Drug-Drug Interactions Between COVID-19 Treatments and Psychotropic Medications: An Updated Study

The recent evolution of coronavirus disease 2019 (COVID-19) treatments has created challenges for healthcare providers in terms of new potential interactions between these COVID-19 treatments and psychotropic drugs in patients with psychiatric disorders. Current clinical practice guidelines on managing interactions between psychotropic medications and COVID-19 treatments do not account for the newer COVID-19 medications. There is a need for updated patient management recommendations that take into account drug interactions between psychotropic drugs and the latest pharmacological approaches to COVID-19 treatment. A search of literature pertaining to drug interactions and outcomes in patients concurrently prescribed COVID-19 treatments and psychotropic medications was conducted. Drug databases were also analyzed to screen for interactions. Our review focuses on the most recent and effective COVID-19 treatments, including PaxlovidTM (nirmatrelvir/ritonavir), remdesivir, dexamethasone, tocilizumab, and baricitinib. The study provides condensed and easily interpretable tables for healthcare providers to screen for potentially harmful drug interactions. We discuss the implications of our findings on appropriate treatment plan selection by healthcare providers for patients taking select antipsychotics, antidepressants, mood stabilizers, and benzodiazepines while receiving COVID-19 treatments. Notably, PaxlovidTM may interact with several medications, particularly antipsychotics and anxiolytics, necessitating close monitoring and, in some cases, reconsideration of use. We find that dexamethasone, remdesivir, tocilizumab, and baricitinib have fewer reported interactions with psychotropics, and while some monitoring is necessary, no major adjustments are recommended for their administration in conjunction with psychotropic medications. These findings underscore the importance of careful consideration and monitoring when combining COVID-19 treatments with other medications to mitigate the risk of adverse interactions and ensure patient safety.


Introduction And Background
Patients with coronavirus disease 2019 (COVID-19) often present with comorbidities, including psychiatric disorders such as schizophrenia spectrum disorders, bipolar spectrum disorders, anxiety disorders, and major depressive disorders.Many of these individuals are on maintenance treatment for their psychiatric conditions, but the stress and isolation associated with COVID-19 can lead to an exacerbation of psychiatric symptoms, necessitating medication management adjustments or additional psychiatric interventions [1].Moreover, in some cases, COVID-19 can induce new-onset psychiatric manifestations, including delirium, mood disturbances, anxiety, and psychosis, which may require treatment with antipsychotics such as haloperidol and sedatives such as lorazepam [1].These observations align with scientific research and clinical experience, underscoring the intricate interplay between COVID-19 and mental health and emphasizing the importance of individualized patient assessments in guiding treatment decisions [1,2].
Psychotropic medications may interact with medical treatments for COVID-19, potentially exacerbating adverse effects and influencing the course and outcome of the underlying medical condition [3].To address this concern, numerous studies have investigated the interactions between psychotropics and COVID-19 medications [3][4][5].However, it is essential to acknowledge several noteworthy limitations inherent in these investigations.Firstly, these studies have primarily examined a restricted subset of psychotropic medications, thus omitting several widely used psychotropics in clinical practice, including lurasidone, oxcarbazepine, topiramate, lamotrigine, temazepam, fluphenazine, and ziprasidone.This limitation raises concerns about the comprehensiveness of the findings and necessitates further exploration into the interactions involving these specific psychotropics.Secondly, the dynamic nature of COVID-19 treatments has significantly evolved over the past one to two years, leading to a notable shift in the medications employed to manage the infection.For instance, treatments such as hydroxychloroquine and azithromycin, which were once considered, are no longer recommended for COVID-19 management.Furthermore, the most current guidelines for COVID-19, as of January 2022, now incorporate a combination therapy involving nirmatrelvir and ritonavir [6,7].
Regrettably, these evolving aspects have not been adequately addressed in previous review articles investigating the interactions between psychotropics and COVID-19 medications [3][4][5]8].The prevalence rates of various psychiatric symptoms during the COVID-19 epidemic, such as an overall prevalence of depressive symptoms (depression) at 23.9%, anxiety symptoms (anxiety) at 23.4%, stress at 14.2%, distress at 16.0%, insomnia symptoms at 26.5%, post-traumatic stress symptoms (PTSS) at 24.9%, and poor mental health at 19.9% [1].Many patients with underlying psychiatric disorders may be infected with COVID-19, and up to 25% of patients affected by COVID-19 were shown to experience new-onset psychiatric manifestations [3].These statistics provide insights into the mental health impact of the COVID-19 pandemic, highlighting the strong comorbidity between COVID-19 and psychiatric illness and the importance of consideration of drug interactions in the concurrent management of these conditions.
The authors performed a literature search using updated COVID-19 treatment regimens to identify novel interactions between psychotropics and COVID-19 treatments.Our objective was to leverage the latest evidence on pharmacological interactions to furnish valuable guidance for the prudent and effective administration of psychotropic medications in individuals with psychiatric conditions undergoing treatment for COVID-19.

Review Methods
A literature search was conducted with search terms COVID-19 treatment AND (Sars-CoV-2 treatment OR Coronavirus Disease-19 treatment OR Sars Coronavirus 2 treatment OR Coronavirus 2019 treatment) through Google Scholar and PubMed databases.National Institute of Health (NIH), Centers for Disease Control and Prevention (CDC), Wolters Kluwer's UpToDate, and Merck Manual were also consulted to determine the currently recommended COVID-19 treatments to consider for interaction with psychotropic medication.Paxlovid (nirmatrelvir/ritonavir), dexamethasone, remdesivir, tocilizumab, and baricitinib were determined to be the recommended COVID-19 treatments to consider for interactions with psychotropics.Previously reported COVID-19 treatments, such as hydroxychloroquine, were not considered due to newer guidelines detailing their lack of efficacy.Psychotropic medications to consider for drug interaction were selected by determining the most commonly used medications in the four major categories of psychopharmacology, antipsychotics, antidepressants, mood stabilizers, and benzodiazepines.The next step was to review the drug-drug interactions between the aforementioned COVID-19 medications and commonly used psychotropic medications in patients with COVID-19.The search strategy used the syntax: COVID-19 AND (psychotropics OR antipsychotics OR antidepressants OR mood stabilizers OR benzodiazepines OR Paxlovid OR dexamethasone OR remdesivir OR tocilizumab OR baricitinib).Additional drug interaction databases, namely Lexicomp, Micromedex, and Epocrates, were used to construct tables summarizing known interactions between selected drugs using data such as interaction type, severity, and management recommendations.
Two researchers independently conducted the screening, data extraction, and quality assessment processes, with any discrepancies resolved through a consensus-driven approach and the involvement of two additional researchers.This methodological strategy was implemented to ensure a rigorous and transparent synthesis of evidence concerning drug interactions between psychotropic medications and COVID-19 treatments.The integration of both quantitative and qualitative methods is pursued to achieve a comprehensive understanding of the subject matter.
The qualitative analysis focused on data derived from case studies, case reports, and pharmacological studies pertaining to drug interactions.Parameters such as study type, drug interactions, clinical outcomes, changes in management, and sample size were systematically extracted by the researchers.A narrative synthesis was then crafted to elucidate common mechanisms through which these interactions manifested.
In addition to the aforementioned sources, data on drug interactions was sourced from reputable drug databases, including Lexicomp, Micromedex, and Epocrates.A systematic categorization approach was adopted: interactions flagged as severe by one or more databases were labeled as "contraindicated," while those identified as having moderate interactions by two or more databases were characterized as requiring "therapy modification" or "monitoring."The absence of reported drug interactions across all databases led to the characterization of the interaction as "no known interaction."This meticulous process enhances the reliability and validity of our findings, contributing to a robust analysis of drug interactions in the context of psychotropic medications and COVID-19 treatments.
Inclusion criteria were set to filter for review, case reports/series, and randomized controlled studies that reported on clinical events and outcomes (Figure 1).Exclusion criteria were set to those that focused solely on pharmacodynamics/kinetics and those that did not report clinically relevant outcomes.Articles older than 10 years were excluded.Articles published before 2013 were excluded.Data extracted from reviewed articles included diagnosis, clinical outcomes, drug interaction, interaction type, and intervention.Suggestions (e.g., consider a switch, monotherapy) based on the articles reviewed were also summarized and used in recommendations for managing medication interactions.A summary of the findings from the literature on drug-drug interactions is shown in Table 1.

Review
Authors used drug interaction checkers such as Lexicomp in conjunction with pharmacokinetic modeling to propose dose adjustments for drug interactions between nirmatrelvir/ritonavir and select psychotropic medications.

Case series
In summary, the study found a significant drop in neutrophil count in psychiatric inpatients on clozapine with COVID-19.Clinicians should closely monitor neutrophil counts in these patients, considering the potential interaction between clozapine and COVID-19.

Drug-Drug Interactions: Antipsychotics and COVID-19 Treatments
Paxlovid TM , a combination of the antiviral drugs nirmatrelvir and ritonavir, is a CYP3A4 substrate and also inhibits CYP3A4 [9].This can result in potentially harmful interactions when used in combination with certain antipsychotics, as they too are heavily metabolized by CYP3A4 [9].Interactions have been reported with lurasidone and should be avoided, while the use of Paxlovid TM with aripiprazole [21], brexpiprazole [22], cariprazine [23], Iloperidone [24], and quetiapine [25] should be reconsidered and closely monitored.
Haloperidol [26], clozapine [27], olanzapine [28], and risperidone [27] are also metabolized by CYP3A4 and should be closely monitored, but can be considered for combination therapy if the patient's drug levels and health are closely monitored.On the other hand, no known interactions have been reported between Paxlovid TM and chlorpromazine, fluphenazine, loxapine, perphenazine, trifluoperazine, asenapine [29], or paliperidone.
Remdesivir, an antiviral that inhibits viral RNA polymerase, and tocilizumab, a monoclonal antibody that inhibits interleukin-6 (IL-6) receptors, have not shown any known interactions with antipsychotics based on data from various databases [5].However, tocilizumab may have potential hepatotoxic side effects when used in combination with clozapine [5].In addition, there are some reports that tocilizumab may decrease the serum concentration of CYP3A4 substrates [4].As a result of the findings in Table 2, Table 3 provides a summary of recommendations for the combinations of antipsychotics and medications used to treat COVID-19.

Drug-Drug Interactions: Antidepressants and COVID-19 Treatments
Based on information from various databases, there are no known interactions reported between remdesivir and most antidepressants.However, it is not recommended to use remdesivir in combination with St. John's Wort as St. John's Wort may lower the plasma levels of remdesivir [5].Similarly, no known interactions have been reported between tocilizumab and most antidepressants [5].Paxlovid TM is a medication used for the treatment of COVID-19, and its use with certain antidepressants warrants close monitoring due to potential interactions [10].Specifically, the use of Paxlovid TM with desvenlafaxine should be monitored closely due to the potential risk of reduced substrate concentrations, which could result in treatment inefficacy through CYP3A4 inhibition [11].Similarly, the use of Paxlovid TM with trazodone [30] should be reconsidered, monitored, and potentially reduced in dosage due to the potential risk of increased substrate concentrations, which could lead to toxicity through CYP3A4 inhibition.The use of Paxlovid TM with mirtazapine should also be closely monitored due to the potential risk of increased substrate concentrations, which could result in toxicity through CYP3A4 inhibition [11].
However, according to data from various databases, no known interactions have been reported between Paxlovid TM and several commonly used antidepressants, including fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, venlafaxine, duloxetine, and vortioxetine [30].Additionally, there are no known interactions between tocilizumab and antidepressants based on data from various databases [5].Similarly, no known interactions have been reported between baricitinib and antidepressants.A summary of some of the reported interactions between some antidepressants and COVID-19 medications, as reported in the literature, is shown in Table 4.  On the basis of the findings from the literature, recommendations for combining antidepressants and COVID-19 medications are listed in Table 5.

Drug-Drug Interactions: Mood Stabilizers and COVID-19 Treatments
Paxlovid TM is a medication used for the treatment of COVID-19, and its use with certain mood stabilizers warrants close monitoring due to potential interactions.Specifically, Paxlovid TM is contraindicated with carbamazepine due to the risk of increased exposure to carbamazepine and reduced Paxlovid TM concentrations through CYP3A4 inhibition [31].On the other hand, no known interactions have been reported between Paxlovid TM and several other mood stabilizers, including gabapentin, oxcarbazepine, pregabalin, topiramate, lithium, and zonisamide [31].
The use of Paxlovid TM with lamotrigine [32] and valproic acid [12] should be closely monitored due to the potential risk of reduced serum concentrations of these antiepileptic medications resulting in reduced seizure prophylaxis.However, based on available data from various databases, no known interactions have been reported between baricitinib and mood stabilizers [30].A summary of some of the reported interactions between some mood stabilizers and COVID-19 medications, as reported in the literature, is shown in Table 5  On the basis of the findings from the literature, recommendations for combining mood stabilizers and COVID-19 medications are listed in Table 6.

Drug-Drug Interactions: Benzodiazepines and COVID-19 Treatments
Paxlovid TM is a medication used for the treatment of COVID-19, and its use with certain anxiolytics warrants close monitoring due to potential interactions.The use of Paxlovid TM with alprazolam should be reconsidered and closely monitored due to the potential risk of increased substrate concentrations, which could result in toxicity through CYP3A4 inhibition [34].Conversely, no known interactions have been reported between Paxlovid TM and several other anxiolytics [3], including lorazepam, temazepam, oxazepam, and quazepam.However, Paxlovid TM is contraindicated with midazolam [33] and triazolam [1] due to the risk of increased substrate concentrations with the potential for toxicity through CYP3A4 inhibition.The use of Paxlovid TM with diazepam, clonazepam, chlordiazepoxide, flurazepam, and clorazepate should also be closely monitored due to the potential risk of increased substrate concentrations through CYP3A4 inhibition [30].On the other hand, based on available data from various databases, no known interactions have been reported between baricitinib and anxiolytics [30].It is worth noting that the use of dexamethasone with midazolam and triazolam should also be closely monitored [30].A summary of some of the reported interactions between benzodiazepines and COVID-19 medications, as reported in the literature, is shown in Table 8.

Discussion
The rapid development of treatment regimens for the management of COVID-19 warrants a careful examination of drug interactions.Co-administration of certain psychotropic medications with COVID-19 treatments is a particularly important point of concern as many psychotropics already have narrow therapeutic indices [4].Tables 2, 4, 6, 8 summarize the pharmacological effects of drug interactions, while Tables 3, 5, 7, 9 summarize interactions and recommendations for selected combinations of psychotropics and COVID-19 treatments.Providers can use the tables in the study to help guide treatment plans in the following manner: while interactions labeled X in Tables 3, 5, 7, 9 should always be avoided, D, C, and B require more careful considerations of costs and benefits.If alternative therapies with no known interactions (class A) are available, they should be considered as substitutes for combinations of drugs labeled D and C.
Figure 2 stands as an illustrative model for the construction of a decision flow chart based on the information derived from any of the tables.In this instance, the focus is on benzodiazepines, highlighting contraindications with midazolam and triazolam (labeled X in Table 9) and emphasizing the need for identifying alternative therapies.For patients on benzodiazepines, especially in light of potential interactions highlighted in Table 8, precision in navigating the therapeutic protocol is crucial.The flowchart facilitates a seamless transition to benzodiazepines like lorazepam, temazepam, oxazepam, and quazepam, known for their safety with Paxlovid TM .This systematic approach offers a clear pathway for medication adjustments, minimizing potential risks associated with drug interactions.For example, if a patient is currently prescribed midazolam and requires Paxlovid TM , the recommended transition is to lorazepam, ensuring a seamless continuum of care with minimized risks.It is essential to emphasize that medications within the same row of the flowchart are considered comparable in terms of interaction risk.While the flowchart provides valuable guidance, clinical judgment remains paramount.Medical professionals should tailor their decisions based on individual patient cases, considering nuanced factors and specific needs to optimize patient outcomes.

FIGURE 2: An illustrative guide for the interpretation of the concurrent use of benzodiazepines and Paxlovid
Using Table 9 as an example, this figure serves as an illustrative guide for the interpretation of the concurrent use of benzodiazepines and Paxlovid TM .
Consistent with previous publications on interactions between ritonavir-containing drugs and psychotropics, Paxlovid TM , has numerous drug interactions with varying classes of psychotropics primarily through inhibition of cytochrome P450 enzymes [12].Co-administration of Paxlovid TM with drugs such as lurasidone, carbamazepine, midazolam, and triazolam should always be avoided and is categorized as X.Coadministration with drugs such as quetiapine and trazodone should warrant consideration of alternative therapies or dose modifications and is categorized as D.
Interactions categorized as C, such as co-administration of Paxlovid TM with clozapine, olanzapine, risperidone, bupropion, lamotrigine, and diazepam, warrant close monitoring.One case report detailed an occurrence of neutropenia after co-administration of clozapine and Paxlovid TM and advised close monitoring of white blood cell and neutrophil counts when co-administering these medications [16].
Additional case series of clozapine use in COVID-19 patients support its use with close monitoring of absolute neutrophil counts and serum clozapine levels [15].Considering the many interactions antipsychotics have with antivirals such as Paxlovid TM , our inquiry revealed that first-generation antipsychotics such as fluphenazine and atypical antipsychotics such as paliperidone are relatively safe to co-administer [10].Although antidepressants do undergo metabolism through the cytochrome P450 systems, certain drugs such as sertraline and fluoxetine do not have significant reported drug interactions with Paxlovid TM [11].Benzodiazepines, such as lorazepam, oxazepam, and temazepam, that rely on glucuronidation as opposed to cytochrome P450 as the mode of elimination are reported in drug databases to have fewer interactions with Paxlovid TM and are consistent with previous literature on the subject [12].
Paxlovid TM co-administration with mood stabilizers such as gabapentin, topiramate, lithium, and zonisamide has no reported drug interactions [11].As such, these drugs should be considered as alternatives for patients administered Paxlovid TM concurrently with drugs such as lamotrigine or valproic acid [20].
The remaining COVID-19 treatments, dexamethasone, remdesivir, tocilizumab, and baricitinib have fewer reported interactions [9].Dexamethasone is both metabolized by CYP3A4 and induces the enzyme [3].Coadministration of dexamethasone with drugs such as clozapine may reduce serum concentrations of clozapine and should be monitored for dose modification.Conversely, co-administration of dexamethasone with CYP3A4 inducers such as carbamazepine can reduce dexamethasone exposure and should prompt consideration of alternative therapies.Consistent with previous literature [4], there are no reported interactions between remdesivir, tocilizumab and baricitinib and the psychotropic medications discussed in this study.Clozapine and baricitinib co-administration, which is cautioned due to both agents having immunosuppressive effects [4], there are no evidence-based adjustments to be made to clinical practice in the administration of remdesivir, tocilizumab, and baricitinib to patients receiving psychotropic medications.
The pharmacological mechanisms of aforementioned drug interactions can be generalised into interactions that involve inhibition of cytochrome enzymes, increasing concentrations of drugs metabolised through this pathway and induction of cytochrome enzymes that reduces concentrations of drugs metabolised through the said pathway.The COVID-19 treatment with the greatest number of interactions was Paxlovid TM , commonly involved CYP3A4, across multiple drug classes.Close monitoring of adverse effects of the drug concurrently administered with Paxlovid TM should be considered as the serum concentration of these can be elevated due to CYP3A4 inhibition.For antipsychotics such as haloperidol, clinicians should monitor for extrapyramidal symptoms, sedation, confusion, and QT prolongation [9,26].Co-administration of Paxlovid TM with benzodiazepines can increase serum concentration resulting in symptoms of benzodiazepine toxicity such as altered mental status [11].The induction of cytochrome enzymes is another major mechanism of drug interaction between COVID-19 medications and psychotropics.Paxlovid-related induction of CYP-1A2 has the potential to decrease olanzapine levels, resulting in subtherapeutic dosing [28].Carbamazepine-related induction of CYP-3A4 can result in increased metabolism of dexamethasone, resulting in reduced corticosteroid exposure, potentially warranting an increase in dexamethasone dosing [30].

Limitations
The length of time used to study drug interactions, especially for the newer COVID-19 medications, may be too short to observe longer-term interactions that may be significant.In addition, given the epidemiology of COVID-19, the sample sizes of the subset of patients with psychiatric disorders in some instances may not be large enough to draw useful conclusions about drug-drug interactions.

Conclusions
In conclusion, the COVID-19 pandemic has posed numerous challenges to healthcare providers, including managing patients with COVID-19 and comorbidities, such as those requiring psychotropic medications.
Understanding potential interactions between COVID-19 treatments and psychotropic medications is crucial for optimizing patient outcomes.This discussion has highlighted the potential interactions between Paxlovid TM , remdesivir, tocilizumab, and baricitinib and commonly used psychotropic medications such as antipsychotics, antidepressants, mood stabilizers, and anxiolytics.Healthcare providers should be aware of these potential interactions and closely monitor patients for adverse effects.Using the tables provided in the study providers will be able to easily find information regarding potentially dangerous interactions and adjust their treatment plans accordingly.As new data and treatments become available, ongoing vigilance and collaboration among healthcare providers will be essential for managing the complex needs of patients with COVID-19 and comorbidities.

FIGURE 1 :
FIGURE 1: PRISMA flowchart for the study selection process PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
concentration through CYP3A4 inhibition.Monitor for weight gain, sedation, confusion, respiratory depression.Dosage adjustment should be considered[25].concentration through interaction with CYP3A4, CYP2D6, and CYP1A2[27].Clinical significance is not clear, and therapy should be closely monitored for toxicity and dose reduction.

Year Title Study Type Notes/Conclusions
baricitinib, anakinra, and dexamethasone and an extensive list of psychotropic medications.Also included case reports published pre-covid of DDI with similar mechanisms.Stratified DDIs and shortlisted drugs that were contraindicated for concurrent use with select COVID-19 therapies.Shah et al. [12]Benzodiazepine interaction with COVID-19 drugs.BriefReportThis report examines benzodiazepine interactions with COVID-19 drugs like Lopinavir/ritonavir and atazanavir, intensifying effects due to ritonavir's enzyme inhibition.Pairing midazolam, triazolam, or alprazolam with atazanavir or ritonavir can cause sedation, confusion, respiratory depression, and adverse effects, emphasizing the preference for temazepam, oxazepam, or lorazepam over alprazolam.