatric Diagnosis With Mortality Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Infection[END_REF]. Moreover, psychotropic drugs could increase COVID-19 mortality in the elderly [START_REF] Lee | Risk of Mortality in Elderly Coronavirus Disease 2019 Patients With Mental Health Disorders: A Nationwide Retrospective Study in South Korea[END_REF]. This reinforces the need for studying the reported drug prophylactic factor in psychiatry settings. Conflicting data exist for nicotine (see previously). Moreover, it is important to assess whether the increased risk of aggravation in mental health patients hospitalized for COVID-19 arise from the reduction or cessation of all or part of their psychotropic medications with potential anti-SARS-CoV-2 activity.

Taken together, these data suggest that the use of certain substances usually prescribed in psychiatric settings, like phenothiazines or some antidepressants, should be studied for their potential efficacy against SARS-CoV-2 [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Javelot | Psychoactive compounds as multifactorial protection factors against COVID-19[END_REF][START_REF] Plaze | Repurposing chlorpromazine to treat COVID-19: The reCoVery study[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF]; see Table 4 for a summary of data on psychotropic drugs and antiviral activity against coronaviruses. However, one must have in mind the side effects that come with such treatments; their sedative potential -particularly dangerous for patients with respiratory depression [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF][START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF] -, their anticholinergic effects, and most importantly their possible cardiovascular impact and their risk for increasing the QT interval [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF], call for caution.

Up until now, the data presented on the prophylactic properties of psychotropic drugs are not enough to change the existing guidelines for them, since these should be primarily guided by safety criteria [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF]. Nevertheless, having in mind the unpredictable evolution of the COVID-19 pandemic, the possibility of having an extended sanitary crisis that could last months, or even years, should be taken into account, and in this case new and more conclusive information on the eventual benefits of psychotropics against coronavirus disease could change existing recommendations on these treatments. For instance, if based only on the safety information currently available, sedative neuroleptic medication like phenothiazines and tricyclic antidepressants should be avoided because of their multiple undesirable anticholinergic and antihistaminic side effects (recommendation n°4 in Ostuzzi et al. [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF] and see Jarvis et al. [START_REF] Jarvis | Evaluation of drugs for potential repurposing against COVID-19 using a tier-based scoring system[END_REF]). However, if for example new data appears that is able to strongly confirm the benefits of chlorpromazine for COVID-19 patients (see clinical trials in Table 4), then certainly these guidelines could be subject to changes.

It should be noted that, if phenothiazines do show chemoprophylaxis for mentally ill patients, then other related treatments should also be investigated. Thiethylperazine has already shown anti-MERS-CoV activity [START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF] and anti-SARS-Cov-2 activity on the data in Weston et al. [START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF], and metopimazine could show class effect activity. Since they are both antiemetic medications, they could be doubly indicated against COVID-19 cases showing digestive symptoms. Also, investigating other drug classes, loperamide, which has minimal central nervous system side effects and has shown structural similarity both with fluspirilene -was shown to have anti-SARS-CoV-1, anti-MERS-CoV [START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF] and anti-SARS-CoV-2 [START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF] activity and with pimozide and penfluridol (diphenylbutylpiperidine) -presents anti-SARS-CoV-1, anti-MERS-CoV and anti-HCoV229E [START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF] efficacy. Overall, this should lead us to be aware of symptoms such as nausea / vomiting and diarrhea following COVID-19, and to target them first with a combination of thiethylperazine or metopimazine + loperamide.

Evidence for severe adverse reactions

Data is also ambiguous concerning the potential cardiologic effects of some treatments. On the one hand, caution is rightfully strongly encouraged for psychotropics with torsades de pointes (TdP) risk (see Osttuzi et al. [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF]recommendation n°6; [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]), however, on the other hand a few of these drugs which present potential risk of the QTc interval prolongation also show prophylaxis and/or healing potential against SARS-CoV-2 ( [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF] and see Table 4). This shows that clinical investigation on these treatments should still be conducted in order to establish the existing risks and benefits of them in COVID-19 cases.

For drugs such as clozapine and lithium, the monitoring required is even more necessary, given their potential toxicity in patients suffering from COVID-19 (this is particularly the case for clozapine) [START_REF] Siskind | Consensus statement on the use of clozapine during the COVID-19 pandemic[END_REF][START_REF] Govind | Clozapine treatment and risk of COVID-19 infection: retrospective cohort study[END_REF][START_REF] Llesuy | Death From COVID-19 in a Patient Receiving Clozapine: Factors Involved and Prevention Strategies to Consider[END_REF][START_REF] Suwanwongse | Lithium Toxicity in Two Coronavirus Disease 2019 (COVID-19) Patients[END_REF]. However, given the therapeutic gains associated with them, notably for suicide prevention (see [START_REF] Müller-Oerlinghausen | The Contributions of Lithium and Clozapine for the Prophylaxis and Treatment of Suicidal Behavior[END_REF][START_REF] Zalsman | Suicide prevention strategies revisited: 10-year systematic review[END_REF] and see above), these treatments should also be carefully investigated to check for their benefits in patients with COVID-19 [START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF]. Furthermore, concerning sleep disorders -which, as mentioned previously, now affect both COVID-19 patients and people suffering from anxiety due to the pandemic -melatonin appears as the first choice hypnotic therapy in the SARS-CoV-2 crisis thanks to its good tolerance, to the absence of withdrawal syndrome risk and impact on respiratory capacities, and to its potential benefits of use on COVID-19 [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] Zhou | Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2[END_REF]. This is all the more true since melatonin is now considered to be one of the first line treatments for agitation [START_REF] Baller | Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19[END_REF].

While there is data which seems to confirm positive effects of some drugs for COVID-19 cases, there is also evidence that suggests otherwise, recommending further investigation for dangerous effects of certain medications. Dextromethorphan, for instance, can be used to treat dry cough, a symptom present in almost 70% of COVID-19 cases according to the World Health Organisation [START_REF] Lima | Information about the new coronavirus disease (COVID-19)[END_REF], and can also be associated to quinidine in the first and only FDAapproved treatment against pseudobulbar affect. However, as recently proposed by data in Gordon et al. [START_REF] Gordon | A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing[END_REF], it appears that dextromethorphan evoked pro-viral activity, which is contradictory with other sources of information that considered it safe for patients affected by COVID-19 [START_REF] Li | Existing bitter medicines for fighting 2019-nCoV-associated infectious diseases[END_REF].

Practical recommendations

As it can be demonstrated by the conflicting information mentioned in the last paragraphs, rigorous clinical evaluation of the prophylactic and/or healing potential of psychotropics for COVID-19 must be conducted. An accurate adjusted framework of their risks and benefits can be constructed by examining the danger of its side effects -central nervous systems risks, respiratory depression, increased infectious and cardiovascular risks -in perspective alongside the possibility of creating different psychopharmacotherapeutic strategies for COVID-19 and mentally ill patients [START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] Farsalinos | Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system[END_REF][START_REF] Polosa | COVID-19: counter-intuitive data on smoking prevalence and therapeutic implications for nicotine[END_REF]].

Since it is not possible to retrospectively identify the substance(s) involved in the initial prophylaxis in patients with mental health disorders, it is necessary to prospectively investigate whether a possible shared pharmacological effect by a group of substances play a role in this hypothetical chemoprotection. It appears particularly relevant to check whether the "antihistamine load" (with potentially one or more drugs presenting anti-H1 antihistamine effects and with a profile of CAD and +/-FIASMA) in mental health patients reduces the risk of having severe forms of Covid-19. If such is the case, a multifactorial chemoprophylaxis, based on the additive or synergistic efficacy of several psychoactive compounds with the different endocytic pathways that they affect [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Glebov | Understanding SARS-CoV-2 endocytosis for COVID-19 drug repurposing[END_REF], might have played a protective role against Covid-19 in patients with mental health disorders at the onset of the pandemic.

Conclusion

Considering the unforeseen sanitary situation caused by the COVID-19 pandemic, a number of difficulties arise in structuring relevant recommendations for clinicians.

The speed which information can be become obsolete encourages people to turn to on-line and regularly updated sources, such as the AZCERT website (for QT informations), the Liverpool and Oxford universities sites (for drug-drug interactions and general recommendation for psychiatric care during the pandemic, respectively), even though there are necessary adjustments to be made in order to adapt these general recommendations to the restrictions and available treatments of each country.

Another challenge is knowing whether the most relevant recommendations come from the best constructed pharmacoepidemiological reviews evaluating similar, but not identical, situations [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF], or from individual psychopharmacological knowledge of each treatment concerning the evolving information available for this emerging disease [START_REF] Jamwal | An updated insight into the molecular pathogenesis, secondary complications and potential therapeutics of COVID-19 pandemic[END_REF]. Similarly to what was recently suggested by Ostuzzi et al. [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF], although drug safety seems to be feasible in all psychotropic drug classes, this analysis by the AMSTAR-2 criteria can only rely on very few high quality data whose extrapolability to the current sanitary situation is debatable: only two studies with antidepressants in adults with depression and ischemic heart and chronic obstructive pulmonary diseases presented high AMSTAR-2 scores. This information must be analyzed in order to establish cautionary measures for the respiratory and cardiovascular systems (recommendations n°3 to 5 and n°6, 7 and 9, respectively), for the infection risk (recommendation n°8), and central effects risk (recommendation n°10). This shows that the data in academic studies must be constantly re-evaluated, so that the risk associated with the drug can be anticipated (preventive pharmacovigilance; e.g. clozapine and risk of pneumonia -[2,3,8]), while recommendations are progressively adjusted according to new knowledge on the disease.

A distinction should also be made between the guidelines on psychopharmacologic treatments given to patients suffering from COVID-19 [START_REF] Ostuzzi | Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations[END_REF] with little or no history of psychiatric disease and the drug safety recommendations for patients with chronic use of psychotropics, even in the case of similar treatments. For instance, the guidelines in case of acute hallucinations in COVID-19 patients may be different if the person has not had any psychiatric treatment before or if he or she has had previous hallucination episodes that were controlled with regular medication that was potentially interrupted; in the latter case it would be preferable to reintroduce or readjust treatment despite coronavirus disease.

In addition to this, weighing risks and benefits of psychotropic treatments could also be reconsidered in the medium term because of the positive effects of certain treatments [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF][START_REF] Gordon | A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing[END_REF][START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF][START_REF] Yang | Identification of SARS-CoV-2 entry inhibitors among already approved drugs[END_REF][START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF]. In order to consider this information, clarification and confirmation of the low initial prevalence of COVID-19 cases in psychiatry and the possible implication of chemoprophylaxis by psychotropic drugs is required. This confirmation is even more relevant since certain psychotropic treatments with potentially positive effects on COVID-19 cases, such as the phenothiazines, could cause undesirable adverse side effects which are highly counterproductive for COVID-19 recovery, as: sedation, respiratory depression, anticholinergic effects and accentuation of the disease impact on the central nervous system, prolonged QTc interval and prothrombotic effects.

These facts should encourage the community to observe in the months and years to come how much the preventive pharmacovigilance and antiviral efficacy of psychotropics could influence one another, in order to well determine the risks and benefits assessment guiding their use. It seems recommendable to re-discuss and question regularly the tradeoff of such treatments in the months to come, as new data appears with the evolution of the pandemic.

The observation of long COVID-19 cases reminds us that our concerns about the disease will most likely not vanish with the end of the pandemic [START_REF] Butler | Neuropsychiatric complications of covid-19[END_REF]. The higher rates of psychotic disorders in adulthood for children born during influenza pandemics, the increase of cases of autism, schizophrenia and epilepsy in the case of maternal viral infections during pregnancy and the memory of lethargic encephalitis in the years following the Spanish flu, could build the risk of an "ultimate / third neuropsychiatric wave" after the infectious waves of COVID-19 [START_REF] Butler | Neuropsychiatric complications of covid-19[END_REF][START_REF] Pantelis | Neurological, neuropsychiatric and neurodevelopmental complications of COVID-19[END_REF][START_REF] Shorter | The first psychiatric pandemic: Encephalitis lethargica, 1917-27[END_REF]. These complications and these potential neuropsychiatric consequences also prompt us to define the best use of psychotropic drugs in the face of these emerging issues.

Table 1: General adaptations of prescriptions of psychotropic drugs in patients with co-occurring COVID-19 (adapted from Javelot et al., 2020 [START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF])

General recommendations

-Follow the standard posology (doses and rhythms of administration) -Follow the recommended prescription duration (especially with benzodiazepines for elderly patients and with antipsychotics for dementia) -Adapt the dosage according to country recommended guideline in case of hepatic and renal insufficiency -Check for all drug interactions, especially those that may lead to an increase in: • prescribed drug plasma concentration • torsadogenic risk (which may be related to the previous risk) • respiratory distress risk • anticholinergic load

Targeted recommendations

Overall, therapeutic adaptations must be prudent and weighed in terms of the benefit/risk ratio: → risk of psychic and/or somatic destabilization (drug withdrawal syndrome in a highly anxiety inducing pandemic period) → Always privilege maintaining the necessary and sufficient treatments for psychological wellbeing, without modifications not based on evidence → Due to the particular risks regarding clozapine (see [START_REF] Govind | Clozapine treatment and risk of COVID-19 infection: retrospective cohort study[END_REF]) it is recommended to follow the recommendations established by Siskind et al. [START_REF] Siskind | Consensus statement on the use of clozapine during the COVID-19 pandemic[END_REF] -sedation, confusion -Possible increased risk of pneumonia in combination with carbamazepine or valproate + antipsychotics [START_REF] Yang | Antipsychotic drugs, mood stabilizers, and risk of pneumonia in bipolar disorder: a nationwide case-control study[END_REF] -Reassess all treatments that may increase lithemia -If fever: perform a lithemia Adaptations: -See Table 1 -Adapt dosage according to lithemia and/or signs of lithium overdose (nausea, tremor, thirst and balance disorders).

-There is no indication to switch, as it can compromise the patient's mental wellbeing. Antipsychotics Clozapine Risks: -sedation, confusion -cardiac (QTc prolongation ; see CredibleMeds) -atropine side effects [START_REF] Durán | Systematic review of anticholinergic risk scales in older adults[END_REF][START_REF] Salahudeen | Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review[END_REF] -dyspnea, respiratory distress -Account for the increased risk of pneumonia with antipsychotics, particularly in elderly and patients with dementia.

Risks:

-Elevated risk of infectious pneumonia -Pay special attention to: fever, flu-like symptoms and signs of overdose.

Adaptations:

-See Table 1 -Follow the standard recommendation of avoiding clozapine as first linetreatment, preferring atypical antipsychotics -There is no indication to switch, as it can compromise the patient's mental wellbeing. Suggested 50% reduction in clozapine dose only if fever, flu-like symptoms and signs of clozapine overdose [START_REF] Siskind | Consensus statement on the use of clozapine during the COVID-19 pandemic[END_REF]. = this adjustment should ideally take into consideration previous patient experience with dosage reduction.

Methylphenidate

Risks:

-Rhinopharyngitis, cough, sore throat, dyspnea -Digestive symptoms Adaptations:

-See Table -Antidepressants☨ -Benzodiazepines☨ -Antipsychotics☨ -Lithium☨ -Methylphenidate -Re-evaluate the benefit/risk ratio of the implicated drugs (posology: dose and dose frequency) + Frequent assessments in order to reevaluate implicated treatment -Ensure sufficient hydration -NSAIDs should be avoided due to renal toxicity that can aggravate dehydration.

-Lithium: Lithemia to be performed as soon as possible (possibility of adjusting the dosage in advance) -Valproate and derivatives: perform pancreatic and liver assessment -Methylphenidate: see if side effects improve through food intake -Management of nausea : * metopimazine, * domperidone if there are no cardiovascular contraindications (QTc prolongation in particular) -Diarrhea management: racecadotril, loperamide, diosmectite *During symptoms management, it is recommended to: -take a complete anamnesis, including all of the recent modifications made to psychotropic treatments (introduction, stop, switch, increase, decrease), in order to evaluate the possible iatrogenic involvement, -consider requesting emergency services if the situation requires it + / + Pharmacochemicallyrelated to benztropine with demonstrated antiviral activity against MERS-CoV, SARS-CoV-1, other viruses [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF] and potential anti-SARS-CoV-2 activity [START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF] Trihexyphenidyl* Anticholinergic [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF] + / not confirmed Tropatepine* Anticholinergic [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF] + / not confirmed

Diphenylbutanamine

Cetirizine †

(psychotropic status can be discussed)

Antihistamine [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF] [6]

+ / not confirmed Pharmacochemicallyrelated to chlorphenoxamine with demonstrated antiviral activity against MERS-CoV and SARS-CoV-1 [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Dyall | Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection[END_REF][START_REF] Dyall | Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies[END_REF] and with clemastine and cloperastine with potential antiviral activity against SARS-CoV-2 [START_REF] Gordon | A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing[END_REF][START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF][START_REF] Yang | Identification of SARS-CoV-2 entry inhibitors among already approved drugs[END_REF] Hydroxyzine* † Antihistamine

Table 3 :--

 3 Psychotropic drugs' effects on symptoms of COVID-19 (adapted from Javelot et al.[START_REF] Javelot | Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic[END_REF]) fatigue/confusion: restricted list of main drugs with central effects) Sedative antidepressants: agomelatine, amitriptyline, amoxapine, clomipramine, dosulepin, doxepin, esketamine, imipramine, maprotiline, mianserin, mirtazapine, trazodone, trimipramine) -Antipsychotics☨ -Benzodiazepines☨ -Mood stabilizers -Morphine and analogs (analgesics, antitussives, addictive drugs) -Medications with anticholinergic effects☨ -Sedative Antihistamines H1 -Barbiturics -To be taken into consideration when assessing the general state: * Sedative drugs * Medications which can cause orthostatic hypotension * Blood pressure lowering drugs -Re-evaluate the benefit/risk ratio of the implicated drugs (posology: dose and dose frequency) + Frequent assessments in order to reevaluate implicated Antidepressants☨ (sedative antidepressants: agomelatine, amitriptyline, amoxapine, clomipramine, dosulepin, doxepin, esketamine, imipramine, maprotiline, mianserin, mirtazapine, trazodone, trimipramine) -Medications with anticholinergic effects☨ -Antipsychotics☨ -Benzodiazepines☨ -Carbamazepine or valproate + antipsychotics (pneumonia)[START_REF] Yang | Antipsychotic drugs, mood stabilizers, and risk of pneumonia in bipolar disorder: a nationwide case-control study[END_REF] -Methylphenidate☨ -Morphine and analogs (analgesics, antitussives, addictive drugs) -Sedative Antihistamines H1 -Central Antihypertensives (clonidine, methyldopa, moxonidine, rilmenidine) -Others : NSAIDs, baclofene, beta blockers, barbituriques, pramipexole, prazosin, thalidomide -Re-evaluate the benefit/risk ratio of the implicated drugs (posology: dose and dose frequency) + Frequent assessments in order to reevaluate implicated treatments -Perform supplementary exams to distinguish between infectious and iatrogenic factors -Management of anxiety accompanying dyspnea (primarily through behavioral techniques) Medications with anticholinergic effects☨ -Clozapine (benign hyperthermia initially) ☨ -Antipsychotics☨ (NMS) -Antidepressants☨ (SS) -Mood Stabilizers and barbiturics (DRESS) -Re-evaluate the benefit/risk ratio of the implicated drugs (posology: dose and dose frequency) + Frequent assessments in order to reevaluate implicated treatments -Paracetamol is 1 st line treatment -Ensure sufficient hydration evaluate the benefit/risk ratio of the implicated drugs (posology: dose and dose frequency) + Frequent assessments in order to reevaluate implicated treatments -Prefer non opiate antitussives -Prevent deglutition disorders (especially in the elderly) -Rhinorrhea; contraindicates use of: * all sympathomimetic drugs including methylphenidate, * indirect sympathomimetics such as non-selective MAOIs and MAOI B = due to the risk of hypertensive crisis Diarrhea Nausea / vomits -Gastro-intestinal symptoms secondary to initiation of antidepressant or methylphenidate -Withdrawal syndrome -Lithium overdose -Pancreatitis due to valproate In the case of lithium overdose: look for characteristic symptoms (tremors, thirst and balance problems).

Benz

Table 2 :

 2 Psychotropic treatment adaptation in case of COVID-19 -organized by drug class (adapted from Javelot et al. [1])

	MEDICATIONS
	Benzodiazepines	Risks:	Adaptations:
		-sedation, confusion	-See
		-respiratory distress :
		• in the situations when BZD are
		contraindicated,
		• in the event of exceeding the maximum
		doses and particularly of polydrug
		addiction with morphine,
		• if combined with other high risk
		treatments

Table 1

 1 -if first time prescription, prefer BZD with short half-life (especially in the elderly patient), -There is no indication to switch, as it can compromise the patient's mental wellbeing.

	Antidepressants	Risks:	Adaptations:
		-sedation, confusion	-See Table 1
		-cardiac (QTc prolongation; see	-if first time prescription prefer
		CredibleMeds)	antidepressants that are not (or less)
			sedating and without risk of QTc
			prolongation
			-There is no indication to switch, as it
			can compromise the patient's mental
			wellbeing.
	Mood stabilizers:	Risks:
	carbamazepine,
	valproate and
	lamotrigine
	Lithium

 [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF]and potential anti-SARS-CoV-2 activity [START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF][START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF] Cyamemazine* † ‡ FG antipsychotic [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF][START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF] + / not confirmed Fluphenazine FG antipsychotic + / not confirmed Metopimazine Antiemetic [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF] + / not confirmed Mequitazine Antihistamine [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF] + / not confirmed Pipotiazine FG antipsychotic [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF] + / not confirmed Propericiazine (periciazine/ pericyazine) FG antipsychotic [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF] + / not confirmed Promethazine Antihistamine + / + Pharmacochemicallyrelated to chlorpromazine (and flupentixol) with demonstrated antiviral activity against MERS-CoV, SARS-CoV-1 and other viruses for chlorpromazine [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF] and potential anti-SARS-CoV-2 activity (Chlropromazine [START_REF] Sauvat | On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2[END_REF][START_REF] Weston | Broad Anticoronavirus Activity of Food and Drug Administration-Approved Drugs against SARS-CoV-2 In Vitro and SARS-CoV In Vivo[END_REF] and flupentixol [START_REF] Yang | Identification of SARS-CoV-2 entry inhibitors among already approved drugs[END_REF] T(h)iot(h)ixene [3] [214,215] + / not confirmed Zuclopent(h)ixol [START_REF] Javelot | Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances[END_REF] + / not confirmed

Diphenylbutylpiperidines

Dibenzodiazepines and derivates

Clozapine † SG antipsychotic [START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF] [6]

+ / not confirmed Conflicting data from Govind et al. [START_REF] Govind | Clozapine treatment and risk of COVID-19 infection: retrospective cohort study[END_REF] Quetiapine † SG antipsychotic [START_REF] Villoutreix | Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders[END_REF] + / not confirmed Quinoline derivates Aripiprazole † S/TG antipsychotic [6] [6]

+ / not confirmed Atropine derivates

+ / + Nicotine † Substitution therapy tobacco smokers [3,6,

Partial