Table 1.
Association between Genetic Polymorphisms and Treatment Outcomes.
| Study (First Author, Years) | Diagnoses | Age | Presence/Absence of Intellectual Disabilities | Gene(s) and Polymorphism(s) | Outcomes | Study Design | Number of Subjects | Ethnicity or Nationality | Treatment Duration | Treatment Medication | Main Findings |
|---|---|---|---|---|---|---|---|---|---|---|---|
| AlOlaby et al., 2017 47 | Fragile X syndrome (58.8% of the subjects had ASD) | 46.1 ± 12.6 (range: 24.1 to 71.9) months | Patients with fragile X syndrome were included | SLC6A4 (5-HTTLPR, S or L alleles), BDNF (Val66Met [rs6265]), MAOA-VNTR (2, 3, 3.5, 4, 5 repeat alleles), CYP2C19 (*1, *2, *3, *17), CYP2D6 (*1, *2, *2, *4, *5, *6, *7, *8, *9, *10, *11, *15, * 17, *29, *35, *41) | Treatment response | DBRCT | 51 | Mainly Caucasian | 6 Months | Sertraline | Significant association between the BDNF polymorphism and improvements for several measures, including CGI-I (P = 0.008) and the cognitive T score (P = 0.017) for those treated with sertraline compared to placebo. MAOA, CYP2C19 and CYP2D6, and 5-HTTLPR also significantly correlated with secondary measures. |
| Anderson et al., 2007 48 | Autism (DSM-IV and ADI) | 8.4 ± 2.7 Years | Not reported (approximately 70% of patients treated with risperidone in the RUPP were with mild or more ID) | DRD2 Taq1A (rs1800497), -141C Ins/Del (rs1799732), and C957T (rs6277) | Adverse effect (hyperprolactinemia) | DBRCT (RUPP) | 78 | Various (mainly Caucasian) | 8Weeks | Risperidone | No significant association of the DRD2 variants with increases in prolactin. |
| Bishop et al., 2015 49 | ASD (autism, Asperger disorder, or PDD-NOS; DSM-IV-TR) | 136.7 ± 66.9 (range: 54 to 532) months | Mean ± SD (range)—nonverbal IQ (n = 89): 83.2 ± 31.7 (21 to 146), verbal IQ (n = 79): 76.7 ± 31.7 (11 to 141) | CYP2C19 (rs4244285, rs4986893, and rs12248560) | Treatment response | Prospective | 89 | Various (mainly Caucasian) | 6 Weeks | Escitalopram | No significant difference in the rate of improvement among metabolizer groups (UM, EM, and PM/IM) for the ABC-CV Irritability subscale. |
| Calarge et al., 2009 50 | Various diagnoses including ADHD, disruptive behavior, tic disorder, and PDD (a combination of a review of the psychiatric record and the National Institute of Mental Health Diagnostic Interview Schedule for Children) | 12.1 ± 2.8 Years | Not reported | DRD2 Taq1A (rs1800497), C957T (rs6277), -141C Ins/Del (rs1799732), and A-241G (rs1799978) | Adverse effect (hyperprolactinemia) | Cross-sectional | 90 | Non-Hispanic Caucasians | ≥6 Months | Risperidone | After controlling for risperidone concentration and the dose of psychostimulants, a synergistic effect of the TaqIA and the A-241G variants was found on prolactin concentration, using multiple regression analysis (P = 0.003). |
| Correia et al., 2010 51 | Patients who met the algorithm cutoff for the ADI-R and the ADOS | 8.67 ± 4.30 (range: 3 to 21) years | Absent (IQ ≥ 70): 37.8%, mild (69 ≥ IQ ≥ 50): 31.1%, moderate (49 ≥ IQ ≥ 35): 24.4%, severe (IQ < 35): 6.7% | CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6 gene duplication, ABCB1 (rs1128503, rs1045642), HTR2A (rs6311), DRD2 (rs1800497), HTR2C (rs6318, rs3813928, rs3813929), BDNF (rs6265), HTR6 (rs9659997), DRD3 (rs6280) | Treatment response and adverse effect (AIWG and prolactin elevation) | Prospective | 45 | Various (mainly Caucasian) | Up to 1 year | Risperidone | The HTR2A rs6311 (P = 0.019), DRD3 rs6280
(P = 0.012), HTR2C rs3813928
(P = 0.035), and ABCB1
rs1128503 (P = 0.002) were significantly associated with the decline in the ATEC scores. The HTR2A rs6311 (P = 0.018), HTR2C rs6318 (P = 0.006), HTR6 rs9659997 (P = 9.5 × 10-5), and BDNF rs6265 (P = 0.016) significantly associated with prolactin elevation. The CYP2D6 and HTR2C rs6318 polymorphisms were significantly associated with increase in BMI or waist circumference (P < 0.05). |
| Cote et al., 2015 52 | Various diagnoses including anxiety disorder, mood disorder, ADHD, and PDD (DSM-IV-TR) | 13.1 ± 3.0 Years | Not reported | COMT Val158Met (rs4680) | Adverse effects (blood pressure and other cardiovascular risk factors) | Cross-sectional | 302 | Various (mainly European) | Median = 7 months | SGAs | SGA-treated children with the Met allele showed higher systolic and diastolic blood pressure (P = 0.014 and P = 0.034, respectively) and higher fasting glucose concentrations (P = 0.030) than those who with the Val/Val genotype. |
| dos Santos Júnior et al., 2015 53 | Various diagnoses including mild or moderate mental retardation (n = 36, 30%) and PDD (n = 26, 21.7%; ICD) | 13.0 ± 3.1 Years | Patients with mild or moderate ID were included | DRD2 (rs1799978 and rs6277), HTR2C (rs6318 and rs3813929), CYP2D6*10 (rs1065852), LEP (rs7799039), LEPR (rs1137101), MC4R (rs17782313), SCARB2 (rs3853188) | Adverse effect (hyperprolactinemia) | Cross-sectional | 120 | Various (mainly Caucasian) | 23.4 ± 28.6 Months (cases with hyperprolactinemia) and 30.9 ± 23.9 months (controls without hyperprolactinemia) | Risperidone | Hyperprolactinemia occurred with higher frequency in patients with the C allele of the HTR2C rs6318 polymorphism (P = 0.02). |
| Firouzabadi et al., 2017 54 | ASD (DSM-V) | 6.8 ± 1.3 (2.5 to 14) Years | Patients with severe ID were excluded | DRD3 Ser9Gly (rs6280) | Treatment response | Prospective | 56 | Persian | 8 Weeks | Risperidone | Responder rates (i.e., a 50% or greater decrease from baseline in ABC score) were significantly higher in carriers of Gly allele as well as carriers of Gly/Gly and Ser/Gly genotypes compared with carriers of Ser allele and Ser/Ser genotype (P = 0.027 and 0.014, respectively). |
| Hoekstra et al., 2010 55 | PDD (ADI-R) | 8.74 ± 2.83 (5 to 16) Years | Not reported | HTR2C (rs3813929 and rs1414334) | Adverse effect (AIWG) | Prospective | 32 | Dutch | 8 weeks | Risperidone | Presence of rs3813929T allele was significantly associated with a smaller weight gain (P < 0.001). |
| Hongkaew et al., 2018 56 | ASD (DSM-IV) | Median: 8.96 (quartile 1 to 3: 7.44 to 10.98) years | Not reported | 508 Drug-metabolizing enzymes and transporters SNPs | Adverse effect (hyperprolactinemia) | Observational- retrospective | 84 | Thai | Total sample duration: 43.57 months | Risperidone | Three UGT1A1 SNPs (UGT1A1*80 c.-364C > T [rs887829], UGT1A1*93 c.-3156G > A [rs10929302], and UGT1A1 c.-2950A > G [rs111741722]) showed a suggestive association with hyperprolactinemia (P = 0.0014). |
| Lit et al., 2012 57 | ASD (DSM-IV and ADI-R) | 112.7 ± 51.2 Months | Patients with nonverbal intelligence quotient < 55 were excluded | Exon expression levels in blood assessed using Affymetrix GeneChip Human Exon 1.0 ST Arrays | Gene expression and treatment response | Prospective | 42 | Caucasian (n = 24) and others (n = 18) | 8 Weeks | Risperidone | Expression of exons within 5 genes (GBP6, RABL5, RNF213, NFKBID, and RNF40) was significantly correlated with change in ABC Irritability subscale scores (GBP6, r = 0.78; RABL5, r = 0.72; RNF213, r = −0.73; NFKBID, r = 0.75; and RNF40, r = −0.74; P < 0.001). |
| McCracken et al., 2010 58 | PDD (PDD-NOS, Asperger disorder, or autistic disorder) with clinically significant symptoms of ADHD | 9.03 ± 3.14 Years | Not reported | MDR1 C3435T (rs1045642) | Treatment response | Prospective | 25 | Caucasian (n = 18), African American (n = 6), and Hispanic (n = 1) | 8 Weeks | Guanfacine | Patients with either C/T or C/C genotypes showed a significant greater improvement than T/T MDR1 C3435T genotype in the ABC hyperactivity scores (P < 0.03) and a greater improvement in the Swanson, Nolan, and Pelham (SNAP) scores (P = 0.05). |
| McCracken et al., 2014 59 | ASD (DSM-IV and ADI-R) | 6.90 ± 2.2 (range 5.0 to 13.0) years | Mean intelligence quotient: 65.0 ± 33.3 (range: 16 to 135) | DRD1 (rs4867798, rs5326, rs686), DRD2 (rs6277, rs6589377, rs4938019, rs7131056, rs1800498, rs2283265, rs6275, rs1800497), DRD3 (rs6280 [Ser9Gly], rs2134655, rs9880168, rs7633291, rs167771, rs3732790), DRD4 (rs11246226, rs3758653, Exon 3 VNTR), DRD5 (rs10033951), ADRA2A (rs1800544, rs12246561, rs3750625), SLC6A3 (3’UTR VNTR), SLC6A4 (rs12150214, rs4251417, rs11080121, 5HTT-LPR, STin2 VNTR), MAOA (rs1465108, rs3810709, rs3027399), MAOB (rs10521432, rs1799836), COMT (rs4680 [Val158Met]) | Treatment response and tolerability determined by adherence | Random-order, placebo-controlled, double-blind crossover | 58 | Caucasian (75.9%) | 4 Weeks | Methylphenidate | The DRD1 rs4867798 (P = 0.042), DRD1 rs5326 (P = 0.006), DRD3 rs6280 (P = 0.044), DRD4 rs11246226 (P = 0.038), SLC6A4 STin2 VNTR (P = 0.049), SLCA4 STin2 VNTR (P = 0.041), ADRA2A rs1800544 (P = 0.015), COMT rs4680 (P = 0.049) were significantly associated with responder status assessed using the CGI-I and ABC hyperactivity subscale. The DRD2 rs6275 (P < 0.001) and DRD3 rs6280 (P = 0.031) were significantly associated with tolerability. |
| Medhasi et al., 2016 60 | ASD (DSM-IV) | 8.8 (range: 3.4 to 18.6) years | Not reported | Exploratory analysis using Affymetrix DMETTM Plus Gene Chip microarray interrogating 1931 variants in 231 genes; 483 variants were included for final analysis | Plasma concentrations | Retrospective | 102 | Thai | Median duration of risperidone used: 41.62 months (range: 1.03 to 152.97) | Risperidone | ABCB11 (c.3084A>G, c.420A>G, c.368G>A, and c.236G>A) and ADH7 (c.690G>A and c.-5360G>A) were significantly associated with plasma concentrations of risperidone (P < 0.01). Two of the SCLO1B1 polymorphisms (c.-11187G>A and c.521T>C), SLCO1B3 (c.334G>T, c.699A>G, and c.1557G>A), and SLC7A5 c.438C>G were significantly associated with 9-hydroxyrisperidone and the total active-moiety levels (P < 0.01). |
| Najjar et al., 2015 61 | ASD (DSM-IV, Autism Diagnostic Interview–Revised, and Autism Diagnostic Observation Scale, second edition) | 161 ± 86 (range:61 to 532) months | Mean ± SD (range)—nonverbal IQ (n = 44): 80 ± 25 (35 to 130), verbal IQ (n = 38): 78 ± 25 (30 to 120), full scale (n = 38): 80 ± 25 (33 to 130) | SLC6A4 (5-HTTLPR) and HTR2A (rs7997012) | Treatment response | Prospective | 44 | Various (mainly Caucasian) | 6 Weeks | Escitalopram | No significant differences in the rate of symptom improvement assessed using the RBS-R CRS and the ABC-CV Irritability subscale scores over time across genotype groups. |
| Nuntamool et al., 2017 62 | Autistic disorder (91.36%), PDD-NOS (6.17%), Rett disorder (1.23%), and Asperger disorder (1.23%; DSM-IV) | Median:11 (IQR: 9.00 to 14.00) | Not reported | DRD2 (TaqIA [rs1800497], -241A>G [rs1799978]); DRD3 (25T>C [rs6280]); HTR2A (-1438G>A [rs6311]); ABCB1 (3435C>T [rs1045642], 2677G>T/A [rs2032582], 1236C>T [rs1128503]); CYP2D6 polymorphisms | Treatment response as the primary outcome | Cross-sectional | 82 | Thai | Median duration of risperidone used: 67.90 months (IQR: 52.53 to 90.93) | Risperidone | The nonstable symptom group assessed using CGI-I score and a 4-point scale for each of aggression, overactivity, and repetitive behaviors had DRD2 Taq1A non-wild-type (TT and CT) higher frequencies than the stable group (P = 0.048). Other gene polymorphisms showed no significant association. |
| Nurmi et al., 2013 63 | ASD (autism, Asperger disorder, PDD-NOS; DSM-IV) | 96.5 ± 32.3 Months | Not reported (approximately 70% and 40% of patients treated with risperidone in the RUPP and RUPP-PI were with mild or more ID) | FTO (rs1421085, rs6499640, rs1121980, rs17817449, rs8050136, rs9939609); MC4R (rs8087522, rs11872992, rs8093815, rs489693); LEP (rs7799039, rs10244329, rs12706832, rs2071045); CNR1 (rs806378, rs806377, rs1049353, rs806368); FAAH (rs324420) | Adverse effect (AIWG) | Data from 2 trials (RUPP: DBRCT, RUPP-PI: randomized, parallel-groups clinical trial) | 181 | Various (mainly Caucasian) | 8 Weeks | Risperidone | Three gene variants (LEP rs7799039, CNR1 rs806378, and rs1049353) were significantly associated with AIWG (P = 1.4 × 10-4, 1.0 × 10-6, and 9.6 × 10-5, respectively). |
| Owley et al., 2010 64 | ASD (autism, Asperger disorder, PDD-NOS; ADI-R and ADOS-2) | 117 ± 31 (range: 54 to 204) months | Mean ± SD (range); nonverbal IQ: 86 ± 34 (21 to 146), verbal IQ: 76 ± 35 (11 to 141) | SLC6A4 5-HTTLPR (S, LA, LG alleles, TT diplotype) | Treatment response | Prospective | 58 | Various (mainly Caucasian) | 10 Weeks | Escitalopram | A significant interaction between genotype group and time on the ABC Irritability subscale (linear maximum marginal likelihood estimation = −4.84, Z = −2.89, SE = 1.67, P = 0.004). |
| Prows et al., 2009 65 | Various diagnoses including mood disorders, disruptive behavior disorders, PDD (DSM-IV-TR) | 12.7 ± 3.2 Years | Patients with severe ID were excluded | CYP2D6*1, *3, *4, *5 and CYP2C19*1, *2 | Treatment response and adverse effects (the number of adverse effects) | Retrospective | 279 | Various (mainly Caucasian) | Not mentioned | Psychotropics including antidepressants and antipsychotics | Combined phenotype of CYP2D6 and CYP2C19 was significantly associated with the BIS (P = 0.01) and the number of adverse effects (P = 0.03). |
| Roke et al., 2013 66 | ASD or disruptive behavior disorder (no diagnostic tool was reported) | 14.7 ± 2.1 (range: 10 to 19) years | Patients with IQ above 85 were included | DRD2 Taq1A (rs1800497), CYP2D6*3 del A (rs35742686), CYP2D6*4G>A (rs3892097), CYP2D6*6 del T (rs5030655), CYP2D6 gene deletion (CYP2D6*5), and the gene duplication (CYP2D6xN) | Adverse effect (hyperprolactinemia) | Cross-sectional | 47 | Caucasian (97%) | Mean 52 months (range: 16 to 126 months) | Risperidone | No significant correlations between prolactin level and the presence of at least 1 Taq1A A1 allele of the DRD2 gene, using multiple regression analysis (P = 0.12). No significant difference in prolactin level between the CYP2D6 reduced activity group and the normal activity group, using an independent sample t test (P = 0.8). |
| Sherwin et al., 2012 67 | Mainly ASD | 9.6 ± 3.7 (3 to 18.3) Years | Some of the patients had ID (Aman et al., 2007 68 ) | CYP2D6 *2A, *3, *4, *5, *6, *7, *8, *9, *10, *11, *14, *15, *17, *18, *19, *20, *40, *41, *42, deletion, and duplication | Relative clearance of risperidone CL/F (liters/hour) | Prospective in original studies | 45 | Caucasian (93.3%) | Not mentioned. All patients started risperidone treatment prior to age 18 to treat neuropsychiatric disorder | Risperidone | Clearance estimates in the mixture model were 9.38 L/h (PM), 29.2 L/h (IM), and 37.4 L/h (EM). |
| Sugie et al., 2005 69 | Autism (DSM-IV) | Mean: 5 years and 4 months (n = 19) | Not reported | SLC6A4 (5-HTTLPR (S or L alleles) | Treatment response as the primary outcome | Crossover double-blind, placebo-controlled study | 19 (18 subjects were included in the analysis) | Japanese | 12 Weeks | Fluvoxamine | Fluvoxamine was significantly more effective in the L allele variant than the S allele variant when CGI was used as an assessment scale (P = 0.047). |
| Sukasem et al., 2016 70 | ASD (DSM: version was not reported) | 9.52 Years (inclusion criteria: 3 to 19 years) | Not reported | CYP2D6*4 (1846G>A, [rs3892097]), CYP2D6*10 (100C>T [rs1065852]), CYP2D6*41 (2988G>A [rs28371725]), CYP2D6 gene deletion (CYP2D6*5), and DRD2 Taq1A (rs1800497) | Adverse effect (hyperprolactinemia) | Retrospective cross-sectional | 147 | Thai | 46.06 Months | Risperidone | No significant correlation between the concentrations of prolactin among the CYP2D6 genotypes. There were statistically significant differences in prolactin level of patients among the DRD2 Taq1A A2A2, A1A2, and A1A1 groups (P = 0.033). |
| Sukasem et al., 2018 71 | ASD (DSM-IV) | Median: 10.00 (IQR: 8.90 to 13.40) years | Not reported | ABCB1 (2677G>T/A [rs2032582], 3435C>T [rs1045642]), DRD2 (Tag-SNP [T>C; rs4436578], Tag1A [C>T; [rs1800497]), BDNF (196G>A [rs6265]), LEP (-2548G>A [rs7799039]), GHRL (-604G>A [rs27647]), CYP2D6*4 (1846G>A [rs3892097]), CYP2D6*10 (100C>T [rs1065852]), and CYP2D6*41 (2988G>A [r s28371725]); CYP2D6*5 (gene deletion) | Adverse effect (insulin resistance) | Observational | 89 | Thai | 63.92 (40.40 to 83.49) Months | Risperidone | A significant association between insulin resistance and BDNF 196 G>A, using multiple regression analysis (P = 0.025). |
| Troost et al., 2007 72 | PDD (autistic disorder, Asperger disorder, or PDD-NOS; DSM-IV-TR) | 8.6 ± 2.2 Years | Not reported | CYP2D6*3, *4, *5, *6, and *7 | Adverse effect (prolactin elevation) | Prospective | 25 | Dutch | 8 Weeks | Risperidone | Significant positive correlations of serum prolactin level with dose per kilogram (r = 0.648, P < 0.001), number of functional CYP2D6 genes (J = 2.117, P = 0.034), and serum 9-hydroxyrisperidone concentration (r = 0.664, P = 0.001) and a negative correlation with the risperidone/9-hydroxyrisperidone ratio (r = 0.571, P = 0.004). |
| Vanwong et al., 2016 73 | ASD (DSM-IV) | Median: 10.00 (IQR: 6.83 to 11.55) years | Not reported | CYP2D6*1, *2, *3, * 4, *5, *6, *7, *8, * 9, *10, *11, *15, *17, *29, *41, *35, and duplications | Plasma concentrations | Prospective | 84 | Thai | >4 Weeks | Risperidone | IMs showed significantly higher plasma concentration of risperidone than EMs (P < 0.0001) but not UMs (P = 0.14), and significantly higher plasma concentration of risperidone/ 9-hydroxyrisperidone ratio than EMs (P < 0.0001) and UMs (P = 0.02) |
| Vanwong et al., 2017 74 | ASD (DSM-IV) | Median: 10.00 (IQR: 7.00 to 12.15) years | Not reported | CYP2D6*4 (1846G>A [rs3892097]), CYP2D6*10 (100C>T [rs1065852]), CYP2D6*41 (2988G>A [rs28371725]), CYP2D6*5 (CYP2D6 gene deletion), and CYP2D6*1 (absence of SNPs) | Plasma concentrations | Prospective | 97 | Thai | >4 Weeks | Risperidone | A significant association between high plasma levels of risperidone and CYP2D6*5/*10 (P = 0.02), CYP2D6*10/*10 (P = 0.04), and CYP2D6*10/*41 (P = 0.04). |
| Youngster et al., 2014 75 | ASD (autism, Asperger disorder, or PDD-NOS; DSM-IV, ADI-R, and Childhood Autism Rating Scale) | Median: 7 (range: 3 to 18) years | Not reported | CYP2D6*2, *3, *4, *5, *6, *8, *9, *10, *11, *14, *15, *17, *18, *19, *20, *25, *26, *29, *30, *31, *35, *36, *37, *40, *41, *43, *52, and a number of duplicated alleles | Treatment response and adverse effects (e.g., hyperprolactinemia, AIWG, and EPS) | Observational cohort study | 40 | Israeli | A median of 6 months (3 months minimum) | Risperidone | UMs (n = 2) were classified as nonresponders and had no adverse effects. In contrast, PMs (n = 2) were classified as responders and experienced adverse effects. PMs had significantly higher risperidone plasma levels (P = 0.03) and higher risperidone-to-9-OH-risperidone ratio (P = 0.02: as continuous variable, P = 0.004: as dichotomous with a cutoff ratio of 1) |
Note. ABC = Aberrant Behavior Checklist; ABC-CV = ABC–Community Version; ADHD = attention deficit hyperactivity disorder; ADI-R = Autism Diagnostic Interview–Revised; AIWG = antipsychotic-induced weight gain; ADOS = Autism Diagnostic Observation Scale: ASD = autism spectrum disorder; ATEC = Autism Treatment Evaluation Checklist; BIS = Behavioral Intervention Score; BMI = body mass index; CGI-I = Clinical Global Impression Scale–Improvement; DBRCT = double-blind randomized controlled trial; DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision; EM = extensive metabolizer; EPS = extrapyramidal symptom; ICD 10 = International Statistical Classification of Diseases and Related Health Problems, 10th revision; ID = intellectual disability; IM = intermediate metabolizer; IQ = intelligence quotient; IQR = interquartile range; PDD = pervasive developmental disorder; PDD-NOS = pervasive developmental disorder not otherwise specified; PM = poor metabolizer; RBS-R CRS = Repetitive Behavior Scale–Revised, Compulsive Behavior and Ritualistic/Sameness Behavior subscales; RUPP = Research Units on Pediatric Psychopharmacology; RUPP-PI = RUPP–Psychosocial Intervention; SD = standard deviation; SGAs = second-generation antipsychotics; SNP = single nucleotide polymorphism; UM = ultrarapid metabolizer.