Valbenazine, Fluphenazine, and Possible Neuroleptic Malignant Syndrome in a 58-Year-Old Woman

Abstract

The Drug Interaction Probability Scale is modeled after the widely accepted Naranjo ADR Probability Scale but is specifically designed to evaluate the probability of a potential drug interaction. 8 Application of this scale for the aforementioned case resulted in a score of 5, indicating a "probable" drug interaction. Strengths of this case report include the ability to rule out other potential causes for this patient's symptoms. Although isoniazid-induced psychosis is possible, the fact that he improved despite continuation of isoniazid with decreased antipsychotic coverage makes this unlikely. In addition, the decrease in lorazepam dose may have contributed to increased anxiety, but these symptoms did not reemerge with subsequent decreases and discontinuation of lorazepam. Lastly, although not a major metabolism pathway, clozapine is also metabolized via CYP3A4, so an interaction with isoniazid is possible. 9 Angelini et al 10 reported a case where isoniazid initiation led to increased clozapine and norclozapine levels by almost 200%, and the patient exhibited excess sedation. Although our patient's clozapine level did increase with the addition of isoniazid, the symptoms displayed would be in opposition of an increased clozapine level, and the symptoms resolved without a decrease in clozapine dose. On the other hand, his symptoms are consistent with known clinical effects of therapeutic use of aripiprazole, namely, activation and agitation. Although inhibition interactions occur quickly after initiation, the time for the substrate to reach a new steady state will depend on its half-life. Aripiprazole has a half-life of 75 hours, so new steady state after isoniazid inhibition would be reached after 12 to 16 days. Clozapine, with a half-life of 12 hours, would reach a new steady state in 2 to 2.5 days. The case patient's symptoms emerged on day 16 of isoniazid therapy, which is more in line with aripiprazole rather than clozapine, further strengthening this case report.A limitation of the current case report is the lack of aripiprazole levels because this would help to corroborate the drug interaction theory. Another limitation is the fact that isoniazid was not dechallenged. Because the patient returned to baseline after decrease and discontinuation of aripiprazole, isoniazid was continued. Consideration was given to switching to rifampin but was ultimately decided against because of the concern for destabilization given the interaction with clozapine. Future research should seek to confirm the hypothesis of an aripiprazole-isoniazid interaction with measurement of aripiprazole levels before and during isoniazid therapy.