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

Abstract

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.

Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

“…Studies relying on large sample size underlined increased weight gain [51], prolactin levels [77], risk of EPS [71], and impaired treatment response [52] in patients deprived from at least one functional allele for CYP2D6, resulting in increased drug exposure. While the findings regarding movement abnormalities and lack of therapeutic effect concur with existing evidence [84,85], AIWG [86] and hyperprolactinemia [87] were not consistently linked with CYP2D6 impairments. However, olanzapine is mostly metabolized by CYP1A2 (and to a lesser extent by CYP2D6 and CYP3A4) [88,89], clozapine is mainly metabolized by CYP3A4 and CYP1A2 (with CYP2D6 playing a minor role) [16,90], and loxapine is primarily metabolized by CYP1A2 (then by CYP3A4 and CYP2D6) [19].…”

The Progress and Pitfalls of Pharmacogenetics-Based Precision Medicine in Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis

“…For treatment response, three meta-analysis studies reported in a mixed population, Caucasians and Asians separately [ 40 , 41 , 42 ]; one meta-analysis study reported in a mixed population and Caucasians [ 31 ]; six meta-analysis studies reported in mixed populations only [ 34 , 43 , 44 , 45 , 46 , 47 ]; one meta-analysis study reported in Asians [ 48 ]. For antipsychotic-induced weight/BMI gain, two meta-analysis studies reported in a mixed population, Caucasians and Asians separately [ 49 , 50 ]; two meta-analysis studies reported in a mixed population and Asians separately [ 51 , 52 ]; three meta-analysis studies reported in mixed population only [ 35 , 53 , 54 ]; one meta-analysis study did not state the ethnicity of the population [ 32 ]. One meta-analysis study reported antipsychotic-induced metabolic syndrome in a mixed population, Caucasians and Asians separately [ 49 ].…”

“…For CYP2D6 and CYP2C19 , the number inside represents the number of phenotypes of this enzyme analyzed. References: Study 1, Hwang, 2010 [ 34 ]; 2, Zhang, 2010 [ 46 ]; 3 de Matos, 2015 [ 47 ]; 4, Huang, 2016 [ 43 ]; 5, Gressier, 2016 [ 31 ]; 6, Cargnin, 2016 [ 40 ]; 7, Takekita, 2016 [ 44 ]; 8, Ma, 2019 [ 48 ]; 9, Yoshikawa, 2020 [ 45 ]; 10, Yan, 2022 [ 41 ]; 11, Liu, 2022 [ 42 ]; 12, Sicard, 2010 [ 35 ]; 13, Shen, 2014 [ 51 ]; 14, Ma, 2014 [ 49 ]; 15, Zhang, 2016 [ 32 ]; 16, Suetani, 2017 [ 53 ]; 17, Yoshida, 2020 [ 52 ]; 18, Chen, 2020 [ 50 ]; 19, Wannasuphoprasit, 2021 [ 54 ]; 20, Miura, 2016 [ 55 ]; 21, Calafato, 2020 [ 56 ]; 22, Zai, 2010a [ 59 ]; 23, Zai, 2010b [ 60 ]; 24, Miura, 2014 [ 57 ]; 25, Lv, 2016 [ 58 ]; 26, Islam, 2022 [ 61 ]; 27, Takuathung, 2019 [ 64 ]; 28, Zhang, 2019 [ 63 ]; 29, Milosavljevic, 2021 [ 62 ]. Abbreviation: Chr, chromosome; AP, antipsychotics; AIWG, antipsychotic-induced weight gain; MetS, metabolic syndrome; PRL, prolactin; TD, tardive dyskinesia; CIA, clozapine-induced agranulocytosis.…”

Is the CYP2D6 Genotype Associated with Antipsychotic-Induced Weight Gain?

“…A recently published systematic review examining whether patients with CYP2D6 PM status on long-term antipsychotic drug treatment have an average higher body weight than patients with normal CYP2D6 metabolic capacity shows conflicting results [ 27 ]. This might be a consequence of the small number of PMs (N = 93, 4.5% of all patients), notwithstanding the large size and comprehensive nature of the review.…”