The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naïve patients with first-episode schizophrenia treated with risperidone.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Jovanović
Nikolina
N
Department of Psychiatry, University of Zagreb School of Medicine, University Hospital Center, Kispaticeva 12, 10000, Zagreb, Croatia. nikolina.jovanovic@gmail.com
Božina
Nada
N
Lovrić
Mila
M
Medved
Vesna
V
Jakovljević
Miro
M
Peleš
Alma Mihaljević
AM
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007555:Isoxazoles / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000097:blood; D018967:Risperidone / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics; D018401:Sample Size; D012559:Schizophrenia / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate