Pharmacogenetic Testing of
            <i>Cyp2D6</i>
            in Patients with Aripiprazole-Related Extrapyramidal Symptoms: A Case–Control Study

Surja, Anton A. Subuh; Reynolds, Kristen K.; Linder, Mark W.; El‐Mallakh, Rif S.

doi:10.2217/17410541.5.4.361

Cited by 10 publications

(3 citation statements)

References 27 publications

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“…Template taken from Page et al, 2021). The reasons for excluding the records included insufficient information on weight or BMI (Inada et al, 2003;Plesnicar et al, 2006;Subuh Surja et al, 2008) and ineligible study population such as healthy volunteers receiving a single drug dose (Sun et al, 2019) or schizophrenic patients with acute episodes who were on antipsychotic medication for less than one month before weight measurement (Vandenberghe et al, 2015). Some had genotyped some CYP2D6 single nucleotide polymorphisms (SNPs) but, unfortunately, these selected SNPs did not allow us to call for CYP2D6 alleles and classify participants into CYP2D6 metabolic groups (Lee et al, 2012).…”

Section: Literature Searchmentioning

confidence: 99%

CYP2D6 Genetic Variation and Antipsychotic-Induced Weight Gain: A Systematic Review and Meta-Analysis

et al. 2022

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BackgroundAntipsychotic-induced weight gain is a contributing factor in the reduced life expectancy reported amongst people with psychotic disorders. CYP2D6 is a liver enzyme involved in the metabolism of many commonly used antipsychotic medications. We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsychotic treatment.MethodsWe conducted a systematic review and a random effects meta-analysis of publications in Pubmed, Embase, PsychInfo, and CENTRAAL that had BMI and/or weight measurements of patients on long-term antipsychotics by their CYP2D6-defined metabolic groups (poor, intermediate, normal/extensive, and ultra-rapid metabolizers, UMs).ResultsTwelve studies were included in the systematic review. All cohort studies suggested that the presence of reduced-function or non-functional alleles for CYP2D6 was associated with greater antipsychotic-induced weight gain, whereas most cross-sectional studies did not find any significant associations. Seventeen studies were included in the meta-analysis with clinical data of 2,041 patients, including 93 poor metabolizers (PMs), 633 intermediate metabolizers (IMs), 1,272 normal metabolizers (NMs), and 30 UMs. Overall, we did not find associations in any of the comparisons made. The estimated pooled standardized differences for the following comparisons were (i) PM versus NM; weight = –0.07 (95%CI: –0.49 to 0.35, p = 0.74), BMI = 0.40 (95%CI: –0.19 to 0.99, p = 0.19). (ii) IM versus NM; weight = 0.09 (95% CI: –0.04 to 0.22, p = 0.16) and BMI = 0.09 (95% CI: –0.24 to 0.41, p = 0.60). (iii) UM versus EM; weight = 0.01 (95% CI: –0.37 to 0.40, p = 0.94) and BMI = –0.08 (95%CI: –0.57 to 0.42, p = 0.77).ConclusionOur systematic review of cohort studies suggested that CYP2D6 poor metabolizers have higher BMI than normal metabolizers, but the data of cross-sectional studies and the meta-analysis did not show this association. Although our review and meta-analysis constitutes one of the largest studies with comprehensively genotyped samples, the literature is still limited by small numbers of participants with genetic variants resulting in poor or UMs status. We need further studies with larger numbers of extreme metabolizers to establish its clinical utility in antipsychotic treatment. CYP2D6 is a key gene for personalized prescribing in mental health.

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Section: Literature Searchmentioning

confidence: 99%

CYP2D6 Genetic Variation and Antipsychotic-Induced Weight Gain: A Systematic Review and Meta-Analysis

et al. 2022

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“…We also assessed genetic variations in the CYP2D6, CYP3A4, and CYP3A5 genes that encode enzymes involved in the metabolism of ARI. It is postulated that nonfunctional alleles are associated with potential adverse effects [18] and extrapyramidal reactions, nausea, or vomiting are more frequently observed in IM and PM patients treated with ARI [5,19]. Surprisingly, in both our studied groups, the frequency of functional alleles (*1 plus *2) was similar and accounted for more than 60%, while the frequency of CYP2D6-defective alleles was more than two times higher in the ARI compared to the ARI-ADE group (29% vs. 13%, respectively).…”

Section: Resultsmentioning

confidence: 99%

A Preliminary Study of Genetic Polymorphisms Potentially Related to the Adverse Effects of Aripiprazole

Guzek¹,

Stelmach²,

Rożnowska³

et al. 2023

Arch Pharm Pract

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Aripiprazole is an atypical antipsychotic drug that is mainly transformed by the hepatic enzymes CYP2D6 and CYP3A4. Dose adjustment is recommended for CYP2D6-poor metabolizers. Aripiprazole is generally well tolerated by most adult patients, but occasionally adverse effects can occur in some individuals resulting in the drug being withdrawn. Recent studies suggested that other genes involved in drug metabolism, transport, and elimination can be related to the efficacy and safety of drug therapy. This study aimed to evaluate the differences in genetic variants between patients who tolerated the therapy well and those who experienced adverse effects leading to withdrawing the drug. The genetic profiling of 20 genes was performed using MassARRAY technology. No differences between both groups in the ABCB1, COMT, CYP2D6, CYP3A4, and CYP3A5 polymorphisms were found. Unexpectedly, we observed a higher frequency of homozygous CYP1A21F/*1F (78% vs. 45%) and CYP2B6*1/*1 (80% vs. 45%) as well as the frequency of CYP1A2 ultra-rapid metabolizes in the group with adverse effects. Moreover, a combined homozygous status (CYP1A2*1F/*1F/ CYP2B6*1/*1) has been exclusively identified in patients with adverse effects. To date, there are no findings about the possible role of CYP1A2 and CYP2B6 enzymes in aripiprazole metabolism. Thus, our preliminary data suggest that the CYP1A2*F and/or CYP2B6*1 alleles may contribute to the adverse effects of aripiprazole. Therefore, further studies on larger sample sizes are needed to confirm our findings.

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“…Hendset et al [ 98 ] observed that CYP2D6 -defective alleles patients were associated with more potent adverse effects. In addition, a case–control study with eight patients suggested that IM and PM CYP2D6 status are more frequently associated with extrapyramidal reactions [ 108 ]. Another study found that PM and IM were associated with higher incidence of nausea/vomiting due to higher plasma concentrations of aripiprazole in these subjects [ 101 ].…”

Section: Long-acting Aripiprazolementioning

confidence: 99%

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics

et al. 2021

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Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of life.

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Pharmacogenetic Testing of Cyp2D6 in Patients with Aripiprazole-Related Extrapyramidal Symptoms: A Case–Control Study

Cited by 10 publications

References 27 publications

CYP2D6 Genetic Variation and Antipsychotic-Induced Weight Gain: A Systematic Review and Meta-Analysis

CYP2D6 Genetic Variation and Antipsychotic-Induced Weight Gain: A Systematic Review and Meta-Analysis

A Preliminary Study of Genetic Polymorphisms Potentially Related to the Adverse Effects of Aripiprazole

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics

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