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
Objective: Children with attention-deficit hyperactivity disorder (ADHD) may have oppositional behaviour, conduct problems, and aggression. These symptoms vary in severity, and may be related to a comorbid diagnosis of oppositional defiant disorder (ODD) or conduct disorder (CD). Critical evaluation of the efficacy of ADHD medications may guide the clinician regarding the usefulness of medications for these symptoms.
Method: We performed a systematic review and meta-analysis of psychostimulants, alpha-2 agonists, and atomoxetine for oppositional behaviour, conduct problems, and aggression in youth with ADHD, ODD, and CD. The quality of evidence for medications was rated using the Grading of Recommendations Assessment, Development and Evaluation approach.
Results: Two systematic reviews and 20 randomized controlled trials were included.There is high-quality evidence that psychostimulants have a moderate-to-large effect on oppositional behaviour, conduct problems, and aggression in youth with ADHD, with and without ODD or CD. There is very-low-quality evidence that clonidine has a small effect on oppositional behaviour and conduct problems in youth with ADHD, with and without ODD or CD. There is moderate-quality evidence that guanfacine has a small-to-moderate effect on oppositional behaviour in youth with ADHD, with and without ODD. There is high-quality evidence that atomoxetine has a small effect on oppositional behaviour in youth with ADHD, with and without ODD or CD.
Conclusions: Evidence indicates that psychostimulants, alpha-2 agonists, and atomoxetine can be beneficial for disruptive and aggressive behaviours in addition to core ADHD symptoms; however, psychostimulants generally provide the most benefit.
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
Objective: Attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) are among the most common psychiatric diagnoses in childhood. Aggression and conduct problems are a major source of disability and a risk factor for poor long-term outcomes.
Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) of antipsychotics, lithium, and anticonvulsants for aggression and conduct problems in youth with ADHD, ODD, and CD. Each medication was given an overall quality of evidence rating based on the Grading of Recommendations Assessment, Development and Evaluation approach.
Results: Eleven RCTs of antipsychotics and 7 RCTs of lithium and anticonvulsants were included. There is moderate-quality evidence that risperidone has a moderate-to-large effect on conduct problems and aggression in youth with subaverage IQ and ODD, CD,
or disruptive behaviour disorder not otherwise specified, with and without ADHD, and high-quality evidence that risperidone has a moderate effect on disruptive and aggressive behaviour in youth with average IQ and ODD or CD, with and without ADHD. Evidence supporting the use of haloperidol, thioridazine, quetiapine, and lithium in aggressive youth with CD is of low or very-low quality, and evidence supporting the use of divalproex in aggressive youth with ODD or CD is of low quality. There is very-low-quality evidence that carbamazepine is no different from placebo for the management of aggression in youth with CD.
Conclusion: With the exception of risperidone, the evidence to support the use of antipsychotics and mood stabilizers is of low quality.
Canadian Guidelines on Pharmacotherapy for Disruptive and Aggressive Behaviour in Children and Adolescents With Attention-Deficit Hyperactivity Disorder, Oppositional Defiant Disorder, or Conduct Disorder
Objective: To develop evidence-based guidelines on pharmacotherapy for severe disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), or conduct disorder (CD). The guidelines assume that psychosocial interventions have been pursued but did not achieve sufficient improvement.
Method: A multidisciplinary consensus group used the Grading of Recommendations Assessment, Development and Evaluation approach for rating evidence quality and for grading recommendations. We conducted a systematic review of medications studied in placebo-controlled trials for treating disruptive and aggressive behaviour in children and adolescents with ADHD, ODD, or CD. We followed consensus procedures to make 1 of 4 recommendations for each medication: strong, in favour (↑↑); conditional, in favour (↑?); conditional, against (↓?); and strong, against (↓↓).
Results: For children and adolescents with disruptive or aggressive behaviour associated with ADHD, psychostimulants received a strong recommendation in favour of use, while atomoxetine and alpha-2 agonists received a conditional recommendation in favour of use. If these patients do poorly with ADHD medications, the medication with the most evidence is risperidone. Risperidone also has the most evidence for treating disruptive or aggressive behaviour in the absence of ADHD. However, given risperidone’s major adverse effects, it received only a conditional recommendation in favour of use. We recommended against using quetiapine, haloperidol, lithium, or carbamazepine because of the poor quality of evidence and their major adverse effects.
Conclusion: When severe disruptive or aggressive behaviour occurs with ADHD, medications for ADHD should be used first. Other medications have major adverse effects and, with the exception of risperidone, very limited evidence to support their use.
Evidence-Based Recommendations for Monitoring Safety of Second Generation Antipsychotics in Children and Youth
Background: The use of antipsychotics, especially second generation antipsychotics (SGAs), for children with mental health disorders in Canada has increased dramatically over the past five years. These medications have the potential to cause major metabolic and neurological complications with chronic use.
Objective: Our objective was to synthesize the evidence for specific metabolic and neurological side effects associated with the use of SGAs in children and make evidence-based recommendations for the monitoring of these side effects.
Methods: We performed a systematic review of controlled clinical trials of SGAs in children. Recommendations for monitoring SGA safety were made according to a classification scheme based on the GRADE system. When there was inadequate evidence to make recommendations, recommendations were based on consensus and expert opinion. A multi-disciplinary consensus group reviewed all relevant evidence and came to consensus on recommendations.
Results: Evidence-based recommendations for monitoring SGA safety are provided in the guideline. The strength of recommendations for specific physical examination maneuvers and laboratory tests are provided for each SGA medication at specific time points.
Conclusion: Multiple randomized controlled trials (RCTs) have established the efficacy of many of the SGAs in pediatric mental health disorders. These benefits however do not come without risk; both metabolic and neurological side effects occur in children treated with these SGAs. The risk of weight gain, increased BMI and abnormal lipids appears greatest with olanzapine, followed by clozapine and quetiapine. The risk of neurological side effects of treatment appears greatest with risperidone, olanzapine and aripiprazole. Appropriate monitoring procedures for adverse effects will improve the quality of care of children treated with these medications.
Treatment of Maladaptive Aggression in Youth: CERT Guidelines I. Engagement, Assessment, and Management
Objective: To develop guidelines for management and treatment of maladaptive aggression in the areas of family engagement, assessment and diagnosis, and initial management, appropriate for use by primary care clinicians and mental health providers. Maladaptive aggression in youth is increasingly treated with psychotropic medications, particularly second-generation antipsychotic agents. Multiple treatment modalities are available, but guidance for clinicians’ assessment and treatment strategies has been inadequately developed. To address this need, the Center for Education and Research on Mental Health Therapeutics and the REACH Institute convened a steering group of national experts to develop evidence-based treatment recommendations for maladaptive aggression in youth.
Methods: Evidence was assembled and evaluated in a multistep process that included a systematic review of published literature; a survey of experts on recommended treatment practices; a consensus conference that brought together clinical experts along with researchers, policy makers, and family advocates; and subsequent review and discussion by the steering committee of successive drafts of the recommendations. The Center for Education and Research on Mental Health Therapeutics Treatment of Maladaptive Aggression in Youth (T-MAY) guidelines reflect a synthesis of the available evidence, based on this multistep process.
Results: The current article describes 9 recommendations for family engagement, assessment, and diagnosis as key prerequisites for treatment selection and initiation.
Conclusions: Recognizing the family and social context in which aggressive symptoms arise, and understanding the underlying psychiatric conditions that may be associated with aggression, are essential to treatment planning.
Treatment of Maladaptive Aggression in Youth: CERT Guidelines II. Treatments and Ongoing Management
Objective: To develop guidelines for management and treatment of maladaptive aggression in youth in the areas of psychosocial interventions, medication treatments, and side-effect management.
Methods: Evidence was assembled and evaluated in a multistep process, including systematic reviews of published literature; an expert survey of recommended practices; a consensus conference of researchers, policymakers, clinicians, and family advocates; and review by the steering committee of successive drafts of the recommendations. The Center for Education and Research on Mental Health Therapeutics Treatment of Maladaptive Aggression in Youth guidelines reflect a synthesis of the available evidence, based on this multistep process.
Results: This article describes the content, rationale, and evidence for 11 recommendations. Key treatment principles include considering psychosocial interventions, such as evidence-based parent and child skills training as the first line of treatment; targeting the underlying disorder first following evidence-based guidelines; considering individual psychosocial and medical factors, including cardiovascular risk in the selection of agents if medication treatment (ideally with the best evidence base) is initiated; avoiding the use of multiple psychotropic medications simultaneously; and careful monitoring of treatment response, by using structured rating scales, as well as close medical monitoring for side effects, including metabolic changes.
Conclusions: Treatment of children with maladaptive aggression is a “moving target” requiring ongoing assimilation of new evidence as it emerges. Based on the existing evidence, the Treatment of Maladaptive Aggression in Youth guidelines provide a framework for management of maladaptive aggression in youth, appropriate for use by primary care clinicians and mental health providers.