Abstract
T
Case Report
An 11-year-old boy with past psychiatric diagnoses of bipolar disorder, generalized anxiety disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder, was admitted to inpatient psychiatry for increasing aggression and violence toward family members and animals. History gathered from the patient and his family revealed the absence of any discrete mood episodes that would meet criteria for mania, hypomania, or depression. Developmental history was unremarkable; he met all developmental milestones on schedule. The patient demonstrated the ability to socialize appropriately and to make friends easily both in school and in an inpatient psychiatric facility. He was well behaved and attentive in the inpatient unit, without behavioral disturbances. During his hospitalization, the diagnoses of bipolar disorder and autism spectrum disorder were ruled out following detailed assessment, including detailed clinical interviews with the patient and his parents, as well as behavioral observations from experienced psychiatric nurses. Conduct disorder was diagnosed based on a history of violence toward people and animals, destruction of property, and deceitfulness.
At the time of admission, his psychotropic medications included risperidone 2 mg twice daily and oxcarbazepine 600 mg twice daily. He had been treated with these medications since age 9, and had been on a stable dosage of both medications for 1 month preceding hospital admission. During his inpatient stay, oxcarbazepine was tapered and discontinued over the course of 1 week, given lack of clear indication, as well as lack of beneficial effects in the outpatient setting. The patient tolerated the taper without difficulty.
One day following completion of the oxcarbazepine taper, the on-call psychiatrist was paged to evaluate the patient for new onset of mild dysarthria. Additionally, the patient had a subjective complaint of a “funny feeling” in his tongue. Examination for extrapyramidal symptoms was unremarkable, revealing normal arm swing, normal tone, and absence of tremor or abnormal movements. Abnormal Involuntary Movement Scale (AIMS) score was 0. He was able to move his tongue in and out, side to side, without objective abnormalities. He subjectively reported that it was more difficult than usual to move his tongue. His speech was subtly dysarthric. There was no evidence of tongue swelling. The patient was not having any difficulty breathing or swallowing.
The presentation was consistent with a mild dystonic reaction. Diphenhydramine 25 mg was administered by mouth. Within 30 minutes of administration, the patient's symptoms resolved. His scheduled dosage of risperidone was not administered that evening. The following day risperidone was decreased from 2 mg twice daily to 1 mg twice daily. No further anticholinergic medications were administered. The patient did not have recurrence of symptoms during his hospitalization.
Discussion
Given the patient's stable dosage of risperidone, the emergence of symptoms consistent with a mild dystonic reaction of the tongue was likely caused by increased levels of risperidone and/or active metabolites, resulting from discontinuation of oxcarbazepine. As oxcarbazepine was tapered and discontinued, the mild inducing effects of oxcarbazepine on cytochrome P450 enzymes involved in risperidone metabolism were no longer at play, setting the stage for accumulation of risperidone and/or metabolites.
Carbamazepine is recognized as a strong inducer of several cytochrome P450 enzymes, as well as other metabolic enzymes (Perucca 2006). As a result of its inducing properties, co-administration of carbamazepine with antipsychotic medications leads to decreased serum levels of antipsychotic medication (Daniel et al. 1998; Lucas et al. 1998; Miceli et al. 2000). Structurally, carbamazepine is closely related to oxcarbazepine. Both agents have a tricyclic structure; oxcarbazepine has a ketone substitution at the 10 and 11 positions, but is otherwise structurally identical. Alhough structurally similar, there is less side effect burden associated with oxcarbazepine as well as less enzyme induction (Schmidt and Elger 2004; Bialer 2012). Although enzyme induction is not as significant as carbamazepine, oxcarbazepine has been reported to induce CYP3A4 as well as glucuronyl transferases (Perucca 2006), and these effects may be dose dependent (May et al. 2003).
Risperidone undergoes metabolism primarily in the liver, and is excreted primarily in urine. The primary initial step in risperidone metabolism is conversion to 9-hydroxyrisperidone (i.e., the active metabolite, paliperidone) by CYP2D6. 9-hydroxyrisperidone is then partially (Vermeir et al. 2008) excreted renally in unchanged form, but can also undergo further metabolism to inactive metabolites by CYP3A4 as well as CYP2D6.
A study of oxcarbazepine used in combination with two different antipsychotic medications (risperidone and olanzapine) demonstrated an absence of significant changes in mean plasma levels of risperidone or olanzapine when administered together with oxcarbazepine (Rosaria Muscatello et al. 2005). However, the patient presented in this case report demonstrates that clinically significant effects are possible. One possible mechanism to explain the new-onset extrapyramidal symptoms is that oxcarbazepine may have induced CYP3A4, and that discontinuation led to an accumulation of the active risperidone metabolite 9-hydroxyrisperidone. Clinicians should closely monitor patients when adding or subtracting medications, as even subtle drug interactions may lead to clinically significant effects as the dose of one medication is adjusted.
Disclosures
No competing financial interests exist.