key: cord-0933996-25zqijsw
authors: Knöchel, Christian; Hefner, Gudrun; Stiehl, Thomas; Schmidbauer, Walter
title: Elevated Clozapine Blood Concentrations After Second COVID-19 Vaccination With Spikevax (COVID-19 Vaccine Moderna)
date: 2022-01-28
journal: J Clin Psychopharmacol
DOI: 10.1097/jcp.0000000000001522
sha: 67942b9d5019480c0dfc94a6e392e056d98af4e8
doc_id: 933996
cord_uid: 25zqijsw

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Various studies have been published, reporting about inflammation-mediated changes in drug metabolism. 6-8 The decrease in expression and activity of cytochrome P450 (CYP) enzymes is primarily induced by a transcriptional suppression of the respective CYP mRNAs and can be selective for a distinct isoform of CYP and be dependent on the respective pathophysiology of inflammation. 6, [9] [10] [11] The CYP isoenzymes CYP1A2 and CYP2C19 are the major enzymes involved in drug metabolism of clozapine. 5 In March 2021, Thompson et al 12 reported about a case of elevated clozapine levels after first administration of a Pfizer-BioNTech mRNA vaccine. To date, no reports about elevated clozapine blood concentrations have been published for non-mRNA-based vaccines. Raaska et al 13 found that influenza vaccine does not affect clozapine serum concentrations. We report about a case of increased clozapine blood concentrations after second COVID-19 vaccination with Spikevax (COVID-19 Vaccine Moderna).

Written consent for publication had been obtained from the following case.

A 42-year-old man (born in Eritrea) with diagnosis of paranoid schizophrenia (F20.0) was admitted in December 2019 in the forensic psychiatric hospital in Riedstadt. He had no further comorbidities and smoked 5 cigarettes per day, which was controlled by the nursing staff. Therefore, the access of the patient to cigarettes, and the number of cigarettes smoked per day, was consistent through the period before and after the first and second vaccination. The patient had no history of COVID-19 before immunization and was not febrile at any time. He was tested for COVID-19 two times (September 18, 2020 COVID-19 rapid test, December 07, 2020 COVID-19 PCR test). He did not leave the clinic for free time activities. In April 2021, he received the first COVID-19 vaccination with Spikevax (COVID-19 Vaccine Moderna) without noticeable problems. Prothipendyl (80 mg), haloperidol (8 mg), and lorazepam (2 mg) were prescribed during this time. Because of nonresponse to several antipsychotic drugs, clozapine therapy was started in May 2021, in combination with haloperidol and lorazepam. Seven days later, the patient already received 100-mg clozapine, and the second COVID-19 vaccination was conducted. At this time and during the next 12 days, comedication was haloperidol (8 mg) and lorazepam (1 mg). Clozapine blood concentration was measured under trough-level conditions, considering that steady state conditions 5 requiring 3 to 4 days at the same dose (4-5 half-lives) were not present during dose escalation (Table 1) . Clozapine concentration at the day of vaccination was 270 ng/mL and, therefore, below the therapeutic reference range (Table 1) . 5 As the clozapine concentration was measured with a Saladax MyCare Insite Analyzer laboratory photometer, requiring only a single drop of blood from a finger stick (assay performance validated according to the US Food and Drug Administration and In Vitro Diagnostic Directive standards), measuring of norclozapine was not possible. One day after the vaccination, the patient appeared agitated and constantly left his room at daytime and at night. Five days after vaccination, the patient received 175-mg clozapine, and agitation became worse (Table 1 ). In addition, dizziness, gait disturbances, drowsiness, as well as disorientation to place and time, consistent with delirium, occurred. The patient had hypotension (arterial blood pressure 96/64) and tachycardia (pulse 112). The clozapine blood level was measured and attested that the patient was 868 ng/mL above the therapeutic reference range. 5 Therefore, clozapine therapy was paused, and the blood level decreased in line with the clozapine half-life 5 to 452 ng/mL 1 day later ( Table 1 ). The neurological symptoms had resolved, and the patient's mental state was at the prevaccination baseline.

Ten days after vaccination, concentrationto-dose ratio (C/D, in nanograms per milliliter per milligram) decreased enormously, but steady state was still not given. Over a month after vaccination, the C/D was 2.99 under steady-state conditions (Table 1) , and the patient remained clinically stable.

As the patient was, also before the second vaccination, above the clozapine doserelated reference range with a C/D of 2.7 (Table 1 ; ordinary range, 0.21-0.79 5 ) and born in Eritrea (genetic diversity is greater in Africa than in other continental populations 14 ), a CYP genotyping was conducted. A CYP2C19 intermediate metabolizer status was detected that could explain the increased C/D.

Leucocytes, neutrophils, monocytes, and lymphocytes were without noticeable problems also after the second vaccination (Table 1) , eosinophils were above the ordinary range (possibly due to an allergic reaction). C-reactive protein (CRP) was slightly increased at the day and for weeks after the second vaccination (6-18 mg/L; Table 1 ) without signs of a bacterial/viral infection. Glutamate-pyruvate transaminase and γglutamyl transferase were slightly above the therapeutic range.

There was a close temporal relation between serum level increase of clozapine and the second vaccination with Spikevax in the patient. Because pharmacokinetic drug-drug interactions due to comedication were not identified and smoking status did not change, it seemed likely that the increase in drug serum concentration (C/D) was associated with the second vaccination. Cytochrome P450 genotype of the patient did not explain the increase in C/D.

Bayraktar et al 15 examined the potential interaction between clozapine and COVID-19 vaccines from different perspectives. They indicated that mRNA COVID-19 vaccines brought out strong CD4 + and CD8 + T-cell and antibody responses that led to the production of cytokines, especially interferon γ. Interferon γ could lead to decreased expression of CYP enzymes. Bayraktar et al 15 concluded that COVID-19 vaccines have strong antibody responses, and this would lead to potential interactions with some drugs as well as clozapine. Moreover, Kow and Hasan 16 published a letter about potential interactions between COVID-19 vaccines and antiepileptic drugs. The authors also indicated that administration of the COVID-19 mRNA vaccinations elicited strong antibody responses with a high fraction of specific T cells producing interferon γ, which could lead to reduced expression of CYP1A2 and CYP3A4, which are involved in clozapine metabolism. Nevertheless, T-cell responses with the production of interferon γ are not specific to mRNA vaccines.

C-reactive protein increase after the second vaccination with Spikevax (COVID-19 Vaccine Moderna) and the clozapine level increase was much lower in the prescribed patient, compared with the increase in the predisposed patient after the first Pfizer-BioNTech vaccination in the case report of Thompson et al. 12 A more severe drug increase (perhaps due to higher interferon γ concentration) could have been possible if clozapine would have been administered before the first vaccination. Furthermore, the described patient had no comorbidities or any predisposing conditions, compared with the patient of Thompson et al. 12 Adverse events began on the fourth day after vaccination in the report of Thompson et al, 12 similar to this report after 5 days.

Unfortunately, in this case, CRP values were only measured at the day of second vaccination and then 7 days later. Perhaps, the peak elevation of CRP was earlier than day 7.

Clozapine blood concentrations are highly sensitive to inflammation-related inhibition of especially CYP1A2 activity, 4, 17 but the underlying multifactorial mechanisms are incompletely understood. A vaccinationinduced activation of proinflammatory cytokines and after impairment of hepatic CYP450 synthesis may be a reason of the increased serum levels, but alterations of drug transporters and other drug-metabolizing enzymes could have been affected with corresponding consequences for drug metabolism and excretion. 6,11,18,19 As various reasons may have led to the increased C/D of clozapine after vaccination, this single case report cannot prove a causal relationship between mRNAvaccination and the elevation of clozapine blood concentrations, but caution is required. Nevertheless, the high C/D ratios were consistent with inhibition of CYP1A2 and CYP2C19 metabolism.

During the COVID-19 pandemic, therapeutic drug monitoring should be con-ducted in patients treated with clozapine that receive a first or second mRNA vaccination, as dose adaptation can be necessary in case of adverse effects. At the time of vaccination, instructions to the patient and caregivers to watch for changes in symptoms over the first week after vaccination is recommended. If symptoms occur, seeking medical attention and obtaining a complete blood count/differential, CRP and clozapine level would be advisable, as well as any other assessment and intervention depending on the individual case. Moreover, it has to be considered that dose adaptation may also be necessary after a few days of dose reduction to avoid loss of sufficient antipsychotic drug action.

We emphasize that (1) patients on clozapine ought to be a high priority for vaccination, (2) the results reported do not imply that treatment with clozapine is a contraindication to vaccination, and (3) the results do not imply that clozapine should not be initiated in vaccinated patients. 

To the Editors:

T opiramate is a sulfa derivative antiepileptic drug with a narrow range of approved uses, specifically: epilepsy monotherapy or adjunctive therapy for partialonset seizures, primary generalized tonicclonic seizures and seizures associated with Lennox-Gastaut syndrome, and also as prophylaxis of migraine in adults. However, because of the increasing evidence, based on controlled studies, topiramate has progressively been used in the treatment of many psychiatric conditions, namely, depression, weight loss and obesity, alcohol and drug dependence, eating disorders, posttraumatic stress disorder, and anger and aggressive behavior. 1 Antiepileptic medications share neurochemical effects with alcohol by inhibiting neuronal excitation. The supposed efficacy of topiramate in the treatment of alcohol dependence is based on reversing chronic changes induced by alcohol resulting in dopamine-facilitated neurotransmission in the midbrain. 1 Numerous adverse drug reactions have been associated with the use of topiramate, including acute myopia and secondary angle-closure glaucoma (ACG); metabolic acidosis; oligohidrosis and hyperthermia; hyperammonemia and encephalopathy; fetal toxicity; kidney stones; cognitive dysfunction; and psychiatric/behavioral disturbances with somnolence, fatigue and mood problems. 2 Concerning the ocular adverse effects of topiramate, acute ACG (due to choroidal effusion and resulting anterior displacement of the lens-iris complex) is a harmful condition; patients present with ocular pain, blurred vision, headache, nausea, and vomiting. Optic nerve damage with visual field defect and vision impairment may happen if elevated intraocular pressure is persistent. 3 Although drug-associated bilateral acute ACG is a rare side effect, topiramate is commonly prescribed by psychiatrists; therefore, with the growing off label use of this drug, it is important to raise awareness among physicians about its potentially blinding side effect.

A 45-year-old White man with a history of alcohol abuse, presented to the emergency department (ED) with sudden onset of blurred vision in both eyes for 24 hours associated with eye pain and ocular hyperemia.

He had a medical history of alcoholic hepatitis, hyperlipidemia, and hypertension and was admitted 3 weeks before in a psychiatric ward under alcohol dependence treatment. The patient presented a history of alcohol abuse since he was 28 years old, with periods of remission and abstinence, exhibiting increased alcohol intake in the last 9 months. During this institutionalization, after an initial period on high doses of oxazepam (45 mg daily) to avoid withdrawal symptoms, topiramate 50 mg daily was initiated and raised from 50 mg to 100 mg/daily 2 days after. Within 3 days after initiating topiramate, the patient presented the above symptoms. His medications at that time also included fluoxetine 20 mg, oxazepam 15 mg, furosemide 20 mg, spironolactone 25 mg, and pantoprazole 40 mg, which he had been doing for almost 3 months. He reported no known medical allergy. He had no other relevant medical or previous ocular history, as well as no family ophthalmic history.

On the presentation to the ED his vision was 1/10 in each eye, and intraocular pressure (IOP) was 56 mm Hg right eye and 57 mm Hg left eye. Ocular examination revealed clear corneas, characteristically bilateral shallow anterior chamber and conjunctival hyperemia. Therefore, pilocarpine, timolol, and dorzolamide drops, and oral acetazolamide 250 mg were given. Laboratory test results revealed only increased parameters of alcohol misuse, namely gammaglutamyltranspeptidase, 276 UI/L (normal value, <55 UI/L) and total bilirubin, 2.8 mg/ dL (normal value, 0.2-1.2 mg/dL). Since on reexamination, IOP was 55 mm Hg on both eyes, mannitol 250 mL IV was initiated. Drug-associated ACG was highly suspected based on the finding of shallow anterior chamber and later confirmed by gonioscopy in a patient under topiramate. Thus, topiramate was discontinued, and he was admitted in the ophthalmic inpatient care for further evaluation and management. Therapy was initiated with timolol, brimonidine, and dorzolamide 2 times daily, and dexamethasone 6 times daily. Within 3 days, the signs and symptoms were relieved. At a follow-up appointment, 20 days later, the patient's vision returned to baseline. A written consent was obtained from the patient to publish the case report.

Acute bilateral secondary ACG has been frequently reported as a side effect of many medications, most often topiramate. 4 Shortly after initiating the medication or increasing the dose, patients typically present with headache, vomiting, ocular hyperemia, and sudden onset of vision changes. 5 This clinical presentation should be a red flag to the physician to tell the patient to stop the drug

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Clozapine intoxication in COVID-19

COVID-19 infection may cause clozapine intoxication: case report and discussion

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Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017

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Regulation of cytochrome p450 by inflammatory mediators: why and how?

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Elevated clozapine levels and toxic effects after SARS-CoV-2 vaccination

Effect of influenza vaccination on serum clozapine and its main metabolite concentrations in patients with schizophrenia

African genetic diversity: implications for cytochrome P450-mediated drug metabolism and drug development

The potential interaction between COVID-19 vaccines and clozapine: a novel approach for clinical trials

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Riedstadt Germany