Table 3.
Association between genetic polymorphisms and antipsychotic adverse effects
| Study [Ref.] (year) | Gene(s) | Polymorphism(s) | Study design | Subjects, n | Ethnicity or nationality | Treatment duration | Treatment medication | Outcome | Main findings |
|---|---|---|---|---|---|---|---|---|---|
| Antipsychotic-induced weight gain and metabolic syndrome | |||||||||
| Mittal et al. [109] (2017) | mtDNA and 670 nuclear-encoded mitochondrial genes | mtDNA SNPs and nuclear-encoded mitochondrial genes | mtDNA sequencing and gene set analysis | 74 SCZ and 168 SCZ | Caucasian | 143±11.98 days | Risperidone, quetiapine, olanzapine | AIWG | Thirty nuclear-encoded mitochondrial genes were nominally significantly associated with AIWG; of these, the associations of three genes (CLPS, PAUL, and ACAD10) with AIWG were replicated |
| Piatkov et al. [13] (2017) |
ABCB1 ABCC1 |
rs1045642 rs212090 |
Prospective | 137 SCZ | Caucasian, Asian, Pacific Islander, others | 12 months | Clozapine | AIWG | No significant association; ABCB1 rs1045642 and ABCC1 rs212090 were associated with AIWG in males after 3 months and 12 months of clozapine treatment, respectively |
| Li et al. [160] (2017) |
23 genes | 43 SNPs | Prospective | 339 SCZ and SAD (86 first-episode patients) | Chinese | 12 weeks | Olanzapine, risperidone, clozapine, quetiapine, aripiprazole, ziprasidone | AIWG | TOX rs11777927 and ADIPOQ rs182052 were associated with BMI; BDNF rs6265, BDAF rs11030104, and ADIPOQ rs822396 were significantly associated with a change in waist-to-hip ratio |
| Klemettilä et al. [161] (2017) | 21 genes (NPY gene, NPY receptor genes, and genes encoding arcuate nucleus NPY neuron receptors) | 215 SNPs | Cross-sectional | 180 SCZ (F2 group accordingto ICD-10) | Finnish | ≥3 months (some patients with no data) | Clozapine | AIWG | 21 genes (NPY gene, NPY receptor genes, and genes encoding arcuate nucleus NPY neuron receptors) |
| Daray et al. [89] (2017) | HTR2C | rs3813939 (-759C>T) | Prospective | 48 SCZ or related illness (female) | Caucasian | 6 weeks | Risperidone, olanzapine, clozapine, quetiapine | AIWG | T allele at position −759 (TT or CT) was associated with less weight gain |
| Zhang et al. [162] (2017) | C3 | 3 tag SNPs and rs7951, rs2230199, rs2250656, rs1l672613 |
Cross-sectional | 576 SCZ | Han Chinese | 2 years | Clozapine monotherapy or combination therapy | MetS | Significant association between C3 rs2277984 and MetS |
| Koskinen et al. [105] (2016) | INSIG2 | rs1559509, rs2161829, rs2161830, rs9308762, rs12151787, rs1049626, rs17047733 |
Cross-sectional | 190 SCZ (F2 group accordingto ICD-10) | Finnish | ≥3 months | Clozapine | AIWG | Significant association between INSIG2 SNPs (rs12151787, rs1049626, and rs17047733) and weight gain |
| Brandl et al. [110] (2016) |
Exploratory | Exploratory | GWAS | CATIE sample: 189 SCZ; Toronto sample: 86 SCZ and SAD | CATIE sample: European or African American; Toronto sample: European | CATIE sample: up to 18 months; Toronto sample: up to 6 weeks (Sample A), 6 weeks (Sample B), or 14 weeks | CATIE sample: risperidone, quetiapine, olanzapine; Toronto sample: olanzapine, clozapine | AIWG | None of the SNPs were significantly associated with AIWG, although nominal associations were found for rs9346455 upstream of OGFRL1 and rs1059778 in IBA57 |
| Zai et al. [94] (2016) |
HTR3A HTR3B | 21 SNPs | Sample A: naturalistic; Sample B: prospective; Sample C: double-blind, randomized | 149 SCZ and SAD | European | Sample A: up to 6 weeks; Sample B: 6 weeks; Sample C: up to 14 weeks | Sample A: haloperidol olanzapine, risperidone, aripiprazole, quetiapine, amisulpride; Sample B: clozapine; Sample C: clozapine, olanzapine | AIWG | No significant association |
| Grädinaru et al. [90] (2016) |
HTR2C | rs3813929 (-759C/T) | Prospective | 81 SCZ and bipolar disorder | Romanian | Up to 18 months | Risperidone, aripiprazole, olanzapine | AIWG and hyperinsulinemia | No significant association between HTR2C rs3813929 and AIWG; however, a significant association between insulinemia and T-allele carriers was found |
| Tiwari et al. [163] (2016) | HRH1 HRH3 | 40 tag SNPs | Retrospective | 193 SCZ and SAD | European American, African American, and others | Up to 14 weeks | Clozapine, haloperidol, olanzapine, risperidone, and others | AIWG | No significant associations between the SNPs in HRH1 and HRH3 and AIWG |
| Fang et al. [100] (2016) |
BDNF | rs6265 (Val66Met) |
Cross-sectional | 308 chronic schizophrenia, 304 healthy | Han Chinese | ≥12 months | Clozapine, risperidone, other typical antipsychotics | AIWG | Significant association between BDNF rs6265 and AIWG |
| Rico-Gomis et al. [93] (2016) | HTR2C | rs1414334 | Cross-sectional, observational | 166 SCZ, SAD, schizophreniform disorder, other psychotic disorders, bipolar disorder | Spanish | ≥3 months | Various antipsychotics | MetS | No significant association between the C allele of the rs1414334 polymorphism in the HTR2C gene and MetS |
| Yang et al. [104] (2016) | SCAP SREBF1 | 5 SNPs 11SNPs |
Cross-sectional | 722 SCZ | Han Chinese | ≥1 year | Clozapine, olanzapine, risperidone | MetS | Significant association between the rs11654081 T allele of the SREBF1 gene and an increased risk for MetS |
| Ryu et al. [164] (2016) |
60 candidate genes | 233 SNPs | Prospective | Sample A: 84 SCZ; Sample B: 46 SCZ | Korean | Sample A: up to 8 weeks; Sample B: ≥4 weeks (up to 48 weeks) | Sample A: risperidone, olanzapine, amisulpride, quetiapine, and others; Sample B: risperidone, olanzapine | AIWG and appetite change | No significant association between these SNPs and BMI or appetite change; GHRL rs696217 suggested evidence of an association with weight gain and appetite change |
| Yu et al. [111] (2016) |
Exploratory | Exploratory | GWAS | Discovery sample: 534 SCZ; Replication sample: 547 SCZ | Han Chinese | Discovery sample: 8 weeks; Replication sample: 8 weeks | Various antipsychotics | AIWG | Significant association between rs10977144 and rs10977154 in PTPRD and rs12386481 in GFPT2 and AIWG |
| Tiwari et al. [165] (2016) | HCRTR1 HCRTR2 | Tag SNPs (exploratory) | Sample A: naturalistic; Sample B: prospective; Sample C: double-blind, randomized | Discovery sample: 218 SCZ and SAD (Sample A: n = 88; Sample B: n = 74; Sample C: n = 56); Replication sample: 122 SCZ | Discovery sample: European American, African American, and others; Replication sample: European | Discovery sample: up to 6 weeks (Sample A), 6 weeks (Sample B), or 14 weeks (Sample C); Replication sample: up to 190 days | Discovery sample: clozapine, haloperidol, olanzapine, risperidone, and others (Sample A); clozapine (Sample B); clozapine, haloperidol, olanzapine, risperidone (Sample C); Replication sample: olanzapine, risperidone | AIWG | Genetic variation in HCRTR2 was associated with weight gain; none of the SNPs in HCRTR1 were associated with weight gain |
| Wang et al. [166] (2015) | 85 candidate genes | 768 SNPs | Prospective | 216 SCZ | Han Chinese | 4 weeks | Risperidone | AIWG | Significant association between four SNPs on SLC6A4 (rs3813034, rs1042173, rs4325622, and rs9303628) and AIWG |
| Chen et al. [167] (2015) |
TMEM18 SH2B1 GNPDA2 |
rs6548238 rs7498665 rs10938397 |
Double-blind, randomized | 55 SCZ, SAD (metformin treatment [n = 28] or placebo [n = 27]) | Taiwanese | 24 weeks | Clozapine | AIWG | Significant association in the TMEM18 and GNPDA2 minor-allele carrier groups; body weight reduction in the metformin group |
| Dong et al. [168] (2015) | A2BP1 | rs10500331, rs4786847, rs8048076, rs1478697 |
Prospective | Discovery sample: 328 SCZ; Replication sample: 208 FES and drug-naïve SCZ | Han Chinese | Discovery sample: 8 weeks; Replication sample: 4 weeks | Olanzapine | AIWG | Significant association between A2BP1 rs1478697 and AIWG |
| Bonaccorso et al. [99] (2015) | BDNF | rs6265 (Val66Met) |
Randomized trial, prospective | 76 SCZ and SAD; 90 bipolar disorder | Caucasian, African American, others | 12 months | Olanzapine, risperidone | AIWG, Metabolic parameters | Significant association between BDNF Met66 allele carriers and AIWG in all patients |
| Pouget et al. [66] (2015) |
TSPO VDAC1 ANT1 |
rs739092, rs5759197, rs138911, rs1l3515, rs6971, rs6973, rs80411, rs138926 rs13169435, rs4279383, rs2288834 rs10024068, rs7660552 |
Discovery: Sample A, naturalistic; Sample B, prospective; Sample C, double-blind, randomized; RUPP: prospective; Munich: naturalistic | Discovery: 109 SCZ and others; RUPP: 119 autism spectrum disorder; Munich: not reported | Discovery: European; RUPP: European and Hispanic; Munich: European | Discovery: up to 14 weeks; RUPP: 8 weeks; Munich: ≥4 weeks | Discovery: clozapine, olanzapine, quetiapine, risperidone, and others; RUPP: risperidone; Munich: SGAs | AIWG | TSPO rs6971 was nominally associated with AIWG in the discovery for the clozapine/olanzapine subsample and the RUPP sample, and it interacted with ANT1 rs10024068 in the discovery and RUPP samples |
| Fonseka et al. [169] (2015) |
IL-1β IL-2 IL-6 BDNF |
rs4849127, rs13032029, rs16944, rs3136558, rs1143634, rs1143643 rs2069762, rs2069778, rs2069779, rs2069772, rs2069776 rs2069827, rs1800795, rs2069837, rs2066992, rs2069840, rs2069861, rs10242595 rs6265 |
Sample A: naturalistic; Sample B: prospective; Sample C; double-blind, randomized | 188 SCZ, SAD | European, African, and others | Up to 14 weeks | Clozapine, haloperidol, olanzapine, risperidone, others | AIWG | SNPs across IL-1β and BDNF rs6265 may influence AIWG |
| Zai et al. [170] (2015) |
GABRA2 | rs16859227, rs279858, rs1442060, rs3849591, rs1442062, rs16859354, rs1l503014, rs6856130, rs1372472 |
Sample A; naturalistic; Sample B; prospective; Sample C; double-blind | 160 SCZ, SAD | European | Up to 14 weeks | Various antipsychotics (mainly clozapine and olanzapine) | AIWG | Significant association between GABRA2 rs279858 and AIWG |
| Ono et al. [171] (2015) |
GIPR | rs10423928 | Prospective | 32 SCZ | Japanese | 4 weeks | Olanzapine | AIWG | Significant association between GIPR rs10423928 and AIWG |
| Klemettilä et al. [92] (2015) |
LEP ADIPOQ HTR2C |
rs7799039 (-2548A/G) rs1501299 rs1414334 |
Retrospective | 190 SCZ (clinical diagnosis of F2 group according to ICD-10), 395 healthy | Finnish | ≥3 months | Clozapine (monotherapy or combination therapy with other antipsychotics) | AIWG | No significant associations between LEP rs7799039, ADIPOQ rs1501299, and HTR2C rs1414334 and AIWG |
| Yang et al. [103] (2015) | SREBF2 | rs4822063, rs17002737, rs2267439, rs5996080, rs5996078, rs1569451, rs2228314, rs1052717, rs2267443, rs17379759 |
Case-control | 621 SCZ | Han Chinese | ≥1 year | Clozapine | MetS | Significant associations between SREBF2 A allele of rs2267443 and rs1052717 and MetS |
| Czerwensky et al. [10] (2015) | CYP1A2 | CYP1A2*1D, *1F | Naturalistic and retrospective | 209 SCZ, schizotypal disorder, paranoid disorder, mood disorders, affective disorder, and other disorders treated with SGAs | Caucasian and 1 Asian | ≥4 weeks | Olanzapine, clozapine (monotherapy or in combination with other antipsychotics) | AIWG | No significant association |
|
Antipsychotic-induced movement disorders Kang et al. [113] (2018) |
MAP2K5 | rs1026732, rs11635424, rs12593813, rs4489954, rs3784709 |
Case-control | 190 SCZ | Korean | Not reported | Various antipsychotics | RLS | No significant association; however, the G-G-G-G-T (rs1026732-rs11635424-rs12593813-rs4489954-rs3784709) haplotype was associated with RLS |
| Zai et al. [114] (2017) |
NRG1 ERBB4 | rs35753505, rs6994992 rs839523 |
Cross-sectional | 153 SCZ and SAD | European | ≥1 year | Typical or atypical antipsychotics | TD | Significant association between ERBB4 rs839523 and TD |
| Lanning et al. [115] (2017) | NRXN1 | rs17041112, rs10490162, rs1400882, rs12467557, rs1045881 |
Cross-sectional | 178 SCZ and SAD | European | ≥12 months | Typical antipsychotics | TD | No significant association |
| Hui et al. [124] (2017) |
DBH | DBH5′-Ins/Del polymorphism | Case-control | 742 SCZ | Han Chinese | ≥12 months | Clozapine, risperidone, perphenazine, sulpiride, chlorpromazine, haloperidol | TD | No significant association |
| Sychev et al. [116] (2016) | CYP2D6 | 1846G>A (CYP2D6*4) |
Cross-sectional | 79 SCZ (F2 group according to ICD-10) | Russian and Tatar | Not reported | Haloperidol, risperidone, paliperidone, quetiapine, others | EPS | Significant association of CYP2D6 heterozygous 1846GA genotype and 1846A allele frequency with EPS in patients treated with haloperidol |
| Mas et al. [117] (2016) |
31 candidate genes (involved in dopamine, serotonin, and glutamate pathways) | 202 SNPs | Naturalistic | 113 FEP | Caucasian and others | Up to 12 months | Amisulpride, paliperidone, risperidone, ziprasidone | EPS | Significant associations between four SNPs (rs9567733 [HTR2A], rs363341 [SLC18A2], rs1334802 [GRIK3], and rs1124491 [DRD2]) and EPS |
| Ivanova et al. [118] (2016) |
GRIN2A GRIN2B DRD3 HTR2C DRD4 |
43 tag single nucleotide polymorphisms | Cross-sectional | Sample A: 431 SCZ; Sample B: 168 SCZ, psychosis, affective disorders, and others | Caucasian (Sample A: Siberian; Sample B: Dutch) | Not reported | Not reported | TD | Only GRIN2A rs1345423 exhibited a significant association with TD in both groups |
| Ivanova et al. [119] (2016) |
CYP1A2 CYP2D6 |
CYP1A2*1F CYP2D6*3, CYP2D6*4 |
Case-control | 353 SCZ | Caucasian | Not reported | Various antipsychotics | TD | Significant associations of polymorphic variant CYP1A2*1F(-163C>A) of CYP1A2, polymorphic variant CYP2D6*4 (1846G>A), and genotype A/A of CYP2D6 with TD |
| Kang et al. [120] (2015) |
MEIS1 | rs2300478, rs6710341 |
Cross-sectional | 190 SCZ | Korean | Not reported | Various antipsychotics | RLS | No significant association between MEIS1 (rs2300478 and rs6710341) and antipsychotic-induced RLS |
| Mas et al. [121] (2015) |
Exploratory | Exploratory | Protein-protein interaction network construction and functional annotation analysis | 12 antipsychotic-naïve patients with FEP | Caucasian | 9 days (± 1 day) or as soon as any EPS appeared and prior to starting treatment with anti-parkinsonian drugs | Risperidone, paliperidone | EPS | Suggested association between the NF-κB pathway (inflammatory response) and mTOR pathway (lipid biosynthesis, insulin signaling, and autophagy) and EPS |
| Ivanova et al. [122] (2015) | CYP1A2 | rs762551 (-163C<A) |
Case-control | 319 SCZ, schizotypal disorder; 117 healthy | Caucasian | Not reported | Various antipsychotics | TD | Significant association between the CYP1A2*1F (-163C>A) polymorphism and limb-truncal TD |
| Mas et al. [123] (2015) |
TSC1 TSC2 mTOR AKT1 FCHSD1 PARK2 DISCI RPTOR DDIT4 |
rs7874234 rs13335638 rs2024627 rs1l30214 rs456998 rs1801582 rs3737597 rs7211818 rs1053639 |
Case-control | Sample A: 114 patients treated with risperidone; Sample B: 102 patients treated with antipsychotics (except for risperidone or clozapine); Sample C: 27 antipsychotic- naïve patients with FEP treated with risperidone, paliperidone, or amisulpride | Spanish | Not reported | Sample A: risperidone; Sample B: antipsychotics other than risperidone or clozapine; Sample C: risperidone, paliperidone, amisulpride | EPS | Significant association of a four-way interaction, including AKT1 rs1l30214, FCHSD1 rs456998, RPTOR rs7211818, and DDIT4 rs1053639, with EPS |
| Antipsychotic-induced prolactin increase | |||||||||
| Ivanova et al. [139] (2017) | PRL | rs1341239 (-1149G/T) | Case-control | 443 SCZ and 126 healthy | Russian | Not reported | Various antipsychotics | Hyperprolactinemia | Significant association between the polymorphic variant rs1341239 and hyperprolactinemia |
| Ivanova et al. [140] (2017) |
HTR1A HTR1B HTR2A HTR2C HTR3A HTR3B HTR6 |
29 SNPs | Cross-sectional | 446 SCZ | Caucasian | Not reported | Various antipsychotics | Hyperprolactinemia | Significant association between hyperprolactinemia and the HTR2C X-chromosome polymorphisms rs569959 and rs17326429 |
| Chen et al. [44] (2016) | COMT | rs2075507, rs737865, rs933271, rs5993883, rs740603, rs4646312, rs4633, rs6267, rs4818, rs4680, rs165774, rs174697, rs165599, rs165728 |
Naturalistic | 185 SCZ | Han Chinese | 12 weeks | Amisulpride | Prolactin level | Significant association between COMT rs4680 and prolactin level |
| Clozapine-induced agranulocytosis/granulocytopenia | |||||||||
| Legge et al. [145] (2017) | Exploratory | Exploratory | Combination of GWAS, HLA allele imputation, exome array, and copy number variation | Discovery sample: 5,649 SCZ (clozapine-associated neutropenia: n = 66; control: n = 5,583); Replication sample: up to 163 cases and 7,970 controls | Discovery sample: European; Replication: detailed elsewhere [82] | Not reported | Clozapine | Clozapine-associated neutropenia | Significant association between rs149104283, located between SLCO1B3 and SLCO1B7, and clozapine-associated neutropenia; the association of HLA-DQB1 6672G>C (rs113332494) with clozapine-associated agranulocytosis was replicated |
| Saito et al. [144] (2016) |
Exploratory | Exploratory | GWAS | CIAG patients: n = 50; healthy controls: n = 2,905; clozapine-tolerant controls: n = 380 | Japanese | CIAG patients: up to 180 days; clozapine-tolerant controls: >180 days | Clozapine | CIAG | Significant association between HLA-B*59:01 and CIAG |
AIWG, antipsychotic-induced weight gain; CIAG, clozapine-induced agranulocytosis/clozapine-induced granulocytopenia; EPS, extrapyramidal symptom; FEP, first-episode psychosis; GWAS, genome-wide association study; HLA, human leukocyte antigen; ICD-10, International Statistical Classification of Diseases and Related Health Problems, 10th Revision; MetS, metabolic syndrome; mtDNA, mitochondrial DNA; RLS, restless legs syndrome; RUPP, Research Units on Pediatric Psychopharmacology; SAD, schizoaffective disorder; SGAs, second-generation antipsychotics; SNP, single nucleotide polymorphism; SCZ, schizophrenia; TD, tardive dyskinesia.