There is a critical need for evaluation of the pharmacotherapies used in conduct disorder (CD), due to the high incidence of off-label prescribing. The aim of this review was to identify concerns associated with the safety, efficacy and impact on quality of life (QOL) that pharmacotherapy has in children and adolescents with CD. A systematic review was undertaken using pre-defined search criteria and four databases, including reference searches. We assessed these studies using the Strength of Recommendation Taxonomy, Grading of Recommendations Assessment, Development and Evaluation, and Review Manager Risk of Bias (RevMan®) tools. There were 12 randomised controlled trials that met our inclusion criteria. Studies included: antipsychotics, atomoxetine, lithium, clonidine, divalproex sodium and psychostimulants. The antipsychotics demonstrated efficacy, but were associated with adverse effects. Other agents demonstrated mixed responses, highlighting the lack of clinical significance and increased incidence of adverse effects. The management of related adverse effects was addressed to assist with clinical gaps. Overall, there is limited evidence regarding the role of pharmacotherapy in CD. More research is needed that takes into account the heterogeneity of CD and analysis of pharmacotherapy in pure CD.
AmanMGDe SmedtGDerivanA. (2002) Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence. Am J Psychiatry159: 1337–1346.
2.
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Arlington, VA: American Psychiatric Publishing.
3.
Australian Medicines Handbook (2015) Adelaide: Australian Medicines Handbook Pty Ltd.
4.
BarzmanDHFindlingRL (2008) Pharmacological treatment of pathologic aggression in children. Int Rev Psychiatry20: 151–157.
5.
BendzLMScatesAC (2010) Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder. Ann Pharmacother44: 185–191.
6.
BladerJCPliszkaSRJensenPS. (2010) Stimulant-responsive and stimulant-refractory aggressive behavior among children with ADHD. Pediatrics126: e796–806.
CamporealeAPorsdalVDe BruyckereK. (2015) Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: An integrated analysis of 15 clinical trials. J Psychopharmacol29: 3–14.
9.
ConnorDFBarkleyRADavisHT (2000) A pilot study of methylphenidate, clonidine, or the combination in ADHD comorbid with aggressive oppositional defiant or conduct disorder. Clin Pediatr39: 15–25.
10.
ConnorDFFletcherKESwansonJM (1999) A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry38: 1551–1559.
11.
ConnorDFFletcherKEWoodJS (2001) Neuroleptic-related dyskinesias in children and adolescents. J Clin Psychiatry62: 967–974.
12.
ConnorDFMclaughlinTJJeffers-TerryM (2008) Randomized controlled pilot study of quetiapine in the treatment of adolescent conduct disorder. J Child Adolesc Psychopharmacol18: 140–156.
DipiroJT (2011) Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill Medical.
15.
DonovanSJStewartJWNunesEV. (2000) Divalproex treatment for youth with explosive temper and mood lability: A double-blind, placebo-controlled crossover design. Am J Psychiatry157: 818–820.
16.
DulcanMK (2010) Dulcan’s Textbook of Child and Adolescent Psychiatry. Washington DC: American Psychiatric Publishing.
17.
EbellMHSiwekJWeissBD. (2004) Strength of Recommendation Taxonomy (SORT): A patient-centered approach to grading evidence in the medical literature. Am Fam Physician69: 548–556.
18.
EfronDJarmanFBarkerM (1997) Side effects of methylphenidate and dexamphetamine in children with attention deficit hyperactivity disorder: A double-blind, crossover trial. Pediatrics100: 662–666.
19.
ErskineHEFerrariAJNelsonP. (2013) Epidemiological modelling of attention-deficit/hyperactivity disorder and conduct disorder for the Global Burden of Disease Study 2010. J Child Psychol Psychiatry54: 1263–1274.
20.
ErskineHEFerrariAJPolanczykGV. (2014) The global burden of conduct disorder and attention-deficit/hyperactivity disorder in 2010. J Child Psychol Psychiatry55: 328–336.
21.
Food Drug Administration Center for Drugs Evaluation Research (2008) Prescribing Information Depakote ER (divalproex sodium) tablet, extended release. In: Safety Labeling Changed Approved by FDA Center for Drug Evaluation and Research. North Chicago: AbbVie Inc., pp.1–51.
22.
GarlandEJ (1998) Pharmacotherapy of adolescent attention deficit hyperactivity disorder: Challenges, choices and caveats. J Psychopharmacol12: 385–395.
23.
GormanDAGardnerDMMurphyAL. (2015) Canadian guidelines on pharmacotherapy for disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, or conduct disorder. Can J Psychiatry60: 62–76.
GrahamJBanaschewskiTBuitelaarJ. (2011) European guidelines on managing adverse effects of medication for ADHD. Eur Child Adolesc Psychiatry20: 17–37.
26.
Guevara-CamposJGonzalez-GuevaraLVacaro-BolivarI. (2009) Acute pancreatitis associated to the use of valproic acid. Arq Neuropsiquiatr67: 513–515.
27.
HazellPLStuartJE (2003) A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. J Am Acad Child Adolesc Psychiatry42: 886–894.
28.
HoJPanagiotopoulosCMccrindleB. (2011) Management recommendations for metabolic complications associated with second-generation antipsychotic use in children and youth. Paediatr Child Health16: 575–580.
29.
HollanderESooryaLWassermanS. (2006) Divalproex sodium vs. placebo in the treatment of repetitive behaviours in autism spectrum disorder. Int J Neuropsychopharmacol9: 209–213.
30.
HubandNFerriterMNathanR. (2010) Antiepileptics for aggression and associated impulsivity. Cochrane Database Syst Rev2: 1–123.
31.
HuntRDCapperLO’ConnellP (1990) Clonidine in child and adolescent psychiatry. J Child Adolesc Psychopharmacol1: 87–102.
32.
KaplanSHeiligensteinJWestS. (2004) Efficacy and safety of atomoxetine in childhood attention-deficit/hyperactivity disorder with comorbid oppositional defiant disorder. J Atten Disord8: 45–52.
33.
KemphJPDevaneCLLevinGM. (1993) Treatment of aggressive children with clonidine: Results of an open pilot study. J Am Acad Child Adolesc Psychiatry32: 577–581.
34.
KlahrAMBurtSA (2014) Practitioner review: Evaluation of the known behavioral heterogeneity in conduct disorder to improve its assessment and treatment. J Child Psychol Psychiatry55: 1300–1310.
35.
KleinDJCottinghamEMSorterM. (2006) A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. Am J Psychiatry163: 2072–2079.
36.
LoyJHMerrySNHetrickSE. (2012) Atypical antipsychotics for disruptive behaviour disorders in children and youths. Cochrane Database Syst Rev9: CD008559.
37.
MaloneRPDelaneyMALuebbertJF. (2000) A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry57: 649–654.
38.
McConvilleBJSorterMT (2004) Treatment challenges and safety considerations for antipsychotic use in children and adolescents with psychoses. J Clin Psychiatry65: S20–29.
39.
MillanMJ (2013) An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy. Neuropharmacology68: 2–82.
40.
MillerDD (2004) Atypical antipsychotics: Sleep, sedation and efficacy. Prim Care Companion J Clin Psychiatry6: 3–7.
41.
MoherDLiberatiATetzlaffJ. (2009) Preferred reporting items for systematic reviews and meta-analyses: The Prisma statement. J Clin Epidemiol62: 1006–1012.
42.
National Institute for Health and Care Excellence (NICE) (2013) Conduct Disorders and Antisocial Behaviour in Children and Young People: Recognition, Intervention and Management. Leicester: The British Psychological Society.
43.
NelsonWMFinchAJHartKJ (2006) Conduct Disorders: A Practitioner’s Guide to Comparative Treatments. New York: Ig Publishing, Springer Publishing Company.
44.
NewcornJHSpencerTJBiedermanJ. (2005) Atomoxetine treatment in children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder. J Am Acad Child Adolesc Psychiatry44: 240–248.
45.
PadhyRSaxenaKRemsingL. (2011) Symptomatic response to divalproex in subtypes of conduct disorder. Child Psychiatry Hum Dev42: 584–593.
46.
PappadopulosEWoolstonSChaitA. (2006) Pharmacotherapy of aggression in children and adolescents: Efficacy and effect size. J Can Acad Child Adolesc Psychiatry15: 27–39.
47.
PattersonGR (2002) The Early Development of Coercive Family Process. Washington DC: American Psychological Association.
48.
PillingSGouldNWhittingtonC. (2013) Recognition, intervention and management of antisocial behaviour and conduct disorders in children and young people: Summary of NICE-SCIE guidance. Brit Med J346: f1298.
49.
PringsheimTDojaABelangerS. (2011) Treatment recommendations for extrapyramidal side effects associated with second-generation antipsychotic use in children and youth. Paediatr Child Health16: 590–598.
50.
PringsheimTHirschLGardnerD. (2015) The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder and conduct disorder: A systematic review and meta-analysis. Part 1: Psychostimulants, alpha-2 agonists, and atomoxetine. Can J Psychiatry60: 42–51.
51.
PringsheimTHirschLGardnerD. (2015) The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: A systematic review and meta-analysis. Part 2: Antipsychotics and traditional mood stabilizers. Can J Psychiatry60: 52–61.
52.
Review Manager (RevMan) [Computer program]. Version 5.3 (2014) Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration.
53.
SavillNCBuitelaarJKAnandE. (2015) The efficacy of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: A comprehensive review of over a decade of clinical research. CNS Drugs29: 131–151.
54.
SawyerMGArneyFMBaghurstPA. (2000) The Mental Health of Young People in Australia. Mental Health and Special Programs. Canberra: Commonwealth Department of Health and Aged Care.
55.
ScahillLFarkasLHamrinV (2001) Lithium in children and adolescents. J Child Adolesc Psychiatr Nurs14: 89–93.
56.
SchneiderCTaylorDZalsmanG. (2014) Antipsychotics use in children and adolescents: An on-going challenge in clinical practice. J Psychopharmacol28: 615–623.
57.
SchwartzSCorrellCU (2014) Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: Results from a comprehensive meta-analysis and meta-regression. J Am Acad Child Adolesc Psychiatry53: 174–187.
58.
SinzigJDopfnerMLehmkuhlG. (2007) Long-acting methylphenidate has an effect on aggressive behavior in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol17: 421–432.
59.
SpencerTJBiedermanJHardingM. (1996) Growth deficits in ADHD children revisited: Evidence for disorder-associated growth delays?J Am Acad Child Adolesc Psychiatry35: 1460–1469.
60.
SteinerHPetersenMLSaxenaK. (2003) Divalproex sodium for the treatment of conduct disorder: A randomized controlled clinical trial. J Clin Psychiatry64: 1183–1191.
61.
SteinerHRemsingLWork Group on Quality. (2007) Practice parameter for the assessment and treatment of children and adolescents with oppositional defiant disorder. J Am Acad Child Adolesc Psychiatry46: 126–141.
62.
SteinerHSaxenaKSCarrionV. (2007) Divalproex sodium for the treatment of PTSD and conduct disordered youth: A pilot randomized controlled clinical trial. Child Psychiatry Hum Dev38: 183–193.
63.
SteinerHSaxenaKChangK (2003) Psychopharmacologic strategies for the treatment of aggression in juveniles. CNS Spectr8: 298–308.
64.
StocksJDTanejaBKBaroldiP. (2012) A Phase 2a randomized, parallel group, dose-ranging study of molindone in children with attention-deficit/hyperactivity disorder and persistent, serious conduct problems. J Child Adolesc Psychopharmacol22: 102–111.
65.
TurgayA (2004) Aggression and disruptive behavior disorders in children and adolescents. Expert Rev Neurother4: 623–632.
66.
Van’t HoffWOffringaMStar Child Health (2015) Star Child Health: Developing evidence-based guidance for the design, conduct and reporting of paediatric trials. Arch Dis Child100: 189–192.
67.
WehmeierPMSchachtADittmannRW. (2011) Effect of atomoxetine on quality of life and family burden: Results from a randomized, placebo-controlled, double-blind study in children and adolescents with ADHD and comorbid oppositional defiant or conduct disorder. Qual Life Res20: 691–702.
68.
WetmoreDZGarnerCC (2010) Emerging pharmacotherapies for neurodevelopmental disorders. J Dev Behav Pediatr31: 564–581.
69.
World Health Organisation (WHO) (1991) ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: WHO.
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