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.
Highlights
Antipsychotic drugs are an important treatment option for psychotic disorders including schizophrenia, bipolar disorder, and other psychoses (Taylor et al, 2021)
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 crosssectional 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 ultra-rapid metabolizers (UMs)
Summary
Antipsychotic drugs are an important treatment option for psychotic disorders including schizophrenia, bipolar disorder, and other psychoses (Taylor et al, 2021). Antipsychotics have been shown to improve psychotic symptoms with fewer relapses in the first year (Leucht et al, 2012) and reduce excess mortality in people living with schizophrenia (Taipale et al, 2018, 2020) Their adverse effects, including extrapyramidal side effects in typical antipsychotics and metabolic side effects in atypical antipsychotics, can have an impact on physical health and quality of life and contribute to drug discontinuation (Lieberman et al, 2005; Leucht et al, 2013). Antipsychotic-induced weight gain is a frequently reported adverse drug reaction, to second-generation antipsychotics (Miyamoto et al, 2012), leading to increased risk for cardiovascular diseases, diabetes and some types of cancer (Newcomer, 2005; Osborn et al, 2013) These are some of the key reasons for the 10–20-year average reduction in life expectancy observed in people with schizophrenia (Chesney et al, 2014; Galderisi et al, 2021). We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsychotic treatment
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