II-80 Zdrav Vestn 2007; 76: SUPPL II
MDR1 GENE POLYMORPHISMS AND EXTRAPYRAMIDAL SIDE
EFFECTS FOLLOWING ACUTE ANTIPSYCHOTIC TREATMENT
Matej Kastelic1, Jure Koprivšek2, Laura Mandelli3, Alessandro Serretti3, Katja
Breskvar1, Blanka Kores-Plesničar2, Vita Dolžan1
1 Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
2 Dept. of Psychiatry, Teaching Hospital Maribor, Maribor, Slovenia
3 Institute of Psychiatry, University of Bologna, Bologna, Italy; matej.kastelic@mf.uni-lj.si
Background Multidrug resistant protein (MDR1) gene, which codes for P-glycoprotein is amongst the
best understood mediators of drug resistance. It functions as an ATP dependant efflux
transporter and is widely localized in normal tissues including the gastrointestinal tract,
blood cells, biliary tract, kidney and brain. It plays a major role in absorption, distribution
and elimination of various xenobiotics by excreting them into bile, urine and intestinal
lumen. It transports drugs against a concentration gradient across the blood-brain barrier
back into the plasma and thereby reduces their bioavailability in the brain. Studies using
mice models reported that P-glycoprotein-deficient mice had greater drug penetration into
brain than wild-type animals. Two common single nucleotide polymorphisms (SNP), a
silent mutation C3435T in exon 26 and SNP G2677T in exon 21 were described in MDR1
gene. A twofold reduction in intestinal P-gp expression has been reported in homozygous
carriers of the 3435 T allele in exon 26. Because most second generation antipsychotics
were shown to be P-gp substrates we hypothesized that polymorphisms in MDR1 that alter
P-gp function may influence individual’s response to antipsychotic drugs. Differential en-
try of antipsychotics into the brain might explain differences in response and side effects,
even if plasma concentrations do not differ.
Aim The present study was therefore designed to examine whether C3435T and G2677T/A
polymorphisms in MDR1 are related to extrapyramidal side effects in acute antipsychotic
treatment of schizophrenia.
Methods A genotyping approach using sequence specific PCR and TaqMan genotyping assays (Ap-
plied Biosystems) and was used to determine C3435T and G2677T/A MDR1 polymorphisms,
respectively in total of 65 patients acutely treated with haloperidol or risperidone either for
the first episode of schizophrenia spectrum disorders or for the psychotic episode after
tapering their maintenance treatment. Extrapyramidal side effects were assessed with the
Simpson-Angus Extrapyramidal Side Effects Scale (EPS), the Barnes Akathisia Scale (BARS)
and the Abnormal Involuntary Movement Scale (AIMS). The Slovenian Ethics Committee
for Research in Medicine approved the study.
Results Haloperidol was significantly more administered in patients with high BPRS and CGI base-
line scores. Further, patients with high baseline BPRS and CGI scores received higher dos-
ages of drugs. Nevertheless, haloperidol and high dosages of treatment were associated
with a poor outcome in terms of final BPRS scores. A poor outcome was also associated
with old age and elevated body mass index (BMI). Akathisia (BARS) was dependent on
drug dosage, extrapyramidal symptoms (EPS) were more severe in patients treated with
haloperidol and at a high dosage and, finally, tardive dyskinesia (AIMS) was marginally
dependent on age but mostly on illness duration and it was more severe in patients treated
with haloperidol and a high dosages. The frequencies of C3435T (exon 26) genotypes
were: CC = 13.5 %, CT = 42.3 %, TT = 44.2 % and the frequencies of G2677T/A (exon 21)
genotypes were: GG = 13.5 %, GT = 51.9 %, GA = 5.8 %, TT = 26.9 %, TA = 1.9 %. Both
polymorphisms were in Hardy-Weinberg Equilibrium (HWE) (respectively p = 0.15. p =
0.55) and they were in strong Linkage disequilibrium (LD) (D’ = 0.85. Chi-sq = 71.1 d.f. = 2
p < 0.0001). We did not find any association between MDR1 variants and extrapyramidal
side effects (BARS: MDR1ex21 p = 0.53. MDR1ex26 p = 0.42; AIMS: MDR1ex21 p = 0.22.
MDR1ex26 p = 0.52; S-A ESP: MDR1ex21 p = 0.53. MDR1ex26 p = 0.91)
Conclusion Neither MDR1 C3435T (exon 26) nor G2677T/A (exon 21) were associated with the oc-
currence of EPS effect in schizophrenic patients acutely treated with antipsychotics.