Table 1.
Review of irritability of autism randomized controlled trials involving children and adolescents
| Lead Author/Year/Journal | # of pts; % ♂; Age (years) | Drug/Dose; Duration | Monotherapy? | Efficacy results (bold=1º outcome(s)) | Adverse effects | Weight gain/metabolic effects |
|---|---|---|---|---|---|---|
| Risperidone Trials | ||||||
|
RUPPAN 2002; New Engl J Med |
n=101; 82% ♂; 8.8 ± 2.7; (range: 5–17) |
Flexible Dose R:(< 20 kg):0.25–2.5 mg/day (20–45 kg): 0.5–2.5 mg/day (> 45 kg): 0.5–3.5 mg/day (mean: 1.8 ± 0.7 mg/day) vs PBO; 8 weeks duration |
Yes (anticonvulsants OK for seizures - 2% in each group on unspecified anticonvulsant(s)) |
†ABC-I: R: −14.9** PBO: −3.6 % with CGI-I ≤ 2 at endpoint: R: 75.5% vs PBO: 11.5% |
% above PBO: drowsiness (37%), fatigue (32%), increased appetite (24%), constipation (17%), dizziness (12%), nasal congestion (12%), tremor (12%), tachycardia (10%), vomiting (9%), dry mouth (8%), muscle rigidity (8%), sore throat (8%), drooling (6%), URTI (6%) |
R: 2.7 ± 2.9 kg; PBO: 0.8 ± 2.2 kg |
|
Shea 2004; Pediatrics |
n=79; 77% ♂; R: 7.6 ± 2.3 PBO: 7.3 ± 2.3 |
Flexible Dose (at investigator’s discretion) R: 0.02 – 0.06 mg/kg/day (mean: 1.17 mg/day) vs PBO; 8 weeks duration |
Yes - 62% receieved concomitant medications including: analgesics, anti-asthmatics, antibiotics, anticholinergics, cough and cold preparations and sedative/hypnotics |
†ABC-I: R: −12.1** PBO: −6.5 % with CGI-I ≤ 2 at endpoint: R: 26% vs PBO: 9% †N-CBRF conduct problem: R: −10.4 PBO: −6.6 †VAS-MS (aggression): R: −38.4 PBO: −26.2 |
% above PBO: somnolence (64.8%), URTI (22.2%), rhinitis (17.2%), apathy (12.5%), tachycardia (12.5%), abdominal pain (12.3%) increased appetite (12.2%), tremor (10%), constipation (9.9%), fatigue (7.5%), headache (7.4%), increased saliva (7.4%), increased weight (7.4%) |
R: 2.7 ± 2.0 kg; PBO: 1.0 ± 1.6 kg |
|
Hellings 2006; J Autism Dev Disord |
n=40; 58% ♂; mean: 22 ± 13.1 (range: 8–56) |
Complex Crossover Design Low dose R: 1 mg/day High dose R: 0.05 mg/kg/day (mean high dose 2 mg/day, in children and adolescents (range 1.2–2.9 mg/day)) vs PBO; 46 weeks duration‡ |
Yes |
†ABC-I: (acute phase results, comparison vs first PBO phase) R low dose: −8.05** R high dose: −6.85** Responders (≥ 50% reduction in ABC-I): 57.5% (groups not differentiated) |
(Incidence not specified) drowsiness, weight gain, increased appetite, lack of spontaneity, tremor, nasal congestion. Severe akathisia in 1 pt, recurrent oculogyric crisis in 1 pt. |
at 46 weeks: children: 7.9 kg adolescents: 8.3 kg adults: 6 kg weight gain of ≥ 3 kg observed in 70% of pts |
|
Nagaraj 2006; J Child Neurol |
n=39; 87% ♂; R: 4.8 ± 1.7 PBO: 5.25 ± 1.67 |
R: 1 mg/day vs PBO; 6 months duration |
Yes (antipsychotic use OK - 10% of patients received unspecified antipsychotic agent(s)) |
†CARS: R: −7.5** PBO: −1.0 CGAS: R: 11.15** PBO: 2.55 |
% above PBO: sedation (10%), dyskinesia (7.6%) |
R: 2.81 ± 2.04 kg; PBO: 1.71 ± 1.3 kg |
|
Luby 2006; J Child Adolescent Psychopharmacol |
n=23; 74% ♂: R: 4.1 ± 0.9 PBO: 4.0 ± 1.1 |
Flexible Dose R: range 0.5–1.5 mg/day (mean dose: 1.14 ± 0.32 mg/day) vs PBO; 6 months duration |
Yes (implied) |
†CARS: R: −4.6 PBO: −1.8 GARS: non-significant difference, unspecified results |
% above PBO: increased appetite (26%), sedation (22%), hypersalivation (8%) |
R: 2.96 ± 2.53 kg; PBO: 0.61 ± 1.10 kg |
|
Pandina 2007; J Autism Dev Disord |
n=55; 78% ♂; R: 7.4 ± 2.4 PBO: 7.1 ± 2.1 |
Flexible Dose R: 0.5–4.2 mg/day (mean: 1.37 ± 0.7 mg/day) vs PBO; 8 weeks duration |
Yes |
†ABC-I: R: −13.4** PBO: −7.5 % with CGI-C ≤ 2 at endpoint and ≥ 25% ABC-I improvement: R: 58.3% vs PBO: 21.4% †N-CBRF conduct problem: R: −9.0 PBO: −6.0 †VAS-MS (aggression): R: −41.1 PBO: −24.9 |
% above PBO: somnolence (67%), URTI (23%), rhinitis (19%), increased saliva (9%), fever (8%), anorexia (7%), increased appetite (7%), influenza-like symptoms (7%) |
R: 2.4 ± 2.9 kg; PBO: 1.1 ± 0.7 kg |
|
Miral 2008; Eur Child Adolesc Psychopharmacol |
n=30; 80% ♂; R: 10 ± 2.7 H: 10.9 ± 2.9 |
Flexible Dose R: 1.2–4 mg/day (mean: 2.6 ± 0.8 mg/day) vs H: 1–5.7 mg/day (mean: 2.6 ± 1.3 mg/day); 12 weeks duration |
Yes (implied) |
†ABC: R: −48.8 H: −21.3 |
R: URTI (53.1%), constipation (23.1%), nocturnal enuresis (23.1%) H: URTI (53.3%), blunted affect (26.7%), increased appetite (26.7%), constipation (20%), difficulty sleeping (20%), nocturnal enuresis (20%), rigidity (20%) |
R: 4.3 ± 0.7 kg; H: 4.6 ± 0.1 kg |
| Aripiprazole Trials | ||||||
|
Owen 2009; Pediatrics |
n=98; 88% ♂; A: 9.7 ± 3.2 PBO: 8.8 ± 2.6 |
Flexible Dose A: 2–15 mg (mean: 10 mg/day) vs PBO; 8 weeks duration |
Yes (implied) |
†ABC-I: A: −12.9** PBO: −5.0 % with CGI-I ≤ 2 and ≥ 25% ABC-I improvement: A: 52.2% PBO: 14.3% |
% above PBO: fatigue (17%), somnolence (13%), vomiting (11%), sedation (9%), tremor (9%), drooling (9%), fever (7%), EPS (7%), increased appetite (5%) |
Mean weight change: A: +2.0 kg; PBO: +0.8 kg Mean BMI change: A: +0.7; PBO: +0.3 pts with ≥ 7% weight gain: A: 28.9% PBO: 6.1% No significant differences in changes for FBG, TG, LDL, HDL, TChol |
|
Marcus 2009; J Am Acad Child Adolesc Psychiatry |
n=218; 89% ♂; A5: 9 ± 2.8 A10: 10 ± 3.2 A15: 9.5 ± 3.1 PBO: 10.2 ± 3.1 |
A: 5, 10 or 15 mg vs PBO; 8 weeks duration |
Yes - 33% received concomittent medications which included: analgesics, antipyretics, anticholinergics, anxiolytics, and hypnotics/sedatives |
†ABC-I: A5: −12.4**; A10: −13.2**; A15: −14.4**; PBO : −8.4 % with CGI-I ≤ 2 and ≥ 25% ABC-I improvement: A5: 55.8% A10: 49.2% A15: 52.8% PBO: 34.7% |
% above PBO (range for all A dosage levels): sedation (11–18%), tremor (8–12%), cough (7–11%), fever (6–12%), lethargy (5–8%), fatigue (4–18%), drooling (4–14%), EPS (4–11%), decreased appetite (4–8%), somnolence (4–6%), vomiting (2–13%), increased appetite (1–16%), hypersalivation (0–9%), epistaxis (0–7%), URTI (0–6%), weight increased (0–6%), abdominal pain (0–5%), nausea (0–5%) |
Mean weight change: A5: +1.3 ± 0.3 kg; A10: +1.3 ± 0.3 kg; A15: + 1.5 ± 0.3 kg; PBO: +0.3 ± 0.3 kg Mean BMI change: A5: +0.6 ± 0.2; A10: +0.6 ± 0.2; A15: +0.8 ± 0.2; PBO :+0.2 ± 0.2 pts with ≥ 7% weight gain: A5: 32.7% A10: 15.3% A15: 30.2% PBO: 8.2% No significant differences in changes for FBG, TG, LDL, HDL, TChol |
| Olanzapine Trial | ||||||
|
Hollander 2006; J Child Adolesc Psychopharmacol |
n=11; (82% male); O: 9.25 ± 2.9 PBO: 8.9 ± 2.1 |
Flexible Dose O: < 40 kg: 2.5–20 mg/day > 40 kg: 5–20 mg/day (mean: 10 ± 2.04 mg/day) vs PBO; 8 weeks duration |
Yes (implied) |
†CGI-I: O: −2.25 PBO: −1.1 CY-BOCS, OAS-M: findings non-significant, unspecified results |
% above PBO: constipation (50%), sedation (47%), decreased appetite (17%), glazed eyes (17%), insomnia (17%), rhinitis (17%), increased appetite (10%) |
O: 3.4 ± 2.2 kg; PBO: 0.7 ± 0.7 kg |
| Miscellaneous Trials - monotherapy | ||||||
|
Jaselskis 1992; J Clin Psychopharmacol |
n=8; 100% ♂; mean: 8.1 ± 2.8; (range: 5–13.4) |
CLD: 4–10 mcg/kg/day (tapered on and off) vs PBO; Crossover design; 14 weeks duration‡ |
Yes | †ABC-I: ^CLD: −5.3** †CPTQ: ^CLD: −2.8** †CGI-I: ^CLD: −0.1 |
hypotension (38%), drowsiness, irritability | N/A |
|
Quintana 1995; J Autism Dev Disord |
n=10; 60% ♂; mean: 8.5 ± 1.3; (range: 7–11) |
MPH: 10 mg BID x 1 week then 20 mg BID x 1 week vs PBO; Crossover design; 4 weeks duration‡ |
Yes | †ABC: MPH: −28.2** PBO: −17.8 †ABC-I: MPH: −7.8** PBO: − 4.6 significant, modest reduction in hyperactivity symptoms |
Incidence compared to PBO not specified: decreased appetite, increased irritability, insomnia, stomachache, headache |
N/A |
|
Remington 2001; J Clin Psychiatry |
n=36; 83% ♂; mean: 16.3 (range: 10–36) |
Flexible Dose CMP: 100–150 mg/day (mean: 128.4 mg/day) vs H: 1–1.5 mg/day (mean: 1.3 mg/day) vs PBO; 7 weeks duration |
Yes (benztropine use OK - unspecified number of patients) |
†CARS: CMP: −4.0 H: −5.1** PBO: −2.4 †ABC-I: CMP: −3.0 H: −7.0** PBO: −2.0 |
CMP: fatigue/lethargy (31%), tremors (15%), tachycardia (7%), insomnia (7%), diaphoresis (7%), nausea and vomiting (7%), decreased appetite (7%) H: fatigue/lethargy (38%), dystonia (7%), depression (7%) |
N/A |
|
King 2001; J Am Acad Child Adolesc Pyschiatry |
n=39; 87% ♂; mean: 7 (range 5–15) |
AM: 5 mg/kg/day vs PBO; 4 weeks duration |
Yes (psychopharmaco-logical agents OK - including use of serotonin reuptake inhibitors) |
% ABC responders (≥ 25% reduction in irritability and/or hyperactivity subscales) AM: 47% PBO: 37% % CGI-I responders (CGI-I ≤ 2) AM: 53% PBO: 25% |
% above PBO: insomnia (11%), somnolence (5%) |
N/A |
|
Belsito 2001; J Autism Dev Disord |
n=28; 96% ♂; mean: 5.8; (range: 3–11) |
LAM: 5 mg/kg/day vs PBO; 18 weeks duration‡ |
Yes | †AUBC: LAM: −25.7 PBO: −24.1 †ABC: LAM: no significant differences vs PBO in total score or any subscale score †CARS: LAM: +0.1 PBO: −0.6 VABS: LAM: no significant differences vs PBO on any subscale score |
insomnia, hyperactivity (incidence not specified). None of the children were withdrawn from this trial due to rash. |
N/A |
|
Wasserman 2006; International Clin Psychopharmacol |
n=20 85% ♂ |
Flexible Dose LVT: 20–30 mg/kg/day (mean: 862.50 ± 279.29 mg) vs PBO; 10 weeks duration |
Yes (implied) |
†ABC-I: LVT: −3.55 PBO: −2.65 CGI-I: findings non-significant, unspecified results |
% above PBO: Hyperactivity (10%), impulsivity (10%), aggression (10%), weight gain (10%), weight loss (10%), loss of appetite (10%), self injurious behaviour (10%) |
N/A |
|
Amminger 2007; Biol Psychiatry |
n=13 100% ♂; OFA: 10.5 ± 3.2 PBO: 12.1 ± 2.7 |
OFA: 7 capsules/day (120 mg EPA and 100 mg DHA/capsule) vs PBO (contained 1 mg fish oil to mimic taste); 6 weeks duration |
Yes (anticonvulsants OK for patients with seizure disorders) |
†ABC-I: OFA: −4.7 PBO: −4.6 |
reported adverse effects, incidence not stated: OFA: fever PBO: headache, insomnia |
N/A |
|
Hollander 2010; Neuropsychopharmacol |
n=27; 84% ♂; VPA: 9.66 ± 2.64 PBO: 8.97 ± 2.8 |
VPA: weight based dose titrated to achieve clinical response with VPA level above 350 μmol/L vs PBO; 12 weeks duration |
Yes (implied) |
†ABC-I VPA −7.5** PBO: −3.6 % with CGI-I ≤ 2 at endpoint VPA: 63%** PBO: 9% No statistically significant improvement in cY-BOCS, OAS-M Irritability scores |
incidence above PBO: rash (2), polyuria (2), headache (1), severe agitation (1) |
VPA: 1.37 ± 2.91 kg; PBO: 1.34 ± 1.53 kg |
|
Geier 2011: Med Sci Monit |
n=30; 85% ♂; LCAR: 6.3 ± 2.4 PBO: 6.7 ± 1.6 |
LCAR: 50 mg/kg/day vs PBO; 3 months duration |
Yes (implied) | †CARS: LCAR: −1.94** PBO: +0.09 †modified CGI-I: LCAR: −0.5** PBO: + 0.09 |
(incidence not specified) irritability, stomach discomfort | N/A |
| Miscellaneous Trials - adjunctive therapy | ||||||
|
Akhondzadeh 2004; J Clin Pharmacol Ther |
n=40; 60% ♂; CYP: 6.04 ± 0.48 PBO: 6.90 ± 0.42 |
Flexible Dose: CYP: 0.2 mg/kg/day; 8 weeks duration |
No H: 0.05 mg/kg/day and biperiden: 0.04 mg/kg/day |
†ABC: CYP: −10.9** PBO: −3.7 †CARS CYP: −1.85 PBO: −0.37 |
% above PBO: increased appetite (25%), constipation (10%) |
non-significant difference in fasting glucose compared to PBO |
|
Akhondzadeh 2010; Prog Neuropsychopharmacol Biol Psychiatry |
n=40; 70% ♂; PTF: 8.05 ± 2.01 PBO: 7.37 ± 2.41 |
Flexible Dose PTF add-on: (10–40 kg): 400 mg/day (> 40 kg): 600 mg/day vs PBO; 10 weeks duration |
No R: (10–40 kg): 2 mg/day (> 40 kg): 3 mg/day |
†ABC-I: PTF: −9.53** PBO: −4.41 |
% above PBO: increased appetite (15%), daytime drowsiness (10%), flatulence (10%), constipation (5%), weight gain (5%) |
N/A |
|
Rezaei 2010; Prog Neuropshychopharmacol Biol Psychiatry |
n=40; 68% ♂; TOP: 8.17 ± 1.85 PBO: 7.85 ± 1.82 |
TOP: (< 30 kg/age 3–6): 100 mg/day (> 30 kg/age 7–12): 200 mg/day vs PBO; 8 weeks duration |
No R: (10–40 kg): 2 mg/day (> 40 kg): 3 mg/day |
†ABC-I: TOP: −9.05** PBO: −1.5 |
% above PBO: somnolence (30%), decreased appetite (30%), paresthesia (20%), insomnia (20%), nausea (20%), dizziness (15%) |
Mean weight change: TOP: 0.43 kg PBO: 0.52 kg |
|
Hasanzadeh 2012; Child Psych Hum Dev |
n=47; 83% ♂; GB: 6.04 ± 1.61 PBO: 6.76 ± 2.6 |
GB: (<30 kg): 80 mg/day (> 30 kg): 120 mg/day vs PBO; 10 weeks duration |
No R: (10–30 kg): 2 mg/day (> 30 kg): 3 mg/day |
†ABC-I: GB: −4.41 PBO: −4.2 |
% above PBO: nervousness (17.6%), fatigue (13.4%), morning drowsiness (8.7%) |
N/A |
Abbreviations
A=aripiprazole; AM=amantadine; BID=twice daily; BMI=Body Mass Index; CLD=clonidine; CMP=clomipramine; CYP=cyproheptadine; EPS=extrapyramidal symtpoms; FBG=fasting blood glucose; GB=gingko biloba; H=haloperidol; HDL=high-density lipoprotein; LAM=lamotrigine; LCAR=levocarnitine; LDL=low-density lipoprotein; LVT=levetiracetam; MPH=methylphenidate; N/A=not available; O=olanzapine; OFA=omega-3 fatty acids; PBO=placebo; pt=patient
PTF=pentoxifylline; R=risperidone; Tchol=total cholesterol; TG=triglyceride; TOP=topiramate; URTI=Upper Respiratory Tract Infection VPA=divalproex/valproate; vs=versus; ♂ = male; ‡=see body text for trial durations details; †=negative score denotes improvement; ^=net difference compared to placebo reported since baseline values not specified; **=statistically significant result for primary outcome/implied primary outcome measure
Abbreviations of Rating Scales used: ABC: Aberrant Behavior Checklist (Complete scale); ABC-I: Aberrant Behavior Checklist (Irritability subscale); AUBC: Autism Behavior Checklist; CARS: Childhood Autism Rating Scale; CGI-C: Clinical Global Impresssion - Change; CGI-I: Clinical Global Impresssion - Improvement; CGAS: Children’s Global Assessment Scale; CGSQ: Caregiver Strain Questionnaire; cY-BOCS: Children’s Yale-Brown Obsessive-Compulsive Scale; GARS: Gilliam Autism Rating Scale; NCBF: Nisonger Child Behavior Rating Form; OAS-M: Overt Aggression Scale-Modified; PedsQL: Pediatric Quality of Life Inventory; VABS: Vineland Adaptive Behavior Scale; VAS-MS: Visual Analog Scale for Most Troublesome symptom