Letter to the Editor: Stiffness,Parkinsonism,and Fatigue on a Case of Poor Elimination of Risperidone

Case Report

The patient, a 15-year-old girl, was hospitalized after a manic episode and diagnosed with bipolar 1 disorder with psychotic features. She was stabilized on olanzapine 30 mg daily and lithium 600 mg daily before discharge. During a follow-up visit, olanzapine was cross-titrated to risperidone 2 mg daily due to side effects of weight gain and akathisia. She experienced mania with psychotic symptoms 5 days later and was stabilized on 6 mg risperidone daily after hospitalization. She was seen in clinic 2 days after discharge due to significant parkinsonian symptoms. Patient's serum risperidone and metabolite 9-hydroxyrisperidone concentrations were both found to be significantly elevated (Table 1). Her risperidone was tapered down to 0.5 mg, after which her symptoms resolved.

Discussion

The patient developed extrapyramidal side effects from elevated serum risperidone (and active metabolites) on a therapeutic dose of the medication. Drug–drug interaction could be a contributing factor; however, interactions between risperidone and lithium resulting in these symptoms are rare and are more often reported in older adults (Hsu et al, 2016). Variation in risperidone metabolism may also impact serum levels.

Risperidone is metabolized by the enzyme CYP2D6 to its active metabolite 9-hydroxyrisperidone (Hiemke et al, 2017). In children, the half-life and steady state of risperidone can vary significantly based on factors such as age and variations in metabolisms (Vandenberghe et al, 2015). In particular, allelic differences in the CYP2D6 gene impacts enzyme activity and risperidone metabolism (Vandenberghe et al, 2015), as patients with low enzyme activity have an increased likelihood of accumulating serum risperidone and developing the toxic effects (Jukic et al, 2019). These patients would be expected to have normal to low concentrations of the 9-hydroxyrisperidone metabolite (Vandenberghe et al, 2015), but the patient in this case had significantly elevated serum 9-hydroxyrisperidone.

Moreover, the half-life for 9-hydroxyrisperidone is about 20 hours and does not vary between CYP2D6 phenotype (Hiemke et al, 2017), indicating allelic variation alone would not explain accumulation of the metabolite. Another potential explanation is poor renal elimination of 9-hydroxyrisperidone (Hiemke et al, 2017), but this patient had normal renal function. Metabolite 9-hydroxyrisperidone is also degraded through oxidative N-dealkylation by unknown enzymes (Hiemke et al, 2017), so deficiency in these enzymes may predispose patients to building up serum 9-hydroxyrisperidone.

Currently, the efficacy of using CYP2D6 genotyping in a clinical setting is unclear (Jukic et al, 2019). However, factors outside of CYP2D6 genotype, such as other metabolic enzymes that have yet to be discovered, can contribute to risperidone accumulation and development of side effects. This case report highlights the importance of interindividual variability and strategic assessment of drug levels that may be helpful in optimizing treatment and minimizing adverse effects of medications.