TY - JOUR
T1 - Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain
T2 - A Systematic Review and Meta-analysis
AU - Zhang, Jian Ping
AU - Lencz, Todd
AU - Zhang, Ryan X.
AU - Nitta, Masahiro
AU - Maayan, Lawrence
AU - John, Majnu
AU - Robinson, Delbert G.
AU - Fleischhacker, W. Wolfgang
AU - Kahn, Rene S.
AU - Ophoff, Roel A.
AU - Kane, John M.
AU - Malhotra, Anil K.
AU - Correll, Christoph U.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (≥7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples ( n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2–20, n = 81–2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ ADRA2A ], Adrenoceptor Beta 3 [ ADRB3 ], Brain-Derived Neurotrophic Factor [ BDNF ], Dopamine Receptor D2 [ DRD2 ], Guanine Nucleotide Binding Protein [ GNB3 ], 5-Hydroxytryptamine (Serotonin) Receptor 2C [ HTR2C ], Insulin-induced gene 2 [ INSIG2 ], Melanocortin-4 Receptor [ MC4R ], and Synaptosomal-associated protein, 25kDa [ SNAP25 ]) were significantly associated with antipsychotic-related weight gain ( P -values < .05–.001). SNPs in ADRA2A , DRD2 , HTR2C , and MC4R had the largest effect sizes (Hedges’ g ’s = 0.30–0.80, ORs = 1.47–1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1–2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.
AB - Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (≥7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples ( n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2–20, n = 81–2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ ADRA2A ], Adrenoceptor Beta 3 [ ADRB3 ], Brain-Derived Neurotrophic Factor [ BDNF ], Dopamine Receptor D2 [ DRD2 ], Guanine Nucleotide Binding Protein [ GNB3 ], 5-Hydroxytryptamine (Serotonin) Receptor 2C [ HTR2C ], Insulin-induced gene 2 [ INSIG2 ], Melanocortin-4 Receptor [ MC4R ], and Synaptosomal-associated protein, 25kDa [ SNAP25 ]) were significantly associated with antipsychotic-related weight gain ( P -values < .05–.001). SNPs in ADRA2A , DRD2 , HTR2C , and MC4R had the largest effect sizes (Hedges’ g ’s = 0.30–0.80, ORs = 1.47–1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1–2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.
KW - antipsychotics
KW - BMI
KW - meta-analysis
KW - pharmacogenetics
KW - SNP
KW - weight gain
UR - http://www.scopus.com/inward/record.url?scp=84994424517&partnerID=8YFLogxK
U2 - 10.1093/schbul/sbw058
DO - 10.1093/schbul/sbw058
M3 - Article
C2 - 27217270
AN - SCOPUS:84994424517
SN - 0586-7614
VL - 42
SP - 1418
EP - 1437
JO - Schizophrenia Bulletin
JF - Schizophrenia Bulletin
IS - 6
ER -