Table 1 Summary of literature review on CYP2D6 genetic polymorphisms and risperidone use in children and adolescents
Authors | Dose and length of time on risperidone, mean (SD) | Population | CYP2D6-predicted phenotypes | Outcomes measured | Select results, mean (SD) | Limitations |
|---|---|---|---|---|---|---|
Sukasem et al. [27] | 1 (0.93) mg/day for 46.06 months | 147 subjects All Thai ethnicity Age range 3–19, mean age 9.52 127 (86%) males All diagnosed with ASD | UM = none EM = 73 (50%) IM = 74 (50%) PM = none | Serum prolactin concentration Hyperprolactinemia defined as prolactin levels > 97.5‰, normalized for age and sex | Serum prolactin concentration (ng/mL)a: UM = no data EM = 16.90 (9.53–25.50) IM = 16.55 (11.28–24.08) PM = no data No significant difference in serum prolactin concentrations between phenotypes. No significant difference in presence or absence of hyper-prolactinemia between phenotypes | No UM or PM subjects |
Vanwong et al. [18] | 0.5 (0.50–1.00)a mg/day for at least 4 weeks | 84 subjects All Thai ethnicity Age rage 3–20, median age 10 (6.83–11.55)a 75 (89.29%) males All diagnosed with ASD | UM = 4 (5%) EM = 46 (55%) IM = 33 (40%) PM = none 1 subject excluded from phenotyping | Serum risperidone concentration and risperidone/9-hydroxyrisperidone ratio | Serum risperidone concentration (ng/mL)a: UM = 0.0 (0.00–5.18) EM = 0.43 (0.00–1.53) IM = 1.85 (0.67–4.25) PM = no data Concentration in IM phenotype was significantly greater than EM but not UM. Risperidone/9-hydroxy-risperidone ratio in IM phenotype was significantly greater than both EM and UM | No PM subjects. Mean/median length of time on risperidone not reported |
dos Santos Júnior et al. [34] | 2.2 (1.3) mg/day in hyperprolactinemia group and 1.9 (1.2) mg/day in non-hyperprolactinemia group for 23.4 (28.6) months in hyperprolactinemia group and 30.9 (23.9) months in non-hyperprolactinemia group | 120 subjects Varying ethnicities Age range 8–20, mean age 13.0 (3.1), median age 13 98 (82%) males Diagnosed with various psychiatric disorders 197 subjects not taking risperidone included as controls | UM = none EM = 76 (63%) IM = 37 (31%) PM = 7 (6%) | Serum prolactin concentration Hyperprolactinemia defined as > 20 mg/dL in males and > 25 mg/dL in females in absence of hypothyroidism. Patients grouped into “case” (hyperprolactinemia) and “control” (no hyperprolactinemia) | Number of cases/number of controls: UM = no data EM = 51/26 IM = 24/12 PM = 4/3 No significant difference in presence or absence of hyperprolactinemia between phenotypes | No UM subjects |
Youngster et al. [30] | 1.0 mg/daya in IM/EM group; 0.65 mg/daya in PM group; 1.25 mg/daya in UM group for minimum 3 months, median duration 6 months | 40 subjects Race/ethnicity data not given Age range 3–18, median age 7 34 (85%) males All diagnosed with ASD | UM = 2 (5%) EM or IM = 36 (90%) PM = 2 (5%) | Reported ADRs: weight gain and neurological extrapyramidal symptoms Clinical response: improvements in disruptive behaviour Serum prolactin concentration Serum risperidone and 9-hydroxyrisperidone concentrations | Number of subjects who reported ADRs: UM = 0 EM or IM = 9 PM = 2 Clinical response: UM = 0 EM or IM = 24 PM = 2 Serum prolactin concentration (mg/L)a: UM = 18.3 (17.2–19.4) EM or IM = 20.2 (6.5–65.6) PM = 50.3 (48.4–52.2) Serum risperidone concentration (ng/mL)a: UM = 0.75 (0.5–1.0) EM or IM = 1.0 (0–47) PM = 9.0 (6–12) All PM and UM patients diagnosed with hyper-prolactinemia Serum risperidone concentration significantly greater in PM phenotype | Too few UM and PM subjects. Hyperprolactinemia not defined |
Roke et al. [11] | 1.6 (1.0) mg/day for 53.3 (28.7) months | 47 subjects 46 (98%) Caucasian Age range 10–19, mean age 14.7 (2.1) 47 (100%) males 45 (96%) diagnosed with ASD, 2 (4%) diagnosed with DBD | UM = 2 (4%) EM = 25 (54%) IM = 17 (37%) PM = 2 (4%) | Serum prolactin concentration Hyperprolactinemia defined as prolactin levels > 97.5%, normalized for age and sex | Serum prolactin concentration (ng/mL): UM = 6.8 (6) EM = 19.8 (17) IM = 18.4 (17) PM = 49 (0) No significant difference in serum prolactin concentrations between EM and IM phenotypes. Too few subjects for statistical testing in UM and EM. All PM patients met criteria for hyperprolactinemia diagnosis | Too few UM and PM subjects for statistical tests. No suggested mechanism for results, unlike Troost et al. who had contradictory findings |
Sherwin et al. [12] | 2.0 (1.5) mg/day | 45 subjects but only 28 (62%) underwent CYP2D6 genotyping 42 (93%) Caucasian Age range 2–21, mean age 9.6 (3.7) 40 (89%) males Most diagnosed with ASD | UM = none EM = 15 (54%) IM = 6 (21%) PM = 7 (25%) | Relative clearance of risperidone CL/F (litres/hour) | Relative clearance of risperidone CL/F (litres/hour): UM = no data EM = 37.4 IM = 29.2 PM = 9.4 Decreased clearance significantly associated with decreased CYP2D6 | No UM subjects. Length of time on risperidone not reported |
Calarge et al. [36] | 0.03 (0.03) mg/kg/day for at least 6 months | 107 subjects 88 Caucasian, 10 African American, 5 Hispanic, 4 Other Age range 7–17, mean age 11.4 (2.8) 98 (92%) males Diagnosed with various psychiatric disorders | CYP2D6-predicted phenotype not determined. Instead, patients grouped according to concomitant use of CYP2D6 inhibiting drugsb Group 0 = 51 (48%) Group 1 = 13 (12%) Group 2 = 10 (9%) Group 3 = 33 (31%) | Serum risperidone and 9-hydroxyrisperidone concentrations | Concentration of risperidone: Group 3 > Group 0 and Group 1 > Group 0 Concentration of active moiety (risperidone + 9-hydroxyrisperidone): Group 3 > Group 0. All other differences were insignificant. Full numerical data not given, only bar graph | Patients were not genotyped, but implications for CYP2D6-predicted phenotypes combined with CYP2D6 inhibitors are explained |
Correia et al. [29] | 1.0, 2.0 or 3.0 mg/day based on weight for 12 months | 45 subjects 44 (98%) Caucasian Age range 3–21, mean age 8.67 (4.30) 34 (76%) males All diagnosed with ASD | UM = 8 (18%) EM = 24 (53%) IM = 12 (27%) PM = 1 (2%) | Autism Treatment Evaluation Checklist (ATEC) score (for efficacy) BMI Waist circumference. Serum prolactin concentration | BMI: UM = 4.8% lower increase EM = used as reference IM = no significant change PM = no significant change Waist circumference: UM = 5.8% lower increase EM = used as reference IM = no significant change PM = 4% lower increase No significant difference in ATEC score or serum prolactin concentration between phenotypes | Too few PM subjects for statistical tests |
Troost et al. [24] | Maximum 4.0 mg/day (< 45 kg) or 6.0 mg/day (> 45 kg) for 8 weeks | 25 subjects Age range 5–15, mean age 8.6 (2.2) 23 (92%) males Diagnosed with various psychiatric disorders | UM = 2 (8%) EM = 12 (48%) IM = 6 (24%) PM = 5 (20%) | Serum risperidone concentration and risperidone/9-hydroxyrisperidone ratio Serum prolactin concentration | Serum risperidone concentration: negative correlation with number of functional CYP2D6 genesc Risperidone/9-hydroxy-risperidone ratio: negative correlation with number of functional genes Serum prolactin concentration: positive correlation with number of functional genes | Too few UM subjects. Hyperprolactinemia not defined Length of time on risperidone shorter than other studies |
Kohnke et al. [25] | 6 mg/day for 3 months, reduced to 4 mg/day before outcomes measured | Single patient case study Age 17 Male Diagnosed with schizophrenia | PM = 1 (100%) | Serum risperidone and 9-hydroxyrisperidone concentrations. In-depth symptoms observations | Serum risperidone and 9-hydroxyrisperidone concentrations increased after 8 days of concomitant therapy of haloperidol (6 mg/day) and biperiden (2 mg/day). Patient experiences extrapyramidal symptoms while on risperidone | Single case study heightens possibility of weight/age/sex influence on results |