Table 2.

Review of Select Pharmacotherapy^a with Evidence^b for Management of Problem Behaviors in Children with Neurodevelopmental Disorders

Pharmacologic Agent	Receptor Effects	Available Data	Specific Neurodvelopmental Disorders Studied	Ages of Patients Studied	Problem Behavior Types Studied	Strength of Evidence (GRADE)c	Dosed
Risperidone46-50	5-HT1A, 5-HT2A, 5-HT1b, 5- HT1C, 5-HT1D, and D2 receptor agonist; α1 and α2 adrenergic receptor agonist	Randomized, placebo-controlled trials; open-label extension trial	Pervasive Developmental Disorder, Down Syndrome; Fragile X Syndrome49	5-16 years	– Irritability – Aggression – SIBe – Temper tantrums	Irritability associated with ASDf: High Other Problem Behaviors in Other NDDsg: Very Low/Low	Initial: < 20 kg: 0.25 mg/day ≥ 20 kg: 0.5 mg/day Titration: 0.25 – 0.5 mg at ≥ 2 weeks Maintenance: < 20 kg: 0.5 mg once a day or divided in two doses ≥ 20 kg: 1 mg once a day or divided in two doses Maximum: 3 mg/day
Aripiprazole51	Partial D2 and 5-HT1A receptor agonist and 5-HT2A receptor antagonist	Case series; randomized, placebo-controlled trials	ASD	6-17 years	– Irritability – Aggression – SIB – Temper tantrums	Irritability associated with ASD: High Other Problem Behaviors in Other NDDs: Very Low/Low	Initial: 2 mg once a day Titration: 5 mg increments each week Maintenance: 5-10 mg once a day Maximum: 15 mg once a day
Clonidine34,52	α2 adrenoreceptor agonist; activates inhibitor neuron and reduces sympathetic outflow from the central nervous system	Case reports; open-label pilot study	Pervasive Developmental Disorder	5-13 years	– SIBs – Aggression	Very low	Initial: 0.025-0.05 mg/day (~0.002 - 0.003 mg/kg/day in younger children) Titration: 0.025 mg as tolerated every 1-2 weeks to target dose of 0.005-0.01 mg/kg/day in 3-4 divided doses Maximum: 0.01 mg/kg/day Weight-based maximum (in 3-4 divided doses): 27-40.5 kg: 0.2 mg/day 40.5-45 kg: 0.3 mg/day >45 kg: 0.4 mg/day
N-Acetylcysteine40,53-55	Prodrug of cysteine that restores glutathione and scavenges oxidants	Case report; randomized, double-blind, placebo-controlled studies	ASD; excoriation (skin-picking) disorder (adults)56	4-50 years	– Irritability – SIBs – Hyperactivity	Low	Initial dose: 500 - 600 mg once or twice a day Maintenance dose: 1800-2700 mg/day in two to three divided doses
Riluzole33,57	Inhibits glutamate release, enhances glutamate reuptake, inactivated voltage-dependent Na+ channels	Case series; randomized, double-blind, placebo-controlled trial	Fragile X Syndrome; ASD	5-20 years	– Aggression – Irritability – SIBs – Repetitive behaviors	Monotherapy: Very Low Dual Therapy with Risperidone: Low	Children (5-12 years old): Initial: 12.5 mg twice a day Maintenance: 10-40 kg: 25 mg twice a day > 40 kg: 50 mg twice a day Adolescents: Initial: 50 mg once a day Maintenance: 100 mg twice a day
Amantadine58,59	Noncompetitive NMDA receptor antagonist	Double-blind, placebo-controlled trials	ASD	4-19 years	– Hyperactivity – Irritability	Very low	Initial: 2.5 mg/kg/day Maintenance dose: 2.5 mg/kg twice a day Weight-based maximum dose: < 30 kg: 100 mg/day >30 kg: 150 mg/day
Mirtazapine60	Central presynaptic α2 adrenergic antagonist; 5HT2 and 5HT3 serotonin receptor antagonist; H1 histamine receptor and peripheral α1 adrenergic and muscarinic antagonist	Naturalistic, open-label study	Pervasive Developmental Disorders and ASD	3.8-23.5 years	– Aggression – SIB – Irritability – Hyperactivity	Very low	Initial: 7.5 mg/day Titration: 7.5 mg every 1 - 2 weeks Maximum: 45 mg/day in divided doses
Naltrexone61-63	Pure opioid antagonist with high affinity for μ opioid binding sites	Case reports; small case series; small studies	Prader-Willi Syndrome	2-46 years	– SIBs – Hyperactivity	Very low	Fixed-dose: 50 mg/day Weight-based dosing: 0.5-2 mg/kg/day
Topical Anesthetics (EMLAi)64	Stabilizes the neuronal membrane; inhibits ion influx, which is required for conduction of impulses	Case report	– ASD	12-year-old	– SIBs	Very low	1 gram applied to targeted site
Topiramate12,13,65	Blocks neuronal voltage-dependent sodium channels; enhances GABAj activity; antagonizes AMPAk/kainite glutamate receptors; weakly carbonic anhydrase inhibitor	Open-label trial; double-blind, placebo-controlled trial	ASD Prader-Willi Syndrome	4-38 years	– Irritability – Stereotypic behavior – Hyperactivity – SIBs	Very low	Initial: 0.5 - 1 mg/kg/day Titration: 0.5 - 1 mg/kg every week Weight-based maintenance dose: < 30 kg: 100 mg/day >30 kg: 200 mg/day
Divalproex66	Enhances GABA action and availability; mimics GABA action at postsynaptic receptor sites	Randomized, double-blind, placebo-controlled trial	ASD	5 -17 years	– Irritability	Very low	Initial: 10 -15 mg/kg/day Weight-based dosing: Initial: < 40 kg: 125 mg once a day ≥40 kg: 250 mg once a day Titration: 5 – 10 mg/kg/day at weekly intervals; titrate to effect Doses > 250 mg should be given in divided doses
Buspirone67	5-HT1A and 5-HT1B receptor agonist and D2 antagonist	Randomized, double-blind placebo-controlled trial	ASD	4 -17 years	– Irritability	Very low	Initial: 5 mg/day Titration: 5 mg each week Weight-based maximum: <40 kg: 10 mg/day >40 kg: 20 mg/day in two divided doses

^aPharmacologic agents are presented in the order presented in the article text. The order in which the agents are presented does not reflect a treatment algorithm; data supporting monotherapy is presented first then followed by evidence supporting dual therapy.

^bData in this table have been compiled and extrapolated from studies discussed in this review as well as the LexiComp and Micromedex databases. Although these dosing recommendations are meant to provide guidance on the usual dosing ranges for these understudied agents, prescribing clinicians should always consult drug information resources and/or consult with a clinical pharmacist for the most up-to-date and patient-specific dosing recommendations when initiating therapy. Clinicians are urged to prescribe the most conservative initial dose, with titration to the lowest effective dose.

^cEvidence was graded by the manuscript authors using the GRADE system for appraising studies. (Reference: Goldet G, Howick J. Understanding GRADE: an introduction. JEBM 2013;6:50-54.)

^dDosing suggestions have been compiled and extrapolated from studies discussed in this review as well as the LexiComp and Micromedex databases. Although these dosing recommendations are meant to provide guidance on the usual dosing ranges for these understudied agents, prescribing clinicians should always consult drug information resources and/or consult with a clinical pharmacist for the most up-to-date and patient-specific dosing recommendations when initiating therapy. Clinicians are urged to prescribe the most conservative initial dose, with titration to the lowest effective dose.

^eSelf-injurious behaviors

^fAutism Spectrum Disorders

^gNeurodevelopmental Disorders

^hN-Methyl-D-aspartic acid

ⁱeutectic Marcaine lidocaine analgesic

^jGamma-Aminobutyric Acid

^kα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid