Relationship of CYP3A4*1B Single Nucleotide Polymorphism to the Efficiency and Safety Profiles of Haloperidol in Patients Enduring Acute Alcoholic Hallucinosis

Abstract

To date, haloperidol has been widely used to treat patients with acute alcoholic hallucinosis. There is strong evidence that haloperidol therapy is commonly associated with adverse drug reactions (ADRs). The 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) is known to affect the metabolism rates of haloperidol; hence it correlates with both therapy efficacy and safety parameters.

Objective

The study objective was to investigate the effect of 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) on the efficacy and safety profiles of haloperidol in patients with acute alcoholic hallucinosis.

Methods

This study enrolled 100 male patients suffering from acute alcoholic hallucinosis (mean age 41.4 ± 14.4 years). The efficacy profile of haloperidol was assessed using the PANSS (Positive and Negative Syndrome Scale) validated psychometric scale. The safety profile of therapy was assessed with the UKU Side-Effect Rating Scale and the SAS (Simpson-Angus Scale for Extrapyramidal Symptoms) scale. Genotyping was performed using the real-time polymerase chain reaction (Real-time PCR).

Results

There were no statistically significant results for the efficacy rates (dynamics of the PANSS score: AA genotype −14.00 [−16.00; −12.00], AG genotype −13.00 [−14.00; −10.50], p = 0.306). Similarly, there was no statistically significant difference in the safety profiles (dynamics of the UKU score: AA genotype − 9.00 [7.00; 13.00], AG genotype − 8.50 [7.25; 10.50], p = 0.620; dynamics of the SAS score: AA genotype −12.00 [10.00; 16.75], AG genotype − 10.00 [10.00; 12.25], p = 0.321).

Conclusion

The study demonstrated that the 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) in patients with acute alcoholic hallucinosis does not affect the efficacy and safety rates of haloperidol therapy.

Introduction

Haloperidol is a typical antipsychotic drug that exerts its therapeutic effect by blocking postsynaptic dopamine receptors in the mesolimbic system.¹ Haloperidol undergoes biotransformation in the liver with the participation of cytochrome P450 (CYP450) enzymes.²

CYP2D6 and CYP3A4 are the major isoenzymes involved in haloperidol metabolism.³ CYP3A4 is the most abundant CYP enzyme in the human liver accounting for 28% of total hepatic CYP proteins.⁴ The CYP3A4 gene is localized on chromosome 7, at locus 7q22.1.⁵ CYP3A4 catalyzes the conversion of haloperidol to 1,2,3,6-tetrahydropyridine (HHP), which is further metabolized to haloperidol pyridinium with the participation of CYP3A4 and CYP2D6.⁶

Earlier studies that enrolled schizophrenia patients revealed a correlation between the CYP3A4 activity and the biotransformation rate of haloperidol.^1,7,8 In one study, a correlation between CYP3A4 activity and the efficacy and safety rates of haloperidol in patients with alcohol use disorders during the period of craving exacerbation was demonstrated.⁹

Thus, the aim of this study was to investigate the effect of the 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) on the efficacy and safety rates of haloperidol in patients with acute alcoholic hallucinosis.

Material and Methods

The study enrolled 100 male patients (average age—41.4 ± 14.4 years) diagnosed with acute alcoholic hallucinosis who underwent inpatient treatment at Moscow Research and practical center on Addictions. Haloperidol in injections at a dose of 5–10 mg/day was administered to this group of patients for the treatment of acute hallucinatory symptoms. Haloperidol therapy was initiated from the moment of the patient’s admission to the emergency department and lasted for 5 days. Along with haloperidol, all patients received minimal standard therapy for 5 days, which included infusions, ion-containing solutions, and vitamins. The prescription of drugs was carried out in accordance with the national clinical guidelines for the therapy of alcohol-induced psychotic disorder.

Each patient signed an informed consent for voluntary participation in the study (Protocol No. 14 of October 27, 2020), which was approved by the local ethical committee of the Russian Medical Academy of Continuing Professional Education of the Ministry of Health of Russia.

The inclusion criteria were the signed informed consent to participate in the study; the diagnosis of alcohol-induced psychotic disorder with hallucinations (F10.52, according to ICD-10); 5 days of haloperidol treatment. The exclusion criteria were creatinine clearance values < 50 mL/min, creatinine plasma concentration > 1.5 mg/dL (133 mmol/L), body weight less than 60 kg or greater than 100 kg, age ⩾ 75 years, presence of any other psychotropic medications in the treatment regimen other than haloperidol, presence of chronic psychotic disorders, and presence of any contraindications for haloperidol use.

The collection of biomaterial (blood and urine samples) was performed on days 1 and 6 of the inpatient treatment after haloperidol administration. For genotyping, venous blood samples were collected into VACUETTE® (Greiner Bio-One, Austria) vacuum tubes on day 6 of haloperidol therapy. The single nucleotide polymorphism (SNP) rs2740574 (CYP3A4*1B) was analyzed by real-time PCR.

The efficacy of haloperidol therapy was assessed using the PANSS positive subscale.¹⁰ The safety profile of haloperidol therapy was assessed using the UKU Side Effect Rating Scale.¹¹ and the Simpson-Angus Extrapyramidal Side Effects Scale (SAS).¹² Scale scoring and biomaterial collection were performed on days 1 and 6 of haloperidol treatment.

Statistical analysis was performed in StatsoftStatistica v. 10.0 (Dell Statistica, Tulsa, OK, USA). Statistical analysis of the study results was performed using the methods of nonparametric statistics due to the absence of normal distribution of data, which was checked using the Shapiro-Wilk W-test. The Mann-Whitney U-test was used to compare two samples of continuous independent data, and the Wilcoxon test was used to compare two samples of dependent data. In the case of multiple comparisons, we calculated the adjusted p-values using the Benjamini-Hochberg procedure. Research data are presented in the form of the median and interquartile range (Me [Q1; Q3]).

Results

CYP3A4 genotyping by the polymorphic marker 392A > G (rs2740574) performed in 100 male patients with acute alcoholic hallucinosis revealed the following data:

• 1) The number of patients who were homozygous carriers (genotype AA) of the 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) was 94 (94%).

• 2) The number of patients who were heterozygous carriers (genotype AG) of the 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) was 6 (6%).

Thus, we further compared the efficacy and safety profiles between the carriers of AA and AG genotypes of the 392A > G polymorphism of the CYP3A4*1B gene (rs2740574).

The results of data analysis performed for psychometric assessments (PANSS) and side-effect rating scales (UKU and SAS) on days 1 and 6 in patients who received haloperidol are presented in Table 1.

Table 1. Data from the Psychometric Assessments and Side-Effect Rating Scales in Patients who Received Haloperidol, on Days 1 and 6 of the Study.

Scale		AA (N = 94)		AG (N = 6)		P*
Day 1
PANSS score		15.00 [13.00; 18.00]		14.00 [12.25; 15.00]		0.191
SAS score		0 [0; 0]		0 [0; 0]		> 0.999
UKU score		0 [0; 0]		0 [0; 0]		> 0.999
Day 6
PANSS score		1.00 [1.00; 2.00]		1.00 [1.00; 1.75]		0.327
SAS score		12.00 [10.00; 16.75]		10.00 [10.00; 12.25]		0.321
UKU score		9.00 [7.00; 13.00]		8.50 [7.25; 10.50]		0.620

p* – p-value obtained in Benjamini-Hochberg multiple testing correction (based on the results of Mann-Whitney U test).

The dynamics of changes in PANSS positive subscale scores in patients with the AA and AG genotypes is shown in Figure 1. We revealed no statistically significant differences in the efficacy rates of haloperidol therapy in patients with the AA and AG genotypes by the 392A > G polymorphism of the CYP3A4*1B gene: AA −14.00 [−16.00; −12.00], AG −13.00 [−14.00; −10.50], p = 0.306.

Figure 1.

The Dynamics of Changes in PANSS Positive Subscale Scores in Patients with the AA and AG Genotypes from Day 1 to Day 6

Figures 2–3 show the dynamics of changes in SAS and UKU scores in patients carrying different genotypes. We did not reveal any statistically significant differences in the safety profiles of haloperidol therapy in patients with the AA and AG genotypes by the 392A > G polymorphism of the CYP3A4*1B gene:

Figure 2.

The Dynamics of Changes in SAS Scores in Patients with the AA and AG Genotypes from Day 1 to Day 6

Figure 3.

The Dynamics of Changes in UKU Scores in Patients with the AA and AG Genotypes from Day 1 to Day 6

• SAS scale scores: AA 12.00 [10.00; 16.75], AG 10.00 [10.00; 12.25], p = 0.321;

• UKU scale scores: AA 9.00 [7.00; 13.00], AG 8.50 [7.25; 10.50], p = 0.620.

Discussion

The study revealed no statistically significant differences in the efficacy and safety rates of haloperidol therapy in patients with acute alcoholic hallucinosis carrying the AA and AG genotypes by the 392A > G polymorphism of the CYP3A4*1B gene (rs2740574).

One study showed that high CYP3A4 activity is associated with low efficacy and an increased safety profile of haloperidol therapy.⁹

Thus, further studies are needed to investigate the relationship of CYP3A4 activity with the activity and safety profiles of haloperidol in patients with acute alcoholic hallucinosis. We assume that studies in this direction may yield interesting results.

Conclusions

In our study, no effect of the 392A > G polymorphism of the CYP3A4*1B gene (rs2740574) on both efficacy and safety rates of haloperidol therapy in patients with acute alcoholic hallucinosis.