Background
Autonomic nervous system (ANS) activity is lower in patients with schizophrenia than in the general population [
1,
2]. In patients with schizophrenia, antipsychotic medication is known to exacerbate ANS dysfunction [
3‐
9], and reduced ANS activity is associated with cardiovascular morbidity and sudden death [
10]. We previously reported that antipsychotic drugs significantly decrease ANS activity in a dose-dependent manner [
8] and that risperidone, olanzapine, quetiapine, and aripiprazole, all atypical antipsychotics, exert several effects on ANS activity [
11]. We found individual differences in ANS activity in patients with schizophrenia, even among those taking the same atypical antipsychotic (risperidone, olanzapine, aripiprazole, or quetiapine). Thus, in this study, we examined the pharmacogenetic interindividual differences in the effects of particular atypical antipsychotics, with an emphasis on the relationship with the activity of P-glycoprotein (P-gp), to clarify the individual differences in ANS activity during atypical antipsychotic―risperidone, olanzapine, quetiapine, and aripiprazole―treatment in schizophrenia.
P-gp, which is encoded by ATP-binding cassette transport sub-family B member 1 (ABCB1) and is also known as multidrug resistance protein 1 (MDR1), is expressed in various tissues, including the brain, kidney, liver, and intestine. P-gp functions as an important efflux pump in the blood-brain barrier for many kinds of drugs, including antipsychotics, and influences the brain availability of antipsychotics by transporting them against a concentration gradient through the blood-brain barrier and reducing their storage in the brain. Four atypical antipsychotics―risperidone, olanzapine, quetiapine, and aripiprazole―are substrates of P-gp [
12‐
14]. Thus, P-gp activity within the blood-brain barrier in humans may affect antipsychotic tolerability [
13,
14]. In a previous study, we examined the difference in the effects of these four atypical antipsychotics on ANS activity in patients with schizophrenia [
11]. Other studies reported that ABCB1 gene polymorphisms affect the plasma concentrations of antipsychotics [
15,
16]. Furthermore, ABCB1 gene polymorphisms affect the treatment response or adverse effects to antipsychotics such as weight gain or QTc prolongation [
17‐
22]. We also previously reported associations of ABCB1 gene polymorphisms with ANS dysfunction following treatment with aripiprazole in patients with schizophrenia [
23]. However, few studies have investigated the effects of ABCB1 gene polymorphisms on ANS dysfunction due to several other atypical antipsychotics in schizophrenia.
Accordingly, in this study, we investigated the association between ABCB1 genetic polymorphisms and ANS dysfunction in patients with schizophrenia treated with four atypical antipsychotic drugs—risperidone, olanzapine, quetiapine, and aripiprazole—to clarify whether ABCB1 genetic polymorphisms alter their adverse effects. We aimed to identify the biological factors affecting the antipsychotic response, specifically ANS dysfunction.
Results
The demographic and medication data and HRV components of all participants are shown in Table
2. There were 89 participants in the risperidone group (34 men and 55 women; age [mean ± standard deviation], 54.85 ± 14.11 years; CPZ [the daily doses of antipsychotic drugs were converted to an approximate chlorpromazine equivalent], 397.47 ± 224.24 mg/day), 69 participants in the olanzapine group (25 men and 44 women; 51.51 ± 15.87 years; 472.46 ± 227.44 mg/day), 48 participants in the aripiprazole group (24 men and 24 women; 45.13 ± 13.78 years; 465.10 ± 191.14 mg/day), and 27 participants in the quetiapine group (11 men and 16 women; 55.07 ± 18.44 years; 490.63 ± 306.11 mg/day). Table
3 shows the genotypic and allelic frequencies of the four polymorphisms and the HRV in each atypical antipsychotic group. Significant deviation from the expected Hardy–Weinberg proportions were not seen in any of the SNPs. Haplotype analysis revealed perfect linkage disequilibrium between ABCB1 rs1045642 and rs2235048 (r
2 = 1). The aripiprazole group had significantly lower HRV LF and TP components in the rs1045642 T allele carrier–rs2235048 C allele carrier group versus the rs1045642 non-T allele carrier–rs2235048 non-C allele carrier group (LF,
p = .008; TP,
p = .017; Table
3). These patients also showed a tendency toward a lower HRV HF component in the rs1045642 T allele carrier–rs2235048 C allele carrier group versus the rs1045642 non-T allele carrier–rs2235048 non-C allele carrier group (
p = .097). There were no significant differences between all components of HRV and the ABCB1 gene polymorphisms―rs1045642, rs1128503, rs2032582, and rs2235048―in the risperidone, olanzapine, and quetiapine groups. In addition, regarding the association between haplotypes and ANS activity, T-C-T-A haplotype carriers (rs1045642-rs2235048-rs1128503-rs2032582) had significantly lower HRV components versus the non-T-C-T-A haplotype carriers in the aripiprazole group (LF,
p = .005; HF,
p = .036; TP,
p = .008). Table
4 shows the demographic and medication data of both the rs1045642 T allele carrier–rs2235048 C allele carrier group and the rs1045642 non-T allele carrier–rs2235048 non-C allele carrier group in the aripiprazole group. There were no significant differences in age, sex, PANSS total score, and medication data among the groups.
Table 2
Demographic and medication data and log-transformed power values of the LF, HF, and TP frequency bands of all participants
Age (years) | 51.88 ± 15.49 |
Sex (male/female) | 94/139 |
Inpatient/outpatient | 56/177 |
Duration of illness (years) | 20.21 ± 14.44 |
Smoking (smoker/non-smoker) | 17/216 |
BMI (kg/m2) | 24.08 ± 4.47 |
CPZeqa (mg/day) | 444.40 ± 231.41 |
BPDeqb (mg/day) | 0.83 ± 1.55 |
DZPeqc (mg/day) | 5.84 ± 8.71 |
PANSS total score | 71.59 ± 15.55 |
lnLF (ms2) | 4.37 ± 1.22 |
lnHF (ms2) | 3.92 ± 1.45 |
lnTotal Power (ms2) | 4.99 ± 1.21 |
Table 3
Associations between the ABCB1 genotype and ANS activity
Risperidone (n = 89) |
N | 31 | 58 | | 37 | 52 | | 14 | 75 | | 31 | 58 | |
lnLF (ms2) | 4.38 ± 1.16 | 4.51 ± 1.25 | .629 | 4.40 ± 1.15 | 4.51 ± 1.20 | .693 | 4.59 ± 1.02 | 4.44 ± 1.26 | .675 | 4.38 ± 1.16 | 4.51 ± 1.25 | .629 |
lnHF (ms2) | 3.94 ± 1.38 | 3.99 ± 1.68 | .881 | 4.02 ± 1.62 | 3.94 ± 1.55 | .831 | 4.35 ± 1.16 | 3.91 ± 1.63 | .339 | 3.94 ± 1.38 | 3.99 ± 1.68 | .881 |
lnTP (ms2) | 5.00 ± 1.13 | 5.10 ± 1.31 | .721 | 5.05 ± 1.29 | 5.08 ± 1.23 | .898 | 5.26 ± 0.96 | 5.03 ± 1.26 | .529 | 5.00 ± 1.13 | 5.10 ± 1.31 | .721 |
Olanzapine (n = 69) |
N | 20 | 49 | | 35 | 34 | | 15 | 54 | | 20 | 49 | |
lnLF (ms2) | 4.15 ± 1.22 | 4.40 ± 1.09 | .421 | 4.41 ± 1.02 | 4.22 ± 1.23 | .489 | 4.19 ± 1.06 | 4.36 ± 1.15 | .605 | 4.15 ± 1.22 | 4.40 ± 1.09 | .421 |
lnHF (ms2) | 3.92 ± 1.23 | 3.98 ± 1.12 | .851 | 3.98 ± 1.05 | 3.95 ± 1.25 | .926 | 3.82 ± 1.48 | 4.00 ± 1.04 | .581 | 3.92 ± 1.23 | 3.98 ± 1.12 | .851 |
lnTP (ms2) | 4.88 ± 1.05 | 5.05 ± 0.93 | .511 | 5.06 ± 0.90 | 4.95 ± 1.05 | .630 | 4.89 ± 1.07 | 5.04 ± 0.95 | .601 | 4.88 ± 1.05 | 5.05 ± 0.93 | .511 |
Aripiprazole (n = 48) |
N | 17 | 31 | | 17 | 31 | | 9 | 39 | | 17 | 31 | |
lnLF (ms2) | 5.25 ± 0.93 | 4.30 ± 1.23 | .008a | 4.53 ± 1.38 | 4.69 ± 1.13 | .665 | 5.14 ± 1.21 | 4.52 ± 1.20 | .168 | 5.25 ± 0.93 | 4.30 ± 1.23 | .008a |
lnHF (ms2) | 4.61 ± 1.40 | 3.87 ± 1.47 | .097 | 4.40 ± 1.13 | 3.99 ± 1.51 | .372 | 4.61 ± 1.51 | 4.02 ± 1.47 | .287 | 4.61 ± 1.40 | 3.87 ± 1.47 | .097 |
lnTP (ms2) | 5.79 ± 1.05 | 4.90 ± 1.25 | .017a | 5.26 ± 1.35 | 5.19 ± 1.21 | .851 | 5.69 ± 1.29 | 5.10 ± 1.23 | .211 | 5.79 ± 1.05 | 4.90 ± 1.25 | .017a |
Quetiapine (n = 27) |
N | 5 | 22 | | 14 | 13 | | 2 | 25 | | 5 | 22 | |
lnLF (ms2) | 3.85 ± 1.47 | 3.67 ± 1.30 | .790 | 3.37 ± 1.31 | 4.07 ± 1.25 | .170 | 4.18 ± 0.97 | 3.67 ± 1.34 | .602 | 3.85 ± 1.47 | 3.67 ± 1.30 | .790 |
lnHF (ms2) | 4.60 ± 1.64 | 3.09 ± 1.57 | .237 | 3.14 ± 1.71 | 3.41 ± 1.52 | .672 | 5.20 ± 0.27 | 3.11 ± 1.56 | .075 | 4.60 ± 1.64 | 3.09 ± 1.57 | .237 |
lnTP (ms2) | 4.70 ± 1.52 | 4.21 ± 1.38 | .486 | 4.02 ± 1.49 | 4.61 ± 1.26 | .350 | 5.53 ± 0.46 | 4.20 ± 1.39 | .199 | 4.70 ± 1.52 | 4.21 ± 1.38 | .486 |
Table 4
Demographic and medication data between the rs1045642 C–rs2235048 T allele carrier group and the rs1045642 Non-C–rs2235048 Non-T allele carrier group in participants treated with aripiprazole monotherapy
Age (years) | 46.74 ± 14.03 | 42.18 ± 13.21 | .277 |
BMI (kg/m2) | 25.41 ± 5.32 | 24.43 ± 4.43 | .625 |
PANSS total score | 71.32 ± 15.33 | 72.82 ± 17.83 | .761 |
Disease duration (years) | 16.10 ± 13.34 | 16.94 ± 10.66 | .823 |
CPZeqa (mg/day) | 445.97 ± 210.37 | 500.00 ± 149.48 | .354 |
BPDeqb (mg/day) | 1.13 ± 2.78 | 0.47 ± 0.87 | .348 |
DZPeqc (mg/day) | 3.93 ± 5.47 | 6.89 ± 7.50 | .124 |
Multiple regression analysis revealed a significant association between the LF and TP components of HRV and the ABCB1 rs1045642–rs2235048 genotype (LF,
p = .009; TP,
p = .024; Table
5) after adjustment for age, which affects HRV [
11]. There were no significant associations of all components of HRV with BMI or PANSS in the multiple regression analysis. Regarding the aripiprazole group, a significant association was found between the HRV LF and TP components and the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) (LF,
p = .003; TP,
p = .010); the HRV HF component showed a tendency for an association with the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) (
p = .067) in the multiple regression analysis.
Table 5
Multiple regression analysis results using ANS activity, age, body mass index, PANSS, and type of ABCB1 rs1045642–rs22235048 genotype as independent variables in participants treated with aripiprazole monotherapy
Age (years) | −.043 | <.001a | −.037 | .018a | −.0410 | .001a |
BMI (kg/m2) | .042 | .145 | .026 | .534 | .0348 | .277 |
PANSS (total score) | −.001 | .925 | −.014 | .253 | −.006 | .494 |
Type of rs1045642–rs2235048 genotype (reference category: T/C allele carrier) | .798 | .009a | .618 | .148 | .745 | .024a |
Discussion
To our knowledge, this study is the first in which the associations between ABCB1 gene polymorphisms―rs1045642, rs1128503, rs2032582, and rs2235048―and adverse effects, specifically ANS dysfunction, in patients with schizophrenia were compared among atypical antipsychotics. We newly found differences in ANS dysfunction according to ABCB1 genetic polymorphism in schizophrenic patients treated with aripiprazole. On the other hand, there were no significant differences in ANS dysfunction according to ABCB1 genetic polymorphism in schizophrenic patients treated with risperidone, olanzapine, or quetiapine. In terms of ABCB1 rs104542 and rs2235048, the rs1045642 T allele carrier–rs2235048 C allele carrier group had significantly lower LF and TP components of HRV compared with the rs1045642 non-T allele carrier–rs2235048 non-C allele carrier group in the aripiprazole group. This implies an association of the T allele of rs1045642 and the C allele of rs2235048 with reduced sympathetic activity in aripiprazole-treated schizophrenia patients.
ABCB1 rs1045642 at position 3435 on exon 26 does not alter the amino acid sequence [
41] but is associated with changes in the expression of P-gp [
36,
42]. The rs1045642 T variant is linked to decreased intestinal expression of MDR1 and lower plasma levels of digoxin, which is a substrate of P-gp [
36,
42]. Additionally, ABCB1 rs1045642 and rs2032582 affect plasma aripiprazole levels [
43]. Systemic pharmacological inhibition of ABCB1 also results in elevated brain levels of nelfinavir, the ABCB1 substrate, even with only marginal changes in plasma levels [
44]. In addition, ABCB1 polymorphisms have been found to be associated with an increased concentration of the drug in the cerebrospinal fluid [
45]. Regarding a clinical study of adverse effects related to rs1045642, Suzuki et al. reported that the QT interval was significantly longer in patients with schizophrenia treated with risperidone with the rs1045642 T allele than in those with the rs1045642 non-T allele [
20]. Accordingly, we believe that the rs1045642 T variant might also alter the brain levels of aripiprazole and centrally affect sympathetic activity in schizophrenic patients treated with aripiprazole, although this is a matter of speculation.
ABCB1 rs2235048 is localized to the 27th intron of the 3′ end of the gene and, although it is a synonymous SNP, it may influence the structure of P-gp [
46]. ABCB1 rs2235048 has been associated with the efficacy of risperidone and paliperidone in schizophrenia [
37]. However, there are no other studies regarding the association between rs2235048 and the antipsychotic response in schizophrenia.
rs2235048 and rs1045642 are less than 200 bp apart and showed complete linkage disequilibrium in the patients in this study. In fact, a previous study reported that the T > C polymorphism of rs2235048 is associated with low activity of the T allele at rs1045642 [
47]. A low-activity T allele at rs1045642 reduces ABCB1 splicing efficiency, which would lower the rate of production of correctly spliced RNA, and hence P-gp, in low-activity T homozygotes [
36]. We suggest that rs2235048 affects ANS activity by altering the activity of P-gp, particularly in rs1045642 individuals.
Kirschbaum et al. reported that the significant increase in the brain-to-serum concentrations of both aripiprazole and its metabolite dehydroaripiprazole, in particular, after their acute and subchronic administration was related to the expression of P-gp, as indicated by higher levels in ABCB1ab double knockout mice [
13]. In addition, Nagasaka et al. reported that aripiprazole and dehydroaripiprazole have higher inhibition potencies for P-gp activity than risperidone, paliperidone, olanzapine, and ziprasidone [
48]. Rafaniello et al. reported that ABCB1 genetic polymorphisms affected plasma aripiprazole levels [
43]. On the other hand, no associations have been reported between ABCB1 polymorphisms, including rs1128503, rs2032582, and rs1045642, and plasma levels of quetiapine, risperidone, and 9-hydroxyrisperidone [
49,
50]. In addition, olanzapine has lower affinity for P-gp than risperidone or quetiapine [
12]. Thus, the tolerability and response of aripiprazole could be more strongly affected by ABCB1 gene polymorphisms than those of the other atypical antipsychotics, and ABCB1 gene polymorphisms were only associated with aripiprazole-related ANS activity and not with risperidone-, olanzapine-, or quetiapine-related ANS activity.
In this study, there were significant associations between the ABCB1 haplotype and aripiprazole-related ANS activity. In schizophrenic patients treated with aripiprazole, the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) was linked to reduced ANS activity. Previous studies reported that inhibition potency to P-gp was significantly different between ABCB1 T-T-A haplotype (rs1045642-rs1128503-rs2032582) carriers and ABCB1 haplotype non-carriers during treatment with methadone, which is a substrate of P-gp [
51]. In addition, tremor due to antipsychotics significantly differed between C-G-C haplotype carriers (rs1045642-rs20325820-rs1128503) and non-carriers [
37]. The blood prolactin increase due to antipsychotics was also significantly associated with ABCB1 T-A-T haplotype carriers (rs1045642-rs20325820-rs1128503) [
37]. Therefore, we believe that the ABCB1 haplotype might affect P-gp activity and drug response to a greater extent than a single ABCB1 gene polymorphism. Thus, the ABCB1 haplotype could affect aripiprazole brain availability and the aripiprazole response, including ANS activity.
There were no significant differences in the demographic data, symptom severity by PANSS, and medication data between the rs1045642 T allele carrier–rs2235048 C allele carrier group and the rs1045642 non-T allele carrier–rs2235048 non-C allele carrier group for the patients receiving aripiprazole. In addition, multiple regression analysis revealed that sympathetic and total nervous system activity was significantly associated with the ABCB1 rs1045642–rs2235048 genotype and the ACBC1 T-C-T-A haplotype. Although multiple regression analysis also revealed an association between age and both sympathetic and parasympathetic nervous system activity, there was no significant difference in age between the ABCB1 rs1045642 T allele carrier–rs2235048 C allele carrier and rs1045642 non-C allele carrier–rs2235048 non-T allele carrier groups, as mentioned above.
Our study has some limitations. Casual relationships could not be determined due to the cross-sectional design. The sample size was small, particularly that of the quetiapine group. We could not investigate the serum and brain concentrations of the antipsychotics. Although all participants received antipsychotic monotherapy, we did not eliminate the effects of other classes of medications that might influence ANS activity. In addition, we did not investigate QTc interval prolongation, and future studies should clarify the association between ANS dysfunction and QTc interval prolongation related to ABCB1 gene polymorphisms. Because it remains unclear whether ANS activity induces cardiovascular events, we need to follow and monitor the course of ABCB1 rs1045642 T allele carriers–rs2235048 C allele carriers who are under treatment with aripiprazole.