Elevated Clozapine Blood Concentrations After Second COVID-19 Vaccination With Spikevax (COVID-19 Vaccine Moderna).

To the Editors

It is already known that coronavirus disease 2019 (COVID-19) and other inflammatory diseases can lead to elevated clozapine blood concentrations.[1-4] In these conditions, therapeutic drug monitoring of clozapine[5] may help maintain clozapine drug concentrations within the therapeutic reference range, as adequate dose titration of clozapine during infectious diseases can prevent serious adverse drug reactions and intoxication.

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.[6,9-11] 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.

CASE REPORT

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.

TABLE 1

Clozapine Dosage, Blood Concentration, Concentration to Dose Ratio (C/D), and Adverse Drug Reactions With the Passage of Time and Laboratory Measures

Date	Clozapine Dosage, mg	Clozapine Blood Concentration, ng/mL	C/D, ng/mL/mg	Comment
April 13, 2021	First COVID-19 vaccination with Spikevax (COVID-19 Vaccine Moderna)
May 18, 2021	Beginning clozapine therapy with 12.5 mg
May 25, 2021	Second COVID-19 vaccination with Spikevax (COVID-19 Vaccine Moderna)
	100	270	2.7	Steady state not reached; patient is agitated since May 26, 2021, constantly leaves his room day and night
May 30, 2021	175	868	4.96	Steady state not reached; dizziness, gait disturbances and drowsiness, as well as disorientation to place and time, consistent with delirium, tachycardia, and hypotension (19:10 o'clock: arterial blood pressure 96/64, pulse 112)
May 31, 2021	Clozapine paused	452
June 1, 2021	50	246	4.92	Steady state not reached; ECG in normal condition
June 4, 2021	150	282	1.88	Steady state not reached
June 06, 2021	200	391	1.96	Steady state not reached
June 10, 2021	Results of genotyping present
June 29, 2021	112.5	336	2.99	Steady state reached

ECG, electrocardiogram; GFR, glomerular filtration rate; GPT, glutamate-pyruvate transaminase; GT, glutamyl transferase; GOT/AST, glutamic oxaloacetic transaminase/aspartate aminotransferase.

Ten days after vaccination, concentration-to-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 dose-related 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 γ-glutamyl transferase were slightly above the therapeutic range.

DISCUSSION

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 vaccination-induced 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 mRNA vaccination 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 conducted 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.