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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 3  |  Page : 103-108

Drug Interactions Between COVID-19 and Psychiatric Medications: A Mini Review


Department of Psychiatry, Health Sciences University Erenkoy Research and Training Hospital for Psychiatry and Neurological Diseases, Istanbul, Turkey

Date of Submission09-Aug-2020
Date of Decision12-Nov-2020
Date of Acceptance13-Nov-2020
Date of Web Publication25-Dec-2020

Correspondence Address:
Filiz Kulacaoglu
19 Mayis Mah. Sinan Ercan caddesi No: 19, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnbs.jnbs_16_20

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  Abstract 


Coronavirus disease 2019 (COVID-19) has become a pandemic with 8,708,000 confirmed cases and 461,715 death in the world until June 21, 2020. The Severe Acute Respiratory Syndrome Coronavirus 2 virus, which is an enveloped and single-stranded RNA virus belonging to Coronaviridea family, causes multiple organ systems diseases such as respiratory, gastrointestinal, hepatic, and neurological tracts in humans and animals. With the rapid and global spread of COVID-19, the scientific authorities have developed treatment algorithms for COVID-19. Besides the supportive care, chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir, tocilizumab, azithromycin, Vitamin C, and convalescent plasma therapy are frequently used off-label to treat COVID-19. For severe COVID-19 cases, the US Food and Drug Administration has issued an Emergency Use Authorization Remdesivir, which is the first drug to earn the title. COVID-19 treatment may cause many side effects and drug interactions. Psychiatric diseases are also chronic diseases, and psychiatric drugs may have severe interactions with COVID-19 medications. Drug interactions with psychiatric medication and neuropsychiatric side effects should be considered within the action mechanism of COVID-19 treatments. Thus, in this review, we aimed to elucidate the interactions of COVID-19 medications with the antidepressants, antipsychotics, and the other psychotropic drugs that have been frequently used in psychiatric diseases. Chloroquine, hydroxychloroquine, azithromycin, ribavirin, and lopinavir/ritonavir have interactions with psychiatric medications such as antidepressants, antipsychotics, anticonvulsants, and anxiolytics in terms of QTc interval prolongation, hepatotoxicity, myelosuppression, increased or decreased concentration of medications. Remdesivir has lower interactions with most of the psychiatric drugs except St John's Wort and some anticonvulsants. However, favipiravir is considered as the COVID-19 medication, which has lower interaction and side effects in combination with psychiatric medication. The use of tocilizumab is also safe with most of the psychiatric drugs and has a positive effect on depressive symptoms, although there is a risk of hepatotoxicity.

Keywords: Coronavirus disease 2019, drug interactions, psychotropic drugs, psychiatric diseases, treatment


How to cite this article:
Izci F, Kulacaoglu F. Drug Interactions Between COVID-19 and Psychiatric Medications: A Mini Review. J Neurobehav Sci 2020;7:103-8

How to cite this URL:
Izci F, Kulacaoglu F. Drug Interactions Between COVID-19 and Psychiatric Medications: A Mini Review. J Neurobehav Sci [serial online] 2020 [cited 2021 Apr 12];7:103-8. Available from: http://www.jnbsjournal.com/text.asp?2020/7/3/103/304917




  Introduction Top


In December 2019, Coronavirus Disease-2019 (COVID-19) was first identified in Wuhan city, China. This disease was caused by a novel coronavirus was named with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus had not been previously identified in humans before. Since December 2019, COVID-19 has become a severe risk factor for global health. In March 2020, due to a rapid increase in the number of cases outside China, the WHO declared COVID-19 a pandemic.[1]

The SARS-CoV-2 virus, which is an enveloped and single-stranded RNA virus belonging to Coronaviridea family, causes multiple organ system diseases such as respiratory, gastrointestinal, hepatic, and neurological tracts in humans and animals. The symptoms of COVID-19 can range from asymptomatic clinical features to severe symptoms.[2]

With the rapid and global spread of COVID-19, the scientific authorities have developed treatment algorithms for COVID-19. The treatment algorithms of COVID-19 are composed of the medications that have been used in previous pandemics and the medications that have been thought potentially effective for COVID-19. For severe COVID-19 cases, the US Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) Remdesivir, which is the first drug to earn the title. However, numerous medication such as chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir, tocilizumab, azithromycin, Vitamin C, and convalescent plasma therapy is frequently used off-label to treat COVID-19.[3]

Multiple organ systems can be affected by COVID-19, and it also causes psychiatric conditions. It has been reported that COVID-19 causes psychiatric disorders such as panic attacks, anxiety, depression, and insomnia in especially patients and health-care professionals.[1],[2],[4] Since COVID-19 medications have possible side effects and affect multiple organs, psychiatrists should be aware of the mechanism of action of COVID-19 treatments, neuropsychiatric side effects, and potential drug interactions with psychiatric drugs. In this review, we aimed to elucidate the interactions of COVID-19 medications with the antidepressants, antipsychotics, and the other psychotropic drugs that have been frequently used in psychiatric diseases.


  Chloroquine and Hydroxychloroquine Top


Chloroquine and hydroxychloroquine are antimalarial drugs and have also been used for various rheumatic diseases such as systemic lupus erythematosus and rheumatoid arthritis. Besides the antimalarial effects, these two drugs have immune-modulating effects as well.[5]

A synthetic form of quinine, chloroquine, is used for the treatment and prophylaxis of malaria, inhibits glutamate-induced death of a neuronal cell by reducing reactive oxygen species through the sigma-1 receptor. Thus, using chloroquine as a neuroprotector against oxidative stress has been suggested.[6] The hydroxychloroquine is frequently used in inflammatory disorders. Both chloroquine and hydroxychloroquine have been suggested as a possible treatment for COVID-19 due to their immune-modulating and anti-inflammatory effects, antiviral effects by interference with virus-receptor binding.[7]

Antidepressants, antihistamines, antipsychotics, and verapamil were used to investigate the increasing in vitro susceptibility of chloroquine in several studies.[8],[9],[10] In a study that investigated the role of antidepressants in reversing chloroquine resistance, citalopram, which is a selective serotonin reuptake blocker, was found the most effective to reversing the chloroquine resistance among amitriptyline, oxaprotiline, and nomifensine.[11] However, in another study that the pharmacokinetic interaction between chloroquine and imipramine was investigated, no significant change was found in plasma concentrations of chloroquine and its pharmacokinetic parameters when imipramine was coadministered with chloroquine.[12]

Similarly, in another study, chloroquine and chlorpromazine were found to inhibit Crimean-Congo Hemorrhagic Fever virus replication in vitro. Moreover, it was reported that a synergistic effect was observed when ribavirin was added to those two molecules' combination.[13] In sum, the synergistic effect of psychiatric drugs such as citalopram, chlorpromazine may cause increasing in levels of chloroquine should be taken into account during the combination usage of these drugs.

Hydroxychloroquine, which is a less toxic derivative of chloroquine, is also effective in inhibiting SARS-CoV-2 infection in vitro.[14] In a recent observational study, eighty relatively mildly infected inpatients treated with a combination of hydroxychloroquine and azithromycin and a rapid fall of nasopharyngeal viral load was reported at the end of day 7.[15] However, it has been shown that the body temperature recovery time and the cough remission time were shortened and pneumonia was improved in patients with hydroxychloroquine treatment.[16] Both hydroxychloroquine and chloroquine have neuropsychiatric side effects from mild to (mood swings, agitation, nervousness, and sleep disturbances) to severe (psychosis, delirium, and suicidality). Risk factors for induced neuropsychiatric effects caused by hydroxychloroquine and chloroquine include a family history of psychiatric disease, alcohol usage, using of CYP3A4 inhibitors, glucocorticoids, and female gender.[17],[18]


  Psychiatric Drug Interaction with Hydroxychloroquine and Chloroquine Top


CYP3A4 enzyme metabolizes both hydroxychloroquine and chloroquine. Therefore, CYP3A4 inhibitors may cause an increase in the plasma levels and increase the possible effects of hydroxychloroquine and chloroquine, whereas CYP3A4 inducers could decrease the plasma levels so that hydroxychloroquine and chloroquine could be less effective with the combination of CYP3A4 inducers.[19] The cardiogenic side effects of hydroxychloroquine and chloroquine are; QT interval prolongation, AV block.[20] Usage outside of the hospital setting is not recommended, and the cardiogenic side effects should be taken into account when used in combination with QT-prolonging antipsychotics.

Combination with anticonvulsants

The anticonvulsants that have the effects of mood stabilizing, anxiolytic, and sedation are using in psychiatric treatments.

  • Because hydroxychloroquine and chloroquine are metabolized by CYP3A4, CYP3A4 inducers such as carbamazepine, oxcarbazepine may cause lower levels of hydroxychloroquine or chloroquine. Thus, a combination of these drugs is not suggested[18]
  • No interaction has been reported with lamotrigine, valproic acid, and clonazepam
  • Lithium, as a mood stabilizer, should be used cautiously, with chloroquine or hydroxychloroquine due to the QT interval prolongation effect of these drugs.


Combination with antidepressants

  • Antidepressants that have fewer interactions with hydroxychloroquine and chloroquine are sertraline, reboxetine, milnacipran, agomelatine, and bupropion
  • Amitriptyline, clomipramine, citalopram, escitalopram, and trazodone should be used carefully due to the QT interval prolongation effect
  • Paroxetine, fluoxetine, amitriptyline, fluvoxamine, venlafaxine, and mirtazapine may increase the plasma levels of chloroquine and hydroxychloroquine
  • A combination with St John's Wort Oil is not recommended due to decreasing plasma levels of chloroquine and hydroxychloroquine.


Combination with antipsychotics

  • Aripiprazole, amisulpride, asenapine, olanzapine, paliperidone, and perphenazine are the antipsychotics that have lower side effects with the combination of chloroquine and hydroxychloroquine
  • Chlorpromazine, clozapine, haloperidol, pimozide, quetiapine, and zuclopenthixol should be used carefully due to their potential QT interval prolongation effect
  • A combination with ziprasidone is contradicted due to a higher risk for QTc interval prolongation
  • Due to clozapine is associated with myelosuppression risk, monitoring hematological parameters are essential during the combination with clozapine.


Combination with anxiolytics

  • Although the combination with anxiolytics is safe, hydroxyzine combination should be taken into account for prolonged QTc.[21]


Azithromycin

Azithromycin is an antibacterial agent and used in the treatments of respiratory tracts, skin and soft-tissue infections, and urethritis/cervicitis.[22] Besides the antibacterial activity, azithromycin has also antiviral and anti-inflammatory activities that may help the treatment of COVID-19 if used in combination with chloroquine and hydroxychloroquine. In a recent study, azithromycin and hydroxychloroquine combination was found highly more effective against the virus, when compared to hydroxychloroquine treatment alone.[15] Controversially, in another study, no clear benefit was found with the combination of hydroxychloroquine and azithromycin in patients with serious COVID-19 infection.[23] However, the risk of QTc prolongation, cardiogenic comorbidities should be considered when using a combination of both hydoxychloroquine and azithromycin.

Psychiatric side effects of azithromycin are listed as; catatonia, delirium, agitation, anxiety, psychotic depression, and somnolence.[24]


  Psychiatric Drug Interaction with Azithromycin Top


Combination with anticonvulsants

  • Lithium has a moderate risk due to the risk of QTc prolongation.


Combination with antidepressants

  • Citalopram and escitalopram have a severe risk for QTc prolongation
  • Amitriptyline, clomipramine, trazodone, and imipramine have a moderate risk for QTc prolongation.


Combination with antipsychotics

  • Amisulpride, ziprasidone, clozapine, pimozide, haloperidol, and thioridazine have a severe risk for QTc prolongation
  • Aripiprazole, chlorpromazine, olanzapine, paliperidone, perphenazine, quetiapine, and risperidone have a moderate risk for cardiac side effects.


Combination with anxiolytics

  • Due to the risk of QTc prolongation, a combination with hydroxyzine is not suggested.[25]


Remdesivir

Remdesivir is an antiviral which acts by inhibiting RNA polymerase, hence lowering viral RNA levels. It has been shown that remdesivir has activity against SARS-CoV-2. Apparently, it has a clinical safety profile. The most common side effects are hypotension, sweating, and shivering. No neuropsychiatric side effect has been reported so far. However, on May 1, 2020, the US FDA (FDA approved to use remdesivir for the treatment of suspected or confirmed severe COVID-19.[26]


  Psychiatric Drug Interaction with Remdesivir Top


Combination with anticonvulsants

  • Due to carbamazepine is decreasing the plasma levels of remdesivir, combination with carbamazepine is not recommended
  • No interaction has been reported with lamotrigine, valproic acid, topiramate, and lithium.


Combination with antidepressants

  • No interaction has been reported between most of the antidepressants. However, as St John's Wort may decrease the plasma levels of Remdesivir, a combination of those two drugs is not recommended.


Combination with antipsychotics

  • No interaction has been reported with antipsychotics.


Combination with anxiolytics

  • No interaction has been reported with anxiolytics.



  Lopinavir/Ritonavir Top


Lopinavir/ritonavir combination is an antiviral medication. Lopinavir is a protease inhibitor and ritonavir inhibits the metabolism of lopinavir and leads to increasing the plasma levels of lopinavir. This combination is used in treatment of HIV-1 infection, and it was used to treat MERS as well. Recently, this combination is used to treat COVID-19 infection. However, according to a recent randomized, controlled, open-label trial involving hospitalized adult patients with COVID-19 in Wuhan, China, no significant benefit was observed with lopinavir/ritonavir combination. The most common neuropsychiatric effects of lopinavir/ritonavir are reported as agitation, anxiety, confusion, and emotional instability.[27]


  Psychiatric Drug Interaction with Lopinavir/Ritonavir Top


Combination with anticonvulsants

  • A combination with carbamazepine may decrease the plasma levels of lopinavir/ritonavir so that the single dose of carbamazepine per day is recommended
  • Lopinavir/ritonavir lowers the concentration of lamotrigine. The increased dose is required
  • Lopinavir/ritonavir increases the plasma levels of valproic acid. Thus, the dose requirement is needed
  • No change in plasma levels of lithium when it is combined with lopinavir/ritonavir. It should be taken into account for QTc interval prolongation.


Combination with antidepressants

  • Lowering the doses of trazodone is recommended due to side effects such as dizziness and nausea
  • The risk of QTc prolongation increases due to the plasma levels of clomipramine, citalopram, escitalopram, desipramine, imipramine, and amitriptyline increase
  • The concentration of bupropion decreases. Thus, the dose requirement is needed
  • A combination with St John's Wort is not recommended due to it decreases the concentration of antiviral medication.


Combination with antipsychotics

  • A combination with lurasidone ve pimozide is contraindicated due to lopinavir/ritonavir increases drug levels and side effects
  • A combination with quetiapine is contraindicated due to the side effect of a coma
  • No interaction has been shown with amisulpride
  • It is not recommended to use with clozapine due to myelosuppression side effect.


Combination with anxiolytics

  • A combination with midazolam and triazolam is contraindicated due to increased drug levels
  • Combination with anxiolytics, which do not depend on CYP metabolism, is suggested such as lorazepam.[21]


Favipiravir

On February 15, 2020, China has approved Favipiravir for the treatment of influenza, which is an antiviral that acts as a RNA-dependent RNA polymerase inhibitor. It is also used in clinical trials for COVID-19 treatment.[28] In a recent review that 29 studies were identified, it has been reported that favipiravir was tolerable and showed a safety, but more evidence was needed to assess the long-term side effects such as hyperuricemia, teratogenicity, and QTc prolongation.[29] However, no neuropsychiatric side effect has been reported so far.


  Psychiatric Drug Interaction with Favipiravir Top


  • No interaction with anticonvulsants, antidepressants, antipsychotics, and anxiolytics has been reported with the combined use of Favipiravir so far.[21]


Tocilizumab

Cytokine storm has been observed in patients with SARS-CoV-2, and it is caused by elevated interleukin-6 (IL-6).[30] Tocilizumab is a monoclonal antibody and acts as an IL-6 receptor antagonist. Recently, it has been used as an alternative treatment for COVID-19 for lessening cytokine storm.[31] In a recent study that investigates the efficacy and safety of tocilizumab in patients with COVID-19, no obvious side effect was reported, and the rate of secondary infection was not so high. It was reported as an effective treatment to reduce mortality.[32]

According to the literature, the medications that have immune-modulating effects such as adalimumab, etanercept, infliximab, and tocilizumab have positive effects on depressive symptoms.[33] Similarly, it has also been indicated that inflammation and IL-6 activity may be related with clinical features and pathophysiology of schizophrenia.[34]


  Psychiatric Drug Interaction with Tocilizumab Top


Combination with anticonvulsants

  • No major interactions were reported with anticonvulsants.


Combination with antidepressants

  • No major interactions were reported with antidepressants.


Combination with antipsychotics

  • No major interactions were reported with antipsychotics. However, risky used with clozapine is reported for potentially hepatotoxic side effects.


Combination with anxiolytics

  • No major interactions were reported with anxiolytic.[21]



  Conclusion Top


Since COVID-19 impacts multiorgan systems, the infection and its treatment may cause many side effects and drug interactions as well. Psychiatric diseases are also chronic diseases and psychiatric drugs may have severe interactions with COVID-19 medications. Thus, drug interactions should be known for providing the best treatment with lower side effects for psychiatric patients with COVID-19.

It has been reported that chloroquine, hydroxychloroquine, azithromycin, ribavirin, and lopinavir/ritonavir have interactions with psychiatric medications such as antidepressants, antipsychotics, anticonvulsants, and anxiolytics in terms of QTc interval prolongation, hepatotoxicity, myelosuppression, and increased or decreased concentration of medications. Remdesivir has lower interactions with most of the psychiatric drugs except St John's Wort and some anticonvulsants. However, favipiravir is considered as the COVID-19 medication, which has lower interaction and side effects in combination with psychiatric medication. The use of tocilizumab is also safe with most of the psychiatric drugs and has a positive effect on depressive symptoms, although there is a risk of hepatotoxicity.

Patient informed consent

There is no need for patient informed consent.

Ethics committee approval

There is no need for ethics committee approval.

Financial support and sponsorship

No funding was received.

Conflicts of interest

There are no conflicts of interest to declare.

Author contribution area and rate

Filiz Izci wrote the manuscript, collection of review of literature, 50%.

Filiz Kulacaoglu Helped in writing the manuscript and collection of literature, 50%.



 
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