Schizophrenia and COVID 19: A Call for Collaborative Care

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The COVID-19 pandemic increased psychiatric, medical, and treatment risks for patients diagnosed with schizophrenia. This article provides an overview of risk factors and an example of patient-centered, collaborative care to promote safety and stabilization while providing available treatment options for cooccurring diagnoses of COVID-19 and schizophrenia spectrum disorder.

COVID-19 and Increased Risks for Individuals With Schizophrenia

The stress of the COVID-19 crisis crashed in waves across our country and its care continuum. Hospitals, medical offices, and care centers were all impacted significantly. The psychiatric service line was unquestionably negatively affected. Modifications in mental health services occurred in response to growing concerns related to the pandemic and the impacted workforce.

Access to community-based services that many psychiatric patients relied on—such as in-person care, outreach, and transport mechanisms—decreased. There were additional barriers to usual services, such as lab studies and electroconvulsive therapy (ECT), especially during viral surges in respective communities.

Issues with admission procedures and delays in hospitalizations increased emergency room overcrowding and length of time in hospitals without the comprehensive treatment one would receive in a designated psychiatric unit.

Then, during the height of the pandemic, changes to improve patient safety through upgrades to the US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Program (REMS) for clozapine temporarily complicated dispensing and receiving the most effective antipsychotic.¹

The updated REMS requirements increased protection in identifying potential for compromised immune responses. However, the increased demand for phlebotomy and updates to the monitoring system came when clinicians, hospital laboratories, pharmacies, and patients were already overloaded with new data and restrictions set in place to prevent the spread of the virus.

Recognizing complications in the community and serious issues associated with abrupt discontinuation of the gold standard in antipsychotic medication, the FDA exercised discretion in enforcing all requirements to ensure continuity of treatment with clozapine.¹

During swells of the pandemic, many patients impacted by chronic mental illness were seemingly marooned by a fragmented system. Increased barriers and strained systems put psychiatric patients at risk for further decompensation and symptomatology.

As researchers, health officials, and clinicians feared additional problems would plague the persistently mentally ill, data surfaced verifying the legitimacy of concerns. Research noted that schizophrenia spectrum disorders yield a significantly higher risk of morbidity and mortality as a result of COVID-19.²

Known risk factors of morbidity associated with those diagnosed with schizophrenia spectrum disorders include metabolic syndrome, weight gain, obesity, hypertension, cardiac complications, diabetes, propensity toward substance use and abuse, smoking-related illness, and neutropenia, and other hematological abnormalities due to care with antipsychotic and mood-stabilizing medications.^2,3

However, additional psychosocial and socioeconomic factors may also be linked to a higher correlation of morbidity and mortality associated with COVID-19 and schizophrenia spectrum disorders. These factors include limitations related to “fair and equitable resource allocation”³ and access to care and living situations that diminish social distancing, as a disproportionate share of individuals with schizophrenia live among the homeless, are incarcerated, or reside in congregate living situations.^3,4

These factors, along with difficulties in the appraisal of health information and lack of adherence to practices aimed at reducing transmission, may increase the risk of the onset of illness and complications.^3,4

The COVID-19 pandemic increased risks, but also provided opportunities for increased interdisciplinary collaboration to respond to challenges more effectively and to advocate for the appropriate availability of resources.

Schizophrenia and other severe, persistent mental health disorders needed to be discussion topics regarding the risk-benefit analysis of vaccines and antiviral medication. There was a need for individualized education for preventative and clinically appropriate care for this vulnerable population. In addition, significant and potentially life-threatening complications of antiviral medications with psychotropics were identified.

Call for Collaborative Care

A thoughtful, patient-centered, collaborative approach to mitigating symptoms and risks of medical complications while maintaining psychiatric stability is vital to providing optimal care in complex situations. The case presented in this article provides an example of how consideration of, preparation for, and administration of an antiviral agent, Paxlovid, is best completed in a collaboration between psychiatry, medicine, pharmacy, nursing, and patients.

Paxlovid (Nirmatrelvir 300mg/ritonavir 150mg) is an antiviral agent used to treat mild to moderate symptoms of COVID-19.⁵ Paxlovid consists of a 5-day course that is started within the first 5 days of symptoms of a confirmed COVID-19 diagnosis.

Paxlovid consists of 2 products, Nirmatrelvir and Ritonavir, both of which are protease inhibitors. Ritonavir, a pharmacokinetic enhancer, must be coadministered with Nirmatrelvir to achieve the therapeutic concentration required for sufficient desired therapeutic effects. Ritonavir is mainly a substrate of CYP3A4 and, to a lesser extent, CYP2D6; it has inhibitory effects on CYP3A and, to a lesser extent, on CYP2D6.

Nirmatrelvir is a substrate of PGP and CYP3A4, with no induction or inhibitor effects of P450 isoenzymes. CYP3A4 metabolizes many psychiatric medications. Therefore, combining Paxlovid with certain psychotropics can lead to a synergistic effect that can potentially be dangerous to patients.⁶

Safety related to dosing, discontinuation, and alternative medications must be considered when prescribing Paxlovid when a psychiatric medication regimen is being utilized based on the risk-benefit analysis for the patient.

Safety and Stabilization Considerations

A comprehensive review of the patient’s hepatic and renal function, as well as a review of the patient’s current medication regimen, is crucial before starting the patient on Paxlovid. Paxlovid should be avoided in patients with severe renal impairment (eGFR < 30mL/min), but it can be prescribed to patients with moderate renal impairment (eGFR> 30mL/min to eGFR < 60mL/min) with a dose reduction.

Additionally, Paxlovid is not recommended for patients with severe hepatic impairment, as no pharmacokinetic or safety data has been tested in patients with severe hepatic impairment.⁵

Paxlovid has an extensive interaction profile. Pharmacokinetic factors limit the immediate use of medications that are extensively metabolized by CYP3A4, such as antipsychotics pimozide and lurasidone; benzodiazepines triazolam and midazolam; and suvorexant, a drug used in the treatment of insomnia.⁵

Medications that are extensively dependent on elimination via CYP3A isoenzymes are contraindicated with using Paxlovid due to concerns related to highly elevated concentrations of these medications, which may be associated with severe, potentially life-threatening reactions.⁵

Access and Information

Patients with COVID-19 and psychiatric comorbidities should be managed on an individualized basis and should not be excluded from available treatments.⁷ The following case gives an example of this.

A 59-year-old female with a psychiatric diagnosis of schizophrenia spectrum disorder, unspecified, who was taking lurasidone 60 mg daily with dinner, tested positive for COVID-19. This patient had known significant risk factors associated with respiratory comorbidity and habitual risk factors. After onset of mild to moderate symptoms and official diagnostic confirmation of COVID-19, the patient’s psychiatric and medical clinicians considered the benefit of Paxlovid.

The desire to initiate Paxlovid with rationale was discussed with the patient, and she agreed. After consultation, pharmacists provided guidance regarding the wash-out period of lurasidone to allow for safe administration of Paxlovid. The determination on when to start Paxlovid was based on the lurasidone wash-out period time based on its particular half-life (T1/2).

In general, for medications following first order kinetics, such as lurasidone, it takes roughly 4 to 5 half-lives to eliminate 94% to 97% of a drug from the body.⁸ Lurasidone is metabolized extensively by CYP3A4 via oxidative reaction into 2 active (ID-14283 and ID 14326) and 2 non active metabolites (ID-20219 and ID-20220).^9-11 The mean elimination T1/2 is 18 hours, meaning the body would completely eliminate 94% to 97% of the drug in 3 to 3.75 days.⁸

In this case, Paxlovid was discussed on the day it became available for a symptomatic patient with a confirmed diagnosis of COVID-19 and risk factors that warranted consideration of its use. Lurasidone was held after discussion, and Paxlovid was initiated 3 days later.

Paxlovid may be more readily utilized when lurasidone is the psychotropic prescribed and the patient can be transitioned to another drug for psychiatric stabilization. However, the situation would be different if the drug prescribed was a CYP3A inducer, such as carbamazepine, as the deinduction of CYP450 enzymes takes time after discontinuation. Specifically, the carbamazepine deinduction period after discontinuation is 2 weeks.¹²

Some medications—including trazodone, quetiapine, clozapine, aripiprazole, brexpiprazole, iloperidone, lumateperone, pimavanserin, buspirone, clorazepate, diazepam, and zolpidem and many others—may require dose adjustment based on their primary site of metabolism by CYP3A.

It should also be noted that ritonavir appears to induce CYP1A2, CYP2C19, CYP2C9, CYP3A, and CYP2B6, in addition to other enzymes including glucuronosyltransferase, causing a decrease in drug concentration of bupropion and methadone.⁵

In the case reported above, the antipsychotic was quickly transitioned to olanzapine. Additional concerns and cautions would need to be taken if quetiapine, aripiprazole, or clozapine were antipsychotics considered for medication regimen.⁵ This patient tolerated Paxlovid and had no known adverse sequelae due to COVID-19 infection. Olanzapine demonstrated benefit for psychiatric symptom management over the following weeks.

However, if clozapine treatment was necessary for symptom management, more significant challenges could present,⁶ as there may not be another option to maintain adequate stabilization and the medication regimen may not be able to be readily modified. Clozapine is associated with additional risks and potential adverse events when the individual taking it is infected with COVID-19, with or without the addition of an antiviral medication.¹³

Concluding Thoughts

It is imperative to run an interaction report on recent medications and active prescriptions when Paxlovid is being considered to avoid interactions with current medications. There must be careful consideration given to which medications will be used to treat the psychiatric symptoms when medication changes are necessary⁶ to safely maintain adequate stabilization.

An individualized risk-benefit analysis should always be completed when modifying treatment plans to balance the needs of safe and effective medical and psychiatric care.

Dr Sorrell is an advanced practice nurse practitioner for Dartmouth Health. Dr Gibson is a clinical pharmacist at New Hampshire Hospital.

The preparation of this report was financed under a contract with the State of New Hampshire Department of Health and Human Services, with funds provided in part by the State of New Hampshire.

The authors would like to acknowledge contributions made by Karen Goodman, MSLIS, MA, medical librarian; Joseph McKee, PMHNP-BC, who assisted while he was in the student role with a literature search used in part for the final article; and Jeffry C. Fetter MD, chief medical officer of New Hampshire Hospital, for his encouragement in writing on this subject matter.

References

1. FDA is temporarily exercising enforcement discretion with respect to certain Clozapine REMS program requirements to ensure continuity of care for patients taking clozapine. FDA. News release. November 2, 2022. Accessed December 9, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-temporarily-exercising-enforcement-discretion-respect-certain-clozapine-rems-program

2. Fond G, Nemani K, Etchecopar-Etchart D, et al. Association between mental health disorders and mortality among patients with COVID-19 in 7 countries: a systematic review and meta-analysis. JAMA Psychiatry. 2021;78(11):1208-1217.

3. Kozloff N, Mulsant BH, Stergiopoulos V, Voineskos AN. The COVID-19 global pandemic: implications for people with schizophrenia and related disorders. Schizophr Bull. 2020;46(4):752-757.

4. Wang Q, Xu R, Volkow ND. Increased risk of COVID-19 infection and mortality in people with mental disorders: analysis from electronic health records in the United States. World Psychiatry. 2021;20(1):124-130.

5. Fact sheet for healthcare providers: emergency use authorization for Paxlovid. Paxlovid package insert. Revised February 2023. Accessed March 16, 2023. https://www.fda.gov/media/155050/download

6. Marzolini C, Kuritzkes DR, Marra F, et al. Recommendations for the management of drug-drug interactions between the COVID-19 antiviral Nirmatrelvir/Ritonavir (Paxlovid) and comedications. Clin Pharmacol Ther. 2022;112(6):1191-1200.

7. Arbelo N, López-Pelayo H, Sagué M, et al. Psychiatric clinical profiles and pharmacological interactions in COVID-19 inpatients referred to a consultation liaison psychiatry unit: a cross-sectional study. Psychiatr Q. 2021;92(3):1021-1033.

8. Hallare J, Gerriets V. Half life. National Library of Medicine. Revised June 23, 2022. Accessed December 9, 2022. https://www.ncbi.nlm.nih.gov/books/NBK554498/

9. Cruz MP. Lurasidone HCl (Latuda), an oral, once-daily atypical antipsychotic agent for the treatment of patients with schizophrenia. P T. 2011;36(8):489-492.

10. Lurasidone. Lexicomp. Accessed December 9, 2022. https://online.lexi.com/lco/action/home

11. Highlights of prescribing information. Lurasidone package insert. Revised 2013. Accessed February 26, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/200603lbls10s11.pdf

12. Punyawudho B, Cloyd JC, Leppik IE, et al. Characterization of the time course of carbamazepine deinduction by an enzyme turnover model. Clin Pharmacokinet. 2009;48(5):313-320.

13. Veerman SRT, Bogers JPAM, Cohen D, Schulte PFJ. COVID-19: risks, complications, and monitoring in patients on clozapine. Pharmacopsychiatry. 2022;55(1):48-56.