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Delirium Resolving Upon Switching From Risperidone to Quetiapine: Implication of CYP2D6 Genotype

TO THE EDITOR: Atypical antipsychotics, such as risperidone, olanzapine, and quetiapine, are expected to show efficacies similar to those of conventional agents for treating psychotic disorders, as well as better tolerability. These medications were reported to have a lower incidence of side effects than conventional antipsychotics. However, even newer atypical antipsychotics can cause side effects, and responses to antipsychotics are very different among patients with various psychotic disorders, including delirium. Recent pharmacogenetic studies have identified genetic polymorphisms of cytochrome P450 2D6 (CYP2D6), a drug-metabolizing enzyme, as a factor contributing to interindividual differences in metabolism and response to antipsychotics.¹ In treating delirium, individual pharmacogenetic profiles are important to consider; yet few reports have addressed this issue.

We report a patient whose delirium was treated successfully with quetiapine after switching from risperidone because of prominent extrapyramidal symptoms. We carried out screening for the CYP2D6 genotype of the patient.

Case Report

Mr. A was diagnosed with senile dementia of the Alzheimer’s type at the age of 73 and manifested acute delirium at the age of 74. He was treated initially at an outpatient clinic, but his psychomotor agitation and excitation became so prominent that he was admitted to a hospital.

Mr. A was disoriented and had waxing and waning impairment of consciousness, difficulty in sustaining attention, delayed recall, and emotional lability characterized by angry outbursts and psychomotor agitation. He reported visual hallucinations and showed delusional perceptions. His thought processes were tangential to loose. He was diagnosed with delirium according to DSM-IV.

Initial treatment with 1 mg/day of risperidone caused adverse reactions, including severe truncal dystonia, dysarthria, dysphagia, tremor, and rigidity 2 days after initiation of treatment. These extrapyramidal symptoms lessened 1 week after discontinuation of risperidone, but his delirium persisted. Switching to 25 mg/day of quetiapine was effective in allowing good sleep on the first day of administration. His behavior and cognitive functioning also improved. The delirium fully resolved 2 days afterward without side effects of medication.

Genetic analyses of Mr. A disclosed a CYP2D6 *5/*10 genotype known to result in defective metabolism of CYP2D6 substrates. These analyses were approved by the ethics committee of Yokohama City University School of Medicine. Written informed consent was obtained from Mr. A.

Discussion

The APA has developed a practice guideline for the treatment of patients with delirium.² The use of haloperidol is a standard treatment in the guideline, although such a high-potency conventional neuroleptic is likely to induce side effects, including extrapyramidal symptoms. On the other hand, Schwartz and Masand³ reviewed the literature considering newer atypical antipsychotics in treating delirium, concluding that atypical antipsychotics represented a reasonable first-line drug treatment in delirium.

In this study, we analyzed the CYP2D6 genotype in a patient with delirium who was switched from risperidone to quetiapine because of severe extrapyramidal symptoms. The CYP2D6 genotype of the patient proved to be *5/*10. CYP2D6, CYP mono-oxygenase isozyme, is responsible for hepatic metabolism of various psychotropic agents, including haloperidol, risperidone, and many other antipsychotics. Several studies have shown that adverse reactions to neuroleptics are associated with decreased or deficient CYP2D6 activity.¹ The *10 allele is known to encode an unstable enzyme with decreased catalytic activity, while the *5 allele (gene deletion) contributes no CYP2D6 activity.¹

Risperidone, a substrate of CYP2D6, is metabolized to 9-hydroxyrisperidone,⁴ which is partially removed through renal excretion. Further hepatic metabolism of remaining 9-hydroxyrisperidone is unclear. Since 9-hydroxyrisperidone has pharmacological properties similar to those of risperidone, the sum of risperidone and 9-hydroxyrisperidone activities is believed to result in an overall antipsychotic effect.⁵ Furthermore, the active moiety (steady-state plasma concentrations of risperidone plus 9-hydroxyrisperidone) correlate well with the occurrence of extrapyramidal symptoms.⁶ Mihara et al.⁵ reported that individuals with the CYP2D6 *5/*10 genotype had the highest active moiety among 85 Japanese schizophrenia patients treated with equal doses of risperidone. These findings suggest that our patient with the CYP2D6 *5/*10 genotype may have been particularly vulnerable to risperidone-induced extrapyramidal symptoms because of defective CYP2D6 metabolism. On the other hand, his presumably decreased CYP2D6 activity did not influence metabolism of quetiapine because quetiapine is metabolized mainly by CYP3A4.⁴

Limitations to our study include a lack of laboratory data concerning serum concentrations of neuroleptics, and symptom resolution conceivably could have represented the natural course of the delirium.

Which atypical antipsychotics should be chosen first in treating delirium has not been established. Impaired drug metabolism can greatly influence a patient’s clinical course. Individual pharmacogenetic profiles are considered important in the psychopharmacotherapy of delirium. Predictive genotyping might be of increasing practical value in guiding safer and more efficient pharmacotherapy in the future.

REFERENCES

1. Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A: Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002; 53:111–122[CrossRef][Medline]
2. American Psychiatric Association: Practice guideline for the treatment of patients with delirium. Am J Psychiatry 1999; 156(suppl 5):1–20
3. Schwartz TL, Masand PS: The role of atypical antipsychotics in the treatment of delirium. Psychosomatics 2002; 43:171–174[Abstract/Free Full Text]
4. Spina E, Scordo MG, D’Arrigo C: Metabolic drug interactions with new psychotropic agents. Fundam Clin Pharmacol 2003; 17:517–538[CrossRef][Medline]
5. Mihara K, Kondo T, Yasui-Furukori N, Suzuki A, Ishida M, Ono S, Kubota T, Iga T, Takarada Y, de Vries R, Kaneko S: Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, in Japanese patients with schizophrenia. Ther Drug Monit 2003; 25:287–293[CrossRef][Medline]
6. Spina E, Avenoso A, Facciola G, Salemi M, Scordo MG, Ancione M, Madia AG, Perucca E: Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia. Psychopharmacology (Berl) 2001; 153:238–243[CrossRef][Medline]

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Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via HighWire Citing Articles via Google Scholar Articles by Kato, D. Articles by Hirayasu, Y. Search for Related Content PubMed Citation Articles by Kato, D. Articles by Hirayasu, Y. Alzheimer's Disease Delirium Atypical Neuroleptics

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