Evidence Table 20Active-control trials of atypical antipsychotics in youths

Author, year
Country
Trial name (Quality score)
NDurationStudy design
Setting
Eligibility criteriaInterventions (drug, dose, duration)Run-in/washout periodAllowed other medications/interventionsAge
Gender
Ethnicity
Other population characteristics (diagnosis, etc)Number screened/eligible/enrolledNumber withdrawn/lost to fu/analyzedOutcome measuresMethod of outcome assessment and timing of assessmentResultsMethod of adverse effects assessmentWithdrawals/withdrawals due to AEsAdverse events
Olanzapine vs. haloperidol
Malone, 2001
US (FAIR)
126 weeksRandomized, open label, pilot study.Children between ages 5 and 17 with a primary diagnosis of pervasive developmental disorder (DSM-IV criteria); at least moderate impairment on 2 or more of the first 28 items on the Children's Psychiatric Rating Scale at baseline.Olanzapine starting dose 2.5 mg every other day for patients who weighed 40 kg or less and 2.5 mg per day for those who weighed more than 40 kg. Dosages could be increased in 2.5 mg increments up to 5 mg per week as needed. Maximum dose 20 mg/day.

Haloperidol starting dose 0.25 mg/day for patients weighing 40 kg or less and 0.5 mg for those who weighed more than 40 kg. Dosages could be increased as clinically indicated in 0.5 mg increments up to 1 mg per week as needed. Maximum dose 5 mg/day.
1 week drug-free baseline washout period.NoMean age 7.8 (SD 2.1) years; range 4.8–11.8 years.
67% male
58% white, 25% African American, 17% Hispanic
11/12 (92%) autistic disorder, 1/12 (8%) pervasive developmental disorder, not otherwise specified. 8% normal cognitive functioning, 8% mild mental retardation, 42% moderate mental retardation, 42% severe mental retardation.# screened not reported/13 eligible/12 enrolled (1 withdrew consent)No withdrawals, losses to followup, 12 analyzed.Primary outcome: CGI Secondary outcome: Children's Psychiatric Rating Scale (CPRS)Principal investigator and one other trained rater performed all ratings; assessments at baseline and end of study.CGI Improvement from baseline
olanzapine:
1/6 (16.7%) very much improved
4/6 (66.7%) much improved
1/6 (16.7% minimally improved
haloperidol:
1/6 (16.7%) very much improved
2/6 (33.3%) much improved
3/6 (50% minimally improved (p=0.494)

Mean change from baseline (olanzapine vs haloperidol)
CGI (Severity): −1.08 vs −0.42
CPRS (Autism): −0.84 vs −0.53
CPRS (Anger/Uncooperative): −1.27 vs 0.15
CPRS (Hyperactivity): −1.1 vs 0.36
CPRS (Speech Deviance): 0.4 vs −0.25
Weight, blood pressure, and pulse at baseline and each visit. Height recorded at baseline. Adverse effects monitored at each visit with the Dosage Record and Treatment Emergent Symptom Scale (DOTES), the Treatment Emergent Symptoms Scale-Write IN (TESS), AIMS, and the Neurologic Rating Scale (NRS). At baseline and end of treatment, complete blood count with differential, liver functions, and EKG.NoneMean weight gain at 12 weeks:
olanzapine: 4.08 kg (SD 1.59, range 2.67 to 7.14)
haloperidol: 1.45 kg (SD 2.22, range −2.49 to 3.97) (p=0.04)
All 6 patients in olanzapine group vs 2 of 6 in haloperidol group gained more than 2.27 kg (5 lbs)

No significant differences between groups on incidence of side effects.
NRS: One haloperidol patient had transient mild rigidity, no olanzapine patient had extrapyramidal symptoms as rated by this measure.
AIMS: No patients in either treatment group had dyskinesia as rated by this measure.
No clinically significant changes in any of the laboratory studies or EKGs.
Medication treatment was not associated with a prolongation of the QTc interval.
Risperidone vs. haloperidol
Gencer 2008
Turkey
2812 weeks after initial studyopen-label continuation study of the randomized, double-blind, controlled trial Single centerChildren and adolescents with a primary diagnosis of AD according to the DSM-IV criteriaHaloperidol mean 2.7 ± 1.3 mg/day
Risperidone mean = 2.5 ± 0.7 mg/day in the risperidone
Followed RCTantianalgesics, antipyretics, decongestants and antibiotics administered by other doctors throughout the study as well as Anticholinergic agents for EPSMean age 10.5
% male 79
Ethnicity NR
None of interestNR/NR/281/0/27Clinical Global Impression Scales-Improvement (CGII), Ritvo-Freeman Real Life Rating Scale (RFRLRS), Aberrant Behavior Checklist (ABC) and Turgay DSM-IV Pervasive Developmental Disorder Rating Scale (TPDDRS)At week 12 of the double-blind study and were repeated at weeks 16, 20 and 24.Risperidone vs. haloperidol baseline/endpoint
RF-RLRS (Sensory-motor) 0.90 ± 0.52/0.44 ± 0.42 vs. 0.69 ± 0.47/0.57 ± 0.48 P = 0.1828
RF-RLRS (Social) 0.62 ± 0.50/0.69 ± 0.42 vs. 0.50 ± 0.41/0.68 ± 0.59 P = 0.6141
RF-RLRS (Affect) 1.09 ± 0.41/1.27 ± 0.37 vs.. 1.05 ± 0.61/1.36 ± 0.68 P = 0.6141
RF-RLRS (Sensory) 0.98 ± 0.46/0.82 ± 0.35 vs. 0.86 ± 0.44/0.81 ± 0.59 P = 0.7551
RF-RLRS (Language) 0.52 ± 0.37/0.44 ± 0.33 vs. 0.15 ± 0.44/0.32 ± 0.51 P = 0.0414
ABC (Total) 85.6 ± 27.3/52.0 ± 14.9 vs. 67.1 ± 25.1/58.1 ± 32.2 P = 0.0746
TPDDRS 91.5 ± 20.1/67.2 ± 17.0 vs. 77.6 ± 23.1/66.2 ± 26.4 P = 0.0594

CGI degree of improvement P = 0.0186 (no other numbers reported for this outcome
Extrapyramidal Symptoms Rating Scale (ESRS) and UKU Side-Effect Rating Scale1 withdrawal
0 due to AEs
Weight gain was observed more frequently in the haloperidol group. P = 0.0414
Risperidone vs. haloperidol %
URTI 53.1 vs. 53.85
enuresis nocturna 23.1 vs. 20
Miral 2008
Turkey
3012 week total ; 2 weeks screening and 10 weeks RCTDB RCT
Single center
Autistic Disorder; be 8–18 years; have his or her parents’ informed consent, and agree to be followed-up.Haloperidol mean = 2.6 ± 1.3 mg/day
Risperidone mean = 2.6 ± 0.8 mg/day
2 week screeningantianalgesics, antipyretics, decongestants and antibiotics administered by other doctors throughout the study as well as Anticholinergic agents for EPSMean age 10.5
% male 80
Ethnicity NR
None of interestNR/NR/322/2 LTF/30Ritvo–Freeman Real Life Rating Scale (RF-RLRS), CGI Severity and ImprovementAssessed at baseline and 2, 4, 8, and 12.Risperidone vs. haloperidol
Ritvo–Freeman Real Life Rating Scale
Social
Baseline 0.62 ± 0.50 vs. 0.50 ± 0.41
Endpoint )0.11 ± 0.38 vs. 0.02 ± 0.57
Sensory motor
Baseline 0.90 ± 0.52 vs. 0.69 ± 0.47
End-point 0.36 ± 0.34 vs. 0.50 ± 0.44
Affect
Baseline 1.09 ± 0.41 vs. 1.05 ± 0.61
End-point 0.54 ± 0.34 vs. 0.64 ± 0.48
Sensory
Baseline 0.98 ± 0.46 vs. 0.86 ± 0.44
End-point 0.51 ± 0.25 vs. 0.58 ± 0.49
Language
Baseline 0.52 ± 0.37 vs. 0.15 ± 0.44
End-point 0.04 ± 0.25 vs. 0.05 ± 0.5
Aberrant Behavior Checklist
Baseline 85.6 ± 27.3 vs. 67.1 ± 25.1
End-point 36.8 ± 13.8 vs. 45.8 ± 20.2
CGI-I scores,
Markedly improved 15.4% vs. 0
Moderately improved,69.2% vs. 60%
Slightly improved 15.4% vs. 33.3%
No change 0 vs. 6.7%
Turgay DSM-IV PDD Rating Scale ABC, ESRS, The UKU Side-effect rating Scale.2 withdrawals
0 due to AEs
Risperidone vs. haloperidol
Enuresis nocturna 23.1% vs. 20%
URTI 53.8% vs. 53.3%
Chouinard Extrapyramidal Symptoms Rating Scale
Section I
Baseline 0.23 ± 0.60 vs. 0.33 ± 0.82
End-point 0.15 ± 0.38 vs. 1.27 ± 1.75
Parkinsonism
Baseline 0.00 vs. 0.00
End-point 0.00 vs. 0.00
Dystonia
Baseline 0.00 vs. 1 0.00
End-point 0.00 vs. 0.00
Dyskinesia
Baseline 0.00 vs. 0.3173 0.40 ± 1.55
End-point 0.08 ± 0.28 vs. 0.13 ± 0.30
Turgay DSM-IV Scores
Baseline 91.5 ± 20.1 vs. 0.0019 77.6 ± 23.1
End-point 53.5 ± 9.6 vs. 59.6 ± 21.3
Aripiprazole
Marcus 2009
United States
2188 weeksRCT, DB
Multicenter (37)
Inclusion: Aged 6 to 17 years weighing ≥15 kg; met DSM-IV-TR criteria for autistic disorder; with behaviors such as irritability, agitation, self-injurious behavior, or a combination of these; and CGI-S ≥ 4 and ABC-Irritability (ABC-I) subscale ≥18 at screening and baseline. Exclusions: bipolar disorder, psychosis, schizophrenia or major depression, fragile X, or another autistic spectrum disorder including PDD not otherwise specified, Asperger's, Rett, or childhood disintegrative disorder; hx of neuroleptic malignant syndrome, stroke, or head trauma; suicide risk; seizure in past year; unstable medical condition or abnormal lab, clinical, or ECG finding.4 groups: Placebo (N=52); Aripiprazole 5 mg/day (N=53); 10 mg/day (N=59); 15 mg/day (N=54)

Subjects randomized to aripiprazole started at 2 mg/day for the first week, increased to 5 mg/day the 2nd week, increasing weekly by 5 mg for higher dose groups.

Subjects unable to tolerate assigned dose were discontinued from study.

8 weeks
Screening/washout phase up to 42 daysAntianxiety (benzodiazepines); sleep aids (diphenhydramine and non-benzodiazepine hypnotics); diphenhydramine up to 50 mg/day for serious behavior problems; psychotropic meds for acute treatment; anticholinergics or propranolol for EPSMean age 9.7 years
76.1% aged 6–12
89.4% male
white 71.1%
black 22.9%
Asian 2.8%
other 3.2%
Mean ABC-I at baseline 28.4
30% CGI-S=4, moderately ill
40% CGI-S=5, markedly ill
30% CGI-S=7, severely ill
368/218/21840/5/213Primary: Mean change from baseline to endpoint in caregiver-rated ABC-Irritability subscale score.
Secondary: CGI-I score at endpoint; change in other ABC subscales and Children's Y-BOCS; response rate (≥ 25% reduction in ABC-I and a CGI-I=1 or 2 at endpoint); Pediatric Quality of Life Inventory (PedsQL); CGI-S; Caregiver Strain Questionnaire (CGSQ).
Assessed at baseline and weeks 1, 2, 3, 4, 5, 6, and 8.Placebo vs. Aripiprazole 5/10/15 mg/day:
Completed study: 73.1 vs. 83/83.1/87%

ABC-I subscale score, mean change from baseline to week 8: −8.4 vs. −12.4 (P=0.032)/−13.2 (P=0.008)/−14.4 (P=0.001)

Response rate at week 8, %:
34.7 vs. 55.8 (P=0.034)/49.2 (P=ns)/52.8 (P=ns)

CGI-I 3.3 vs. 2.6 (P=0.003)/2.5 (P<0.001)/2.5 (P<0.001)

CGI-S mean ±SE change at week 8:
−0.6 ±0.2 vs. −0.9 ±0.1/−1.0 ±0.1/−1.1 ±0.2
Treatment difference (95% CI):
(ref.) vs. −0.3 (−0.7 to 0.1)/−0.4 (−0.8 to −0.0)/−0.6 (−1.0 to −0.2)

Aripiprazole 15mg/day vs. placebo, mean treatment difference:
PedsQL: 8.2 (95%CI 1.2 to 15.2).
CGSQ: −1.1 (95%CI −1.9 to −0.3)
Reports of adverse events; vital signs; ECG findings; and weight and lab assessments, including prolactin levels. EPS assessed using SAS; BARS; AIMS40 withdrawals
21 due to AE
Placebo vs. Aripiprazole 5/10/15 mg/day, % of group:
Sedation 5.9 vs. 17.3/28.8/24.1
Tremor 0 vs. 7.7/11.9/11.1
Somnolence 3.9 vs. 7.7/8.5/9.3
Drooling 0 vs. 3.8/13.6/9.3
Headache 3.9 vs. 5.8/8.5/9.3
Extrapyramidal disorder 0 vs. 3.8/6.8/11.1
Lethargy 0 vs. 7.7/5.1/5.6
Hypersomnia 0 vs. 5.8/0/3.7
Vomiting 7.8 vs. 9.6/20.3/9.3
Salivary hypersecretion 2.0 vs. 1.9/6.8/11.1
Nausea 2.0 vs. 1.9/5.1/7.4
Abdominal pain upper 2.0 vs. 3.8/1.7/7.4
Fatigue 0 vs. 3.8/22.0/18.5
Pyrexia 0 vs. 5.8/11.9/9.3
Increased appetite 3.9 vs. 19.2/5.1/13.0
Weight increased 2.0 vs. 7.7/1.7/3.7
Gained ≥7% body weight: 8.2 vs. 32.7/15.3/30.2
EPS: 11.8 vs. 23.1/22.0/22.2
Presyncope in 1 subject on aripiprazole 5 mg/day, day 17.
HDL <30 mg/dL occurred in 3 subjects on aripiprazole, but 2 had abnormalities at baseline.
Elevated prolactin in 0% on aripiprazole and 4.4% on placebo.
Owen 2009
United States
988 weeksRCT, DB
Multicenter (20)
Inclusion: Aged 6 to 17 years weighing ≥15 kg; met DSM-IV-TR criteria for autistic disorder; with behaviors such as irritability, agitation, self-injurious behavior, or a combination of these; and CGI-S ≥ 4 and ABC-Irritability (ABC-I) subscale ≥18 at screening and baseline. Exclusions: bipolar disorder, psychosis, schizophrenia or major depression, fragile X, or another autistic spectrum disorder including PDD not otherwise specified, Asperger's, Rett, or childhood disintegrative disorder; hx of neuroleptic malignant syndrome, stroke, or head trauma; suicide risk; seizure in past year; unstable medical condition or abnormal lab, clinical, or ECG finding.Flexibly dosed aripiprazole (maximum 15 mg/day) starting at 2 mg/day, with target dose of 5, 10, or 15 mg/day.

Placebo

8 weeks
Screening/washout phase up to 6 weeksLorazepam or alprazolam for anxiety; sleep aids (diphenhydramine, melatonin, or nonbenzodiazepine hypnotics); diphenhydramine up to 50 mg/day for serious behavior problems; benztropine or propranolol for EPS.Mean age 9.2 years
87.8% male
White 74.5%
Black 18.4%
Asian 2.0%
Other 5.1%
ABC irritability subscale score at baseline, mean 29.9
Mean weight, kg 42.2
164 enrolled in screening phase/98 eligible for randomization/98 enrolled in DB phase23/1/95Primary: Mean change from baseline to endpoint in caregiver-rated ABC-Irritability subscale score.
Secondary: CGI-I score at endpoint; change in other ABC subscales and Children's Y-BOCS; response rate (≥25% reduction in ABC-I and a CGI-I=1 or 2 at endpoint); Pediatric Quality of Life Inventory (PedsQL); CGI-S; Caregiver Strain Questionnaire (CGSQ).
Assessed at baseline and weeks 1, 2, 3, 4, 5, 6, and 8.Aripiprazole (N=46) vs. placebo (N=49):
ABC-irritability subscale score mean change at week 8: −12.9 vs. −5.0
Least-squares mean treatment difference −7.9, 95%CI −11.7 to −4.1; P<0.001.
CGI-I at week 8: 2.2 vs. 3.6; treatment difference −1.4; 95%CI −1.9 to −1.0; P<0.001
CGI-S mean change: −1.2 vs. −0.4; treatment difference −0.8; 95%CI −1.2 to − 0.4); P<0.001
CY-BOCS (compulsions only): −3.8 vs. −0.8; treatment difference −3.0; 95%CI
−4.3 to −1.6; p<0.001
Response rate at week 2: 30.4% vs. 4.1%; P<0.001
Response rate at week 8: 52.2% vs. 14.3%; P<0.001

PedsQL combined scales total score, treatment difference 11.4; 95%CI 6.1 to 16.8
CGSQ global score, treatment difference −1.9; 95% CI −2.7 to −1.2
Reports of adverse events; vital signs; ECG findings; and weight and lab assessments, including prolactin levels. EPS assessed using SAS; BARS; AIMS23 withdrawals
8 due to AE
Placebo (N=50) vs. Aripiprazole (N=47), % of group:
Headache 16 vs 6.4
Somnolence 4 vs 17
Sedation 2 vs 10.6
Drooling 0 vs 8.5
Tremor 0 vs 8.5
Diarrhea 10 vs 8.5
Vomiting 4 vs 14.9
Insomnia 8 vs 6.4
Aggression 8 vs 2.1
Fatigue 4 vs 21.3
Pyrexia 2 vs 8.5
Increased appetite 10 vs 14.9
Weight gain ≥ = 7%: 6.1 vs. 28.9; P<0.01
Any EPS event 8 vs 14.9
Tremor 0 vs 8.5
Extrapyramidal disorder 0 vs 2.1
Muscle rigidity 0 vs 2.1
Hypokinesia 0 vs 2.1

Prolactin level change: 1.6 vs −6.3 ng/mL; P<0.001
Prolactin elevation: 6.8% vs. 2.4%

From: Evidence Tables

Cover of Drug Class Review: Atypical Antipsychotic Drugs
Drug Class Review: Atypical Antipsychotic Drugs: Final Update 3 Report [Internet].
McDonagh M, Peterson K, Carson S, et al.
Portland (OR): Oregon Health & Science University; 2010 Jul.
Copyright © 2010 by Oregon Health & Science University, Portland, Oregon 97239. All rights reserved.

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