(032) Clozapine Toxicity Following COVID-19 Infection: A Case Series

Abstract: Background/Significance:

Clozapine, an atypical antipsychotic, is a very effective medication that has been approved for use in treatment-resistant schizophrenia. However, clozapine remains an underutilized medication because of its side effect profile and the need for routine laboratory monitoring due to the risk of agranulocytosis (Kar, 2016). Clozapine levels may also need to be monitored as various factors can affect the level of the medication. For example, clozapine levels may increase in the setting of concomitant use of CYP450 inhibitors, smoking cessation, and severe respiratory infections such as COVID-19, thereby resulting in increased risk of clozapine toxicity (Kar, 2016; de Leon, 2004).

Case:

We report two cases in which patients who had previously been on stable doses of clozapine developed increased clozapine levels and resulting symptomatology in the setting of a recent COVID-19 infection. The first case demonstrates a 70-year-old female with a history of schizophrenia, stabilized with clozapine and haloperidol, who was admitted to the hospital with COVID-19 and was found to have an elevated clozapine level and symptoms of clozapine toxicity including lethargy, constipation, sialorrhea, eosinophilia, and thrombocytopenia. The second case demonstrates a 65-year-old female with a history of schizoaffective disorder, bipolar type, stabilized with clozapine and valproic acid, who was admitted to the hospital with altered mental status in the setting of a recent COVID-19 infection and was found to have an elevated clozapine level and symptoms including lethargy and myoclonus.

Discussion:

Clozapine is metabolized by the cytochrome P450 system, mainly CYP1A2. Cytokines such as interleukin 1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), interferon-α (IFN-α), and IFN-γ which are increased during COVID-19 infection inhibit the activity of CYP1A2. This inhibition of CYP1A2 results in increased and possibly even toxic clozapine levels, even in patients who had been stable for many years (Tio, 2021; Dotson, 2020).

Conclusion/Implications:

Frequent monitoring of clozapine levels and accordant adjustment of clozapine dose is of paramount importance in the setting of COVID-19 infection to avoid potential clozapine toxicity. This underscores the importance of coordinated care and cross-education between medicine and psychiatric services in the context of newly emerging processes.

References:

Kar, N., Barreto, S., & Chandavarkar, R. (2016). Clozapine Monitoring in Clinical Practice:

Beyond the Mandatory Requirement. Clinical Psychopharmacology and Neuroscience, 14(4), 323–329. https://doi.org/10.9758/cpn.2016.14.4.323

de Leon, J. (2004). Respiratory Infections Rather Than Antibiotics May Increase

Clozapine Levels. The Journal of Clinical Psychiatry, 65(8), 1044–1045. https://doi.org/10.4088/jcp.v65n0818a

Tio, N., Schulte, P. F. J., & Martens, H. J. M. (2021). Clozapine Intoxication in COVID-19.

American Journal of Psychiatry, 178(2), 123–127. https://doi.org/10.1176/appi.ajp.2020.20071039

Dotson, S., Hartvigsen, N., Wesner, T., Carbary, T. J., Fricchione, G., & Freudenreich, O. (2020).

Clozapine Toxicity in the Setting of COVID-19. Psychosomatics. https://doi.org/10.1016/j.psym.2020.05.025