The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naïve patients with first-episode schizophrenia treated with risperidone
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To evaluate the role of cytochrome 450 2D6 (CYP2D6) and ABCB1 variants on plasma risperidone concentrations and treatment response in 83 drug-naive patients experiencing a first episode of psychosis.
All patients were treated with risperidone for 8 weeks. The CYP2D6 genotyping was performed by allele-specific PCR–restriction fragment length polymorphism analysis (for alleles *3,*4,*6) and long-distance PCR (for duplications and allele *5), while real-time PCR analysis was used for the ABCB1 G2677T/A and C3435T variants. Plasma concentrations of risperidone and 9-OH risperidone were measured by high-performance liquid chromatography.
The number of patients with the CYP2D6 wild type (wt)/wt, wt/mutation (mut) and mut/mut genotype was 43, 32 and 8, respectively. The number of patients with the ABCB1 2677G/G, G/T and T/T variants was 29, 42 and 12, respectively; those with the 3435CC, C/T and T/T variants was 25, 37 and 21, respectively. The CYP2D6 genotype had a strong effect on the steady-state dose-corrected plasma levels (C/D) of risperidone, its 9-OH metabolite and the active moiety, while the ABCB1 2677 T/T and 3435 T/T genotypes has similarly strong effects on the active moiety C/D. The CYP2D6 poor metabolizers had a significantly higher risperidone C/D and active moiety C/D and lower 9-OH risperidone C/D. The ABCB1 3435 T allele and the ABCB1 2667 T-3435 T haplotype carriers were more frequent among subjects without extrapyramidal syndromes. Patients showed significant improvements in positive and general symptoms, but not in negative symptoms. These changes were not related to variations in genetic and drug concentration data.
Our findings suggest that CYP2D6 and ABCB1 G2677T and C3435T may be useful determinants of risperidone plasma concentrations, but the clinical implications of these associations in relation to treatment response and side-effects remain unclear.
KeywordsRisperidone 9-hydroxirisperidone CYP2D6 ABCB1 Schizophrenia
- 2.Aravagiri M, Marder SR, Wirshing D, Wirshing WC (1998) Plasma concentrations of risperidone and its 9-hydroxy metabolite and their relationship to dose in schizophrenic patients: simultaneous determination by a high performance liquid chromatography with electrochemical detection. Pharmacopsychiatry 31:102–109CrossRefPubMedGoogle Scholar
- 8.Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene. multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478CrossRefPubMedGoogle Scholar
- 11.Yasui-Furukori N, Mihara K, Takahata T, Suzuki A, Nakagami T, De Vries R, Tateishi T, Kondo T, Kaneko S (2004) Effects of various factors on steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone: lack of impact of MDR-1 genotypes. Br J Clin Pharmacol 57:569–575CrossRefPubMedGoogle Scholar
- 12.World Health Organization (WHO) (1990) International classification of Disease, 10th edn (ICD-10). WHO, GenevaGoogle Scholar
- 13.Kay SR, Fiszbein A, Opler LA (1988) Positive and Negative Symptom Scale (PANSS) for schizophrenia. Schizophr Bull 13:21–76Google Scholar
- 18.von Ahsen N, Richter M, Grupp C, Ringe B, Oellerich M, Armstrong VW (2001) No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V allele) on dose-adjusted cyclosporin A trough concentrations or rejection incidence in stable renal transplant recipients. Clin Chem 47:1048–1052Google Scholar
- 27.Kastelic M, Koprivšek J, Plesničar BK, Serretti A, Mandelli L, Locatelli I, Grabnar I, Dolžan V (2010) MDR1 gene polymorphisms and response to acute risperidone treatment. Prog Neuropsychopharmacol Biol Psychiatry 34:387–392Google Scholar
- 30.Leucht S, Busch R, Hamann J, Kissling W, Kane JM (2005) Early-onset hypothesis of antipsychotic drug action: a hypothesis tested, confirmed and extended. Biol Psychiatry 57:1543–1549Google Scholar