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Table 1 Summary of literature review on CYP2D6 genetic polymorphisms and risperidone use in children and adolescents

From: A systematic review of the effects of CYP2D6 phenotypes on risperidone treatment 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
  1. EM extensive metabolizer, IM intermediate metabolizer, PM poor metabolizer, UM ultra-rapid metabolizer
  2. aMedian (interquartile range)
  3. bCalarge et al. drug groups: Group 0 = no CYP2D6 inhibitors. Group 1 = weak CYP2D6 inhibitors (citalopram, escitalopram). Group 2 = intermediate CYP2D6 inhibitors (sertraline). Group 3 = strong CYP2D6 inhibitors (fluoxetine, bupropion, lamotrigine)
  4. cNumber of function genes increases with increased metabolic function: PM < IM < EM < UM
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