A case of recurrent seizures: Drug–drug interaction between low-dose clozapine and extended-release bupropion

To the Editor,

Bupropion is a norepinephrine dopamine reuptake inhibitor used as an antidepressant or adjunctive therapy in smoking cessation. Here, we report that a clozapine-treated patient developed seizures after single doses of an extended-release formulation of bupropion (BXL).

A 35-year-old Chinese female had a 10-year history of schizoaffective disorder. She had been hospitalized repeatedly for recurrent psychotic and affective episodes. Her symptoms had been well controlled for years by clozapine 50 mg/day, lithium 600 mg/day, glycopyrrolate 2 mg/day and estazolam 2 mg/day. In August 2016, the patient was hospitalized because of recurrent major depression and persecutory delusion. To target the latter, the dosage of clozapine was increased to 100 mg/day. Depressed mood persisted, so BXL 150 mg was added. Six hours after a single dose of BXL, the patient had grand mal seizures. Laboratory examinations and a computed tomography brain scan were negative. BXL and clozapine treatments were discontinued, and no further seizures occurred in the following days. As the patient had received clozapine for several years, clozapine treatment was reinitiated, and the dosage was gradually increased to 100 mg/day. When the patient was rechallenged with BXL 150 mg, she experienced another seizure.

This case demonstrated rare reoccurring BXL-induced seizures. A potential reason for this observation is the concomitant use of clozapine with bupropion, a cytochrome P450 2D6 inhibitor, which may elevate in vivo clozapine concentrations. One previous report associated each 100 μg/L increase in clozapine plasma level with a 12% increase in electroencephalogram abnormalities (Varma et al., 2011). Another explanation may be the 2D6 phenotype. Although clozapine is primary metabolized by CYP1A2, in 2014, the US Food and Drug Administration (FDA) approved drug labeling for clozapine stating that reducing the dosage may be necessary in poor CYP2D6 metabolizers. Although the patient did not undergo genetic testing (the prevalence of the 2D6 phenotype in Chinese individuals is below 1%), she had shown a good response to very-low-dose clozapine (50 mg/day) for years, implying the possibility of a reduced functionality allele in the diplotype (Kitada, 2003). The temporal relationship also matched the time needed to reach the maximum concentration (Tmax) of BXL (5 h; the Tmax of the immediate-release and sustained-release formulations is 1 hour and 3 hours, respectively; Connarn et al., 2017). Bupropion and clozapine are seizure-provoking medications, but few studies have described recurrent seizures at this dosage. The mechanism proposed here suggests that any medication interfering with a drug–drug interaction should be examined before initiation.