The novel coronavirus outbreak is a global health emergency that requires rapid adaptation of conventional clinical practices in many medical areas, including psychiatry. Coronavirus disease (COVID-19) is a systemic infection potentially targeting multiple organs and functions.
Interstitial pneumonia is the most important feature of this condition, causing severe respiratory distress requiring intensive life support in approximately one in twenty symptomatic cases. Old age and pre-existing medical comorbidities are associated with increased severity and mortality.
People with COVID-19 may often experience an onset or exacerbation of psychiatric manifestations in response to communication of the diagnosis, the need for forced isolation, the presence of highly distressing medical symptoms, and the possible risk of death.
Furthermore, intensive care support and experimental medical treatments with psychiatric side effects (e.g., antimalarials) could be an additional risk factor for the development of psychiatric symptoms and altered states of consciousness, including delirium.
Epidemiological data, although preliminary, showed that up to one in four patients could experience symptoms of anxiety or depression and approximately 15% could develop impaired states of consciousness, which is likely associated with a notable increased risk of death .
For these reasons, people with COVID-19 may require treatment with medications that target psychiatric manifestations. As in the general population, these medications are associated with a wide range of safety concerns, so in people with COVID-19 their use may be particularly challenging.
Psychotropic drugs may interact with medical treatments for COVID-19, and some of their adverse effects may worsen the course and outcome of the underlying medical condition.
In this context, the aim of this review of evidence and practice recommendations is to make frontline clinicians (including psychiatrists, other specialists and general practitioners) aware of the clinically relevant safety issues of the use of psychotropic drugs in people with COVID-19 and possible management strategies.
Methods
To produce practical evidence-based recommendations on the optimal management of psychotropic medications in people with COVID-19, an international, multidisciplinary working group was established. The methodology of the WHO Rapid Advice Guidelines in the context of a public health emergency and the principles of the AGREE declaration were followed .
The available evidence reporting on the risk of respiratory, cardiovascular, infectious, haemostatic and consciousness alterations related to the use of psychotropic medications and drug interactions between psychotropic and medical treatments used in people with COVID-19 was reviewed and discussed by workgroup.
Evidence synthesis
Drug interactions
In patients with COVID-19, the risks of drug interactions with psychotropic drugs may be relevant.
- First, the bioavailability and disposition of several psychotropic medications may be significantly affected by COVID-19-related systemic inflammation processes, impaired liver function, and abrupt cessation of smoking.
- Secondly, these drugs and medical treatments may reciprocally affect their plasma levels by inducing or inhibiting cytochrome P450 (CYP) activity to an extent that is poorly understood and difficult to predict.
- Third, these combinations are at risk for pharmacodynamic interactions, particularly QTc prolongation, and immune and coagulation abnormalities.
Respiratory risk
Data from randomized trials of antidepressants did not show an increased risk of respiratory distress and overall mortality in COPD patients (including elderly patients) exposed to selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) and guidelines indicate SSRIs as a safe option in people with medical conditions (including respiratory diseases).
However, data from a recent, large observational study showed an increased risk of worsening COPD or COPD-related hospitalization and mortality in elderly patients taking SSRIs and SNRIs compared with those not exposed.
Antipsychotics are associated with an increased risk of serious respiratory, thoracic, and mediastinal adverse events based on data from randomized trials. The risk of respiratory distress is probably greater for highly sedating agents, particularly at higher doses, in combination, and when prescribed in patients with pre-existing respiratory failure.
In case of psychomotor agitation requiring rapid calming with antipsychotics (e.g., hyperkinetic delirium), the risk of acute extrapyramidal symptoms (e.g., dystonia, with difficulty swallowing and consequent risk of aspiration) and reduced mobility may worsen. notably respiratory distress.
Mood stabilizers have mild to moderate sedative profiles, and there is no evidence of a relevant risk of excessive sedation and related respiratory distress. Although the risk of respiratory suppression with benzodiazepines is notably lower than others, it may be significantly high in people with acute respiratory distress and in the elderly. The risk of respiratory distress is related to the differential sedative properties of the different agents, their half-life, and is generally dose dependent.
Cardiovascular risk
People with COVID-19 may have several cardiovascular risk factors, including:
(a) Old age
(b) Pre-existing comorbid cardiovascular diseases.
(c) Use of medical treatments with QTc prolonging properties, often in combination (for example, with antivirals, chloroquine/hydroxychloroquine and antibiotics).
(d) Possible direct cardiotoxic effects of the coronavirus.
(e) Electrolyte alterations related to abnormal respiratory gas exchange.
The most important risk factors for serious arrhythmias, such as torsade de pointes , include the magnitude of QTc prolongation, preexisting heart disease, female sex, bradycardia, hypokalemia, and other electrolyte abnormalities.
Data from randomized studies in people with ischemic heart disease did not show an increased risk of cardiovascular mortality and non-fatal cardiac events for antidepressants (particularly SSRIs).
On the other hand, data from observational studies showed an increased risk of coronary heart disease for tricyclic antidepressants (TCAs), but not for SSRIs, and antidepressants as a class, while SSRIs but not TCAs were associated with an increased risk. of cerebrovascular disease. Tricyclic antidepressants and, to a lesser extent, citalopram, escitalopram, and venlafaxine have been associated with QTc prolongation, with a possibly increased risk in older patients.
Antipsychotics have been shown to be associated with serious cardiovascular events based on data from observational studies evaluating sudden cardiac death, myocardial infarction, and stroke, while data from randomized trials confirmed an increased risk of QTc prolongation for several antipsychotics, but not an increased risk of serious cardiac and vascular adverse events.
Combination antipsychotics and higher cumulative doses may contribute to QTc prolongation. In general, the risk of QTc prolongation should not be neglected for any antipsychotic.
The risk of arrhythmias is probably very low for mood stabilizers and benzodiazepines, with the possible exception of lithium, for which benign electrocardiographic changes and cases of ventricular arrhythmia and sudden cardiac death have been described.
Risk of infections
Systemic dysregulation of the immune response and inflammation is a key feature of COVID-19. The severity of inflammatory parameters (such as IL-6) has been associated with the risk of mortality, and immunosuppressive therapies may play a role in the treatment and prevention of complications.
Antidepressants have consistently been shown to have anti-inflammatory properties , although little is known about their possible role in systemic infections. In vitro studies showed a protective effect against bacteria and fungi, but a possibly increased risk of Clostridium difficile infection has been reported . Tricyclic antidepressants, and particularly clomipramine and imipramine, have been associated with possible blood dyscrasias , including neutropenia.
Antipsychotics have been associated with immunosuppressive properties, such as decreased levels of proinflammatory cytokines, blood dyscrasias, and altered antibody production. The risk of neutropenia is approximately 1% for clozapine (3% in the elderly) and 0.1% for phenothiazines, for other drugs data are scarce.
Additionally, first- and second-generation antipsychotics have been associated with an increased risk of pneumonia in observational studies. Data from randomized trials including mainly second-generation antipsychotics showed an increased risk of infections.
Additionally, multiple mechanisms may contribute, including reduced airway clearance (related to central sedation and cough inhibition), impaired thoracic movements and swallowing due to extrapyramidal symptoms, and sialorrhea. This risk could be particularly relevant for clozapine.
Carbamazepine, oxcarbazepine and, to a lesser extent, sodium valproate, have been associated with an increased risk of neutropenia, while lithium appears to be free of relevant immunological effects.
Data from observational studies showed an increased risk of pneumonia for benzodiazepines compared to non-users, for both older and younger patients, short- and long-term use, short- and long-term acting agents, and current and recent users. .
Clotting risk
Antidepressants have been associated with various alterations in hemostasis. Observational studies showed an increased risk of severe bleeding at different sites for SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) and an increased risk of thromboembolism for all antidepressant classes. The risk of bleeding is possibly higher in vulnerable patients (advanced age, pre-existing coagulation abnormalities, anticoagulant therapy, major surgery).
Antipsychotics have been clearly shown to be associated with an increased risk of thromboembolism in large observational studies, with a possibly increased risk in vulnerable populations with pre-existing risk factors. For mood stabilizers and benzodiazepines, the risk of pro- or anticoagulant effects is likely to be low.
Risk of delirium
Delirium has been frequently described in people with COVID-19 and is associated with a poor prognosis.
Many of the experimental medical treatments used for COVID-19 have a well-known risk of neuropsychiatric side effects (e.g., antimalarials and antivirals, interferons, corticosteroids) and may pose an additional risk.
The use of some psychotropic drugs is also a risk factor for delirium. In particular, benzodiazepines, antidepressants with anticholinergic properties (mainly TCAs, but possibly also paroxetine) and lithium are considered high risk based on data from observational studies.
Anticholinergic medications are often a precipitating factor and are associated with the severity of delirium. Data from a recent meta-analysis showed that olanzapine and risperidone were effective in preventing delirium compared with placebo or usual care, while midazolam increased its incidence.
Practical evidence-based recommendations Based on the considerations reported above and after collegial discussion, and taking into account values, feasibility, use of resources and certainty of evidence, the following practical recommendations were formulated: 1. The risk and severity of pharmacokinetic and pharmacodynamic drug interactions of COVID-19 medical treatments and psychotropic drugs should always be assessed, taking into account additional vulnerability related to the underlying medical condition (e.g. cardiovascular conditions which increase the risk of QTc prolongation). 2. In case of high-risk interactions, the combination should be avoided if possible. In case of moderate risk interactions, dosage adjustments, withdrawal from psychotropic medications, or switching to a safer medication should be considered. In case of low-risk interactions, regular monitoring should be provided, with dose adjustments as clinically appropriate. In case of very low risk interaction, regular monitoring is suggested. 3. The estimation of the risk related to respiratory depression should systematically take into account the following: (a) the intrinsic sedative properties of psychotropic drugs, their half-life (higher risk in those with a longer half-life), the dose and the onset from other aspects that possibly impair breathing (e.g., reduced motility, sialorrhea); (b) pharmacokinetic interactions that increase plasma levels of drugs with a sedative effect (e.g., lopinavir/ritonavir combined with quetiapine) and pharmacodynamic interactions (e.g., co-treatment with opioids); and (c) pre-existing respiratory failure (e.g., COPD) and degree of respiratory depression related to COVID-19. 4. Antipsychotics risk worsening respiratory function in people with COVID-19, particularly at high doses and when used in combination. Antipsychotics with highly sedative profiles should be avoided or used short-term. 5. The risk of respiratory failure associated with benzodiazepines in the general population is debated, but may be particularly relevant in elderly patients with COVID-19 and pre-existing comorbidities (e.g., COPD). Benzodiazepines should be avoided or used short-term (e.g., control of acute agitation), preferring those with a shorter half-life (e.g., etizolam, oxazepam, lorazepam). Although antidepressants are generally considered safe in terms of respiratory failure, caution is advised as the data are controversial. 6. Estimation of the risk of cardiovascular events related to psychotropic drugs should systematically take into account the following: (a) the intrinsic properties of psychotropic drugs that prolong QTc, their cumulative dose and their combined use; (b) pharmacokinetic interactions that possibly elevate plasma levels of QTc-prolonging medications and pharmacodynamic interactions (e.g., co-treatment with antivirals, chloroquine, hydroxychloroquine, and opioids); and (c) pre-existing cardiovascular conditions (particularly ischemic heart disease) and cardiovascular conditions related to COVID-19. 7. For interactions with a low to moderate risk of QTc prolongation, titration to a lower dose of one or both medications is generally required, along with regular monitoring by electrocardiogram. If these interactions are additive with other risk factors for QTc prolongation (e.g., cardiovascular comorbidities, electrolyte abnormalities), the risk drugs should be avoided, withdrawn, or switched to safer drugs as clinically appropriate. 8. Antipsychotics, benzodiazepines, and some mood stabilizers may be associated with an increased risk of secondary infections in people with COVID-19 and possibly an unfavorable course of systemic infections. The risk is likely to be particularly relevant for clozapine, carbamazepine and oxcarbazepine. Therefore, regular monitoring is indicated. 9. In people with COVID-19, both antipsychotics and antidepressants may increase the risk of thromboembolism, particularly in the elderly. In people with COVID-19 on heparin prophylaxis, antidepressants may increase the risk of bleeding, with an increased risk for serotonergic agents (i.e., SSRIs and SNRIs), especially in elderly patients. Regular monitoring is indicated. If additional risk factors for bleeding exist (e.g., other coagulation abnormalities, old age, anticoagulant therapy, major surgery), dosage adjustment or withdrawal of risk drugs should be considered, as clinically appropriate. . 10. In people with COVID-19 and known risk factors for delirium (e.g., old age, dementia, multiple comorbidities), the use of agents with anticholinergic properties (e.g., tricyclic antidepressants and paroxetine), benzodiazepines (particularly midazolam), and lithium should generally be avoided. 11. In patients with COVID-19 who are already being treated with psychotropic drugs, an accurate assessment of current psychiatric symptoms and previous psychiatric history is important to review the need for continued treatment and its dosage. 12. In addition to psychotropic medications, and when drug treatment is clinically inappropriate, clinicians should carefully evaluate whether supportive psychosocial interventions are provided, including electronically administered (remote) interventions. |
Discussion
Overall, the authors found that all classes of psychotropic medications have safety issues potentially relevant to people with COVID-19. The magnitude of the risk of individual agents or drug classes was unclear or unreliable in most cases, the risk of unfavorable outcomes must be carefully weighed on a case-by-case basis, in light of a number of coexisting risk factors. Therefore, it is difficult to provide recommendations limited to specific clinical situations or individual medications.
Although the task force selected a number of safety issues to address, other principles of medication management should not be overlooked. In particular, as acute multifactorial liver and kidney injury has been described in people with COVID-19, liver and kidney function should be closely monitored.
Possibly hepatotoxic drugs (e.g., valproate, carbamazepine, tricyclic antidepressants) and nephrotoxic drugs (e.g., lithium), as well as psychotropic drugs extensively metabolized by the liver (such as most antidepressants, antipsychotics, and mood stabilizers). mood) and subject to renal excretion (e.g., lithium, gabapentin, topiramate, pregabalin, and paliperidone), should be reviewed periodically to adjust the dose or withdraw the medication in case of high clinical risk.
Practical recommendations were made to support clinicians in assessing and managing risk related to psychotropic medications. In many cases, adjusting the dosage of medical or psychotropic medications is probably a satisfactory and pragmatic safety measure. However, when the risk of serious adverse events is relevant, it may be necessary to withdraw the medication or change it to a safer one.
In any case, an accurate assessment of current psychopathology is key, considering that, for some patients, psychotropic treatments are essential (e.g., long-term maintenance with antipsychotics or mood stabilizers) and should be protected, while that, for some other patients, their dose may be reduced or even withdrawn (taking into account, for example, that benzodiazepines and antidepressants are frequently prescribed inappropriately), provided that good practices are followed to control the risk of withdrawal .
Conclusions Currently, many COVID-19 patients require treatment with psychotropic drugs, the proper management of which is particularly difficult in light of the underlying medical condition and the high risk of drug interactions. Clinicians should be vigilant when prescribing psychotropic agents in patients receiving medications for COVID-19. Similarly, when deciding to prescribe experimental treatments in patients under long-term psychopharmacological treatment, doctors should be extremely cautious considering that medical treatments for COVID-19 are still experimental and their effectiveness is debated. Fortunately, as clinical interventions can be best delivered when clear, evidence-based guidance is provided, the pragmatic principles outlined here may support optimal management of psychotropic medications in patients with COVID-19, with the goal of potentially addressing psychopathology. emergent and maintain control of the underlying psychiatric illness, mitigate the potentially aggravating effects of psychological stress, and generally manage the medical condition without worsening the psychiatric condition and vice versa. |
