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Pharmacological Treatment of Child and Adolescent Disruptive Behaviour Disorders: Between the Scylla and Charybdis, What Do the Data Say?

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Pharmacological Treatment of Child and Adolescent Disruptive Behaviour Disorders: Between the Scylla and Charybdis, What Do the Data Say?

www.TheCJP.ca The Canadian Journal of Psychiatry, Vol 60, No 2, February 2015 W 39
CanJPsychiatry 2015;60(2):39–41
In this edition of The Canadian Journal of Psychiatry, comprising a 2-part Systematic
Review by Dr Tamara Pringsheim et al1,2 and a Special Article by Dr Daniel A
Gorman et al,3 we discuss pharmacological treatments for a common presentation in
child and youth mental health—DBDs, such as ADHD, ODD, and CD, or ADHD with
co-occurring ODD or CD. Regarding prevalence rates, a 2001 World Health
Organization report4 indicated the 6-month prevalence rate for any mental health
disorder in children and youth, up to age 17 years, to be 20.9%, with DBDs at 10.3%,
second only to anxiety disorders at 13%.
In Canada, in 2011,5,6 data were published on the pharmacoepidemiology of SGAs as
well as a systematic review of RCTs in children and adolescents, evaluating the metabolic
and neurological complications of SGAs,6 with the authors painting a disconcerting
picture. They reported an increase of 114% in prescribing SGAs, in contrast to increases,
in the same time period, of 36% and 44% in prescribing psychostimulants and selective
serotonin reuptake inhibitors, respectively. The most common reasons an SGA was
prescribed was for a primary diagnosis of ADHD (17%), mood disorder (16%), CD
(14%), and psychotic disorder (13%). The number of antipsychotic recommendations
for treatment in ADHD had more than tripled in those 5 years studied.
In Canadian schools,7 the most common neuropsychiatric disorder in children is ADHD
at about 4.1%, with up to 6% of children with ODD, and up to 2% with CD. It is not
uncommon that ADHD co-occurs with one of the latter disorders. In the rst paper in
this series, Pringsheim et al1 looked extensively at the pharmacological management
of oppositional behaviour, conduct problems, and aggression in children and
adolescents with DBDs using psychostimulants, alpha-2 agonists, and atomoxetine.
The authors searched the Cochrane Central Register of Controlled Trials, MEDLINE,
and PsycInfo and found 2 systematic reviews, 20 RCTs, with the overall quality of
evidence for each medication rated using the GRADE approach. They concluded that
psychostimulants, alpha-2 agonists, and atomoxetine can be benecial for disruptive
and aggressive behaviours, in addition to treating core ADHD symptoms; however,
the psychostimulants generally provided the most benet. The use of guanfacine and
open
access
Pharmacological Treatment of Child and Adolescent Disruptive
Behaviour Disorders: Between the Scylla and Charybdis,
What Do the Data Say?
Thomas C R Wilkes, FRCPC, FAPA1; Mary Kay Nixon, MD, FRCPC2
1 President, Canadian Academy of Child and Adolescent Psychiatry, Ottawa, Ontario; Associate Professor, University of Calgary, Calgary, Alberta; Division
Head, Child and Adolescent Mental Health and Addictions, Calgary, Alberta; Outpatient Section Chief, Child and Adolescent Psychiatry, Calgary, Alberta;
Consulting Psychiatrist, Young Adult Outpatient Services, Calgary, Alberta; Alberta Health Services and University of Calgary, Calgary, Alberta.
Correspondence: Foothills Hospital, Department of Psychiatry, Calgary, AB T2N 2T9; chris.wilkes@albertahealthservices.ca.
2 Chair of the Professional Standards Committee, Canadian Academy of Child and Adolescent Psychiatry, Ottawa, Ontario; Child and Adolescent Psychiatrist,
Early Psychosis Intervention Service, Queen Alexandra Centre for Children’s Health, Island Health, Victoria, British Columbia; Clinical Associate Professor,
Department of Psychiatry, University of British Columbia, Vancouver, British Columbia; Afliate Associate Professor, Division of Medical Sciences, University
of Victoria, Victoria, British Columbia.
The Canadian Journal of Psychiatry
Volume 60, Number 2 February 2015
Guest Editorial
Key Words: biopsychosocial,
metabolic, pharmacological,
pharmacoepidemiology,
neuropsychiatry, antipsychotics,
stimulants, disruptive
behaviour disorder, attention-
decit hyperactivity disorder,
oppositional deant disorder,
conduct disorder
Received July 2014 and
accepted August 2014.
www.LaRCP.ca
40 W La Revue canadienne de psychiatrie, vol 60, no 2, février 2015
Guest Editorial
Abbreviations
ADHD attention-decit hyperactivity disorder
CD conduct disorder
DBD disruptive behaviour disorder
GRADE Grading of Recommendations, Assessment,
Development and Evaluation
NOS not otherwise specied
ODD oppositional deant disorder
RCT randomized controlled trial
SGA second-generation antipsychotic
atomoxetine for oppositional behaviour can be helpful,
but the effect size is small to moderate, while the effect of
clonidine on oppositional behaviour and conduct problems
may not be clinically signicant. Adverse effects related
to psychostimulants in the RCTs were generally mild,
and infrequently led to discontinuation; they included
some appetite suppression and sleep difculties. The most
common adverse events related to alpha-2 agonists were
sedation and headache with decreased blood pressure.
Discontinuation with atomoxetine was uncommon, with
gastrointestinal symptoms, loss of appetite, and fatigue
most commonly reported as adverse events.
In the second paper in this series, using similar methods,
Pringsheim et al2 assessed the pharmacological
management of oppositional behaviour, conduct problems,
and aggression in children and adolescents with DBDs
using antipsychotics and traditional mood stabilizers. They
included 11 RCTs of antipsychotics and 7 RCTs of lithium
and anticonvulsants. They indicated moderate-quality
evidence that risperidone has a moderate-to-large effect in
conduct problems and aggression in youth with subaverage
IQ and ODD, CD or DBD-NOS, 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 or without ADHD.
The evidence was low or very low quality for the use of
haloperidol, thioridazine, quetiapine, valproic acid, and
lithium in aggressive youth with ODD or CD. Very-low-
quality evidence exists that carbamazepine is no different
from placebo for the management of aggression in youth
with CD. Overall, there is a limited number of studies of
antipsychotics and mood stabilizers for the management
of aggression in youth with ADHD, ODD, and CD, but, if
needed, it is conditionally recommended to try risperidone
or valproic acid.
Consequently, it is obviously very important for the
practising child and adolescent psychiatrist in Canada
to be aware of the best evidence-based guidelines on
pharmacotherapy for severe disruptive and aggressive
behaviour in children and adolescents, 6 to 18, with ADHD,
ODD, or CD, after the psychosocial interventions have been
applied and found to be insufcient as a sole treatment.
Gorman et al3 worked as a multi-disciplinary consensus
group across Canada, consisting of 12 members, with
expertise in Child and Adolescent Psychiatry, Pediatrics,
Neurology, Pharmacology, and Knowledge Synthesis, and
in guideline development. They used a GRADE approach
for rating evidence quality and recommendations for
treating disruptive and aggressive children and adolescents
with the above diagnosis of ADHD, ODD, or CD; the
consensus procedures resulted in 1 of 4 recommendations;
strong in favour, conditional in favour, conditional against,
and strong against.
Subsequently, the results of these 3 papers on children
and adolescents with disruptive or aggressive behaviour
associated with ADHD strongly recommended
psychostimulants, while alpha-2 agonists and atomoxetine
received a conditional recommendation only. Where these
youth do poorly with ADHD medications, the adjunct
medication recommended by the evidence was risperidone,
but, given its major side effect burden, it was given
conditional recommendation only. The study did not nd
sufcient evidence to recommend the use of quetiapine,
haloperidol, lithium, or carbamazepine.
It is important, as the authors do, to remind the clinician
that rst-line treatment for children and adolescents with
severe oppositional behaviour, conduct problems, and
aggression should be psychosocial interventions,8 which
are supported by substantial evidence and have low risks for
adverse effects. This is even more critical when we consider
the causal role childhood adversity plays with many
childhood mental health problems and in the comorbidity
of the traumatic spectrum disorders with our patients with
ADHD, ODD, and CD.9 Advocacy for resources and use of
evidence-based psychosocial interventions for our patients
is essential. When these interventions are insufcient, trials
of judicious and monitored pharmacotherapy are warranted.
These recommendations for the treatment of children
and adolescents with ADHD and functionally disabling
behavioural problems that Gorman et al3 have presented
in their paper place a strong emphasis on informed
collaboration with patients and their families.
It is recognized that as busy practitioners, and with the
demands on specialist services for child and youth mental
health, evaluating and treating youth requires navigation
of the scientic literature and considering this in the
individual context for the patient and their caregivers. The
benets of early intervention for serious mental health
problems must always be weighed with the risk of short-
and (or) long-term adverse events. Careful assessment and
reassessment of diagnoses, and treatment management and
monitoring, in children and youth are required, recognizing
their developing central nervous system, with the standard
biopsychosocial assessment as a means to conceptualize
the diagnostic and treatment framework. The goal of
any intervention is to provide healing or, at minimum,
to alleviate suffering to promote, as much as possible,
normal healthy development in their physical, intellectual,
emotional, and social development, without resulting in
www.TheCJP.ca The Canadian Journal of Psychiatry, Vol 60, No 2, February 2015 W 41
Pharmacological Treatment of Child and Adolescent Disruptive Behaviour Disorders: Between the Scylla and Charybdis, What Do the Data Say?
any iatrogenic complications.10 The authors have provided
a review and guide for the pharmacological treatment of
oppositional behaviour, conduct problems, and aggression
in children and adolescents with ADHD, ODD, and CD,
which the Canadian Academy of Child and Adolescent
Psychiatry supports. The promotion of a careful and
logical approach to treatment of this group of patients, as
summarized in their results and implications for practice,
will, it is hoped, minimize some of the potential long-
term health risks of these medicines. The authors have
highlighted the potential problems with antipsychotics
and mood stabilizers, but they have also emphasized the
clinical effectiveness of the standard ADHD treatment,
psychostimulants, as a rst-line choice for pharmacologic
treatment of these children and adolescents with ADHD
and DBDs, with other medications as a conditional second
step when indicated.
Editor’s Note
The opinions expressed in this paper are those of the authors
and do not necessarily reect the opinions of either The
Canadian Journal of Psychiatry (The CJP) or the Canadian
Psychiatric Association (CPA). This paper is not related
to work done by the CPA’s Committee on Professional
Standards and Practice or its Subcommittee on Clinical
Practice Guidelines, and its publication in The CJP should
not be construed as an endorsement of the content.
Acknowledgements
Dr Wilkes has no funding or support to disclose.
References
1. Pringsheim T, Hirsch L, Gardner DM, et al. The pharmacological
management of oppositional behaviour, conduct problems,
and aggression in children and adolescents with attention-
decit hyperactivity disorder, oppositional deant disorder, and
conduct disorder: a systematic review and meta-analysis. Part
1: psychostimulants, alpha-2 agonists, and atomoxetine. Can J
Psychiatry. 2015;60(2):42–51.
2. Pringsheim T, Hirsch L, Gardner DM, et al. The pharmacological
management of oppositional behaviour, conduct problems, and
aggression in children and adolescents with attention-decit
hyperactivity disorder, oppositional deant disorder, and conduct
disorder: a systematic review and meta-analysis. Part 2: antipsychotics
and traditional mood stabilizers. Can J Psychiatry. 2015;60(2):52–61.
3. Gorman DA, Gardner DM, Murphy AL, et al. Canadian guidelines
on pharmacotherapy for disruptive and aggressive behaviour in
children and adolescents with attention-decit hyperactivity disorder,
oppositional deant disorder, or conduct disorder. Can J Psychiatry.
2015;60(2):62–76.
4. World Health Organization (WHO). Mental health: new
understanding, new hope [report]. Geneva (CH): WHO; 2001.
5. Pringsheim T, Lam D, Patten SB. The pharmacoepidemiology of
antipsychotics in Canadian children and adolescents: 2005 to 2009.
J Child Adolesc Psychopharmacol. 2011;21(6):537–543.
6. Pringsheim T, Lam D, Ching H, et al. Metabolic and neurological
complications of second generation antipsychotic use in children:
a systematic review and meta-analysis of randomized controlled trials.
Drug Saf. 2011;34(8):651–668.
7. Brault MC, Lacourse É. Prevalence of prescribed attention-decit
hyperactivity disorder medications and diagnosis among Canadian
preschoolers and school-age children: 1994–2007. Can J Psychiatry.
2012;57(2):93–101.
8. Scotto Rosato N, Correll CU, Pappadopulos E, et al. Treatment of
maladaptive aggression in youth: CERT guidelines II. Treatments and
ongoing management. Pediatrics. 2012;129(6):e1577–e1586.
9. Read J, Fosse R, Moskowitz A, et al. The traumagenic
neurodevelopmental model of psychosis revisited. Neuropsychiatry.
2014;4(1):65–79.
10. Neuhut R, Lindenmayer JP, Silva R. Neuroleptic malignant syndrome
in children and adolescents on atypical antipsychotic medication.
J Child Adolesc Psychopharmacol. 2009;19(4):415–422.
by Virginia St-Denis
Increasing media attention
to research published in The
Canadian Journal of Psychia-
try (The CJP) illustrates the
growing social relevance of the
60-year-old medical journal.
The CJP made front-page
news four times in 2014, ac-
cording to ProQuest’s database
of major daily newspapers in
Canada.
Headlines included Over-
medication in Ontario’s group
and foster homes has reached
catastrophic levels, experts say
in the Toronto Star; History of
This underscores the relevance of
the research published in The CJP
to Canadians and the diffusion of
knowledge from our papers through
Canadian society.
Dr. Scott B. Patten, Editor-in-Chief
news TIMES
The CJP Is Front Page News!
mental illness, PTSD linked in
new study in The Ottawa Citi-
zen; More youths using antide-
pressants in Regina’s Leader
Post; and Number of medicat-
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In total, 59 national and
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and An Observational Study
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nal of Psychiatry.
... 9,20 However, pharmacological interventions remain the most widely administered for youths with DBD: specifically, secondand third-line treatments, such as second-generation antipsychotics (SGAs), 21 are frequently used, and in a Canadian epidemiological study, 14% of all prescribed SGAs were for CD. 22 Weisz et al. 19,23,24 defined psychosocial treatments as any psychological treatment aimed at alleviating psychological distress, reducing dysfunctional behaviors, and enhancing adaptive behaviors through psychotherapy, counseling, and training. Current review and meta-analytic evidence recognizes parental, familial, and integrated psychosocial approaches as effective for inpatient and outpatient adolescents, in both individual and group settings. ...
... Moreover, to the best of our knowledge, previous meta-analyses focused on very young children, 28 and even for those with broader eligibility criteria, 25,29 the proportion of RCTs analyzed that included adolescents was too small to provide robust evidence. The phenotypic differences in DBDs between different age groups, 11 and the increasing proportions of adolescents receiving unsupported treatments for these difficulties, 22 underscore the urgency of quantitatively synthesizing the results of RCTs on the treatment for disruptive behavior problems in adolescence. ...
Article
Objective Disruptive behavior disorders (DBDs) represent a common motive for referral among youths. This meta-analysis aimed at estimating the efficacy of psychosocial interventions for DBD adolescents. Method A PRISMA-compliant systematic review of MEDLINE/PubMED/PsycINFO/Cochrane Central Register of Controlled Trials was conducted. Eligible studies were randomized controlled trials (RCTs) administering psychosocial interventions to DBD adolescents, published before April 5, 2020. From the initial set of 6,006 records, 17 RCTs involving 18 cohorts (16 publications) were subjected to a random-effect meta-analysis (involving sensitivity, subgroup, and meta-regression analyses). Primary and secondary outcomes were externalizing symptoms at RCT endpoint (i.e., standardized mean difference [SMD]) and acceptability (drop-out odds ratio [OR]), respectively. Risk of bias was assessed using the Risk of Bias 2 tool. Results Seventeen RCTs, involving 1,954 adolescents, were included. Mean age was 14.09 (SD 1.33) years; 61% were male. Mean RCT duration was 12 weeks, with a mean follow-up of 8 (SD 3.98) months. Concern over risk of bias emerged in 12 studies, with high concern in 6. Psychosocial interventions had a large effect size at RCT endpoint (SMD=0.98, 95%CI -0.55 to -1.38, k=18) and were acceptable (drop-out OR=1.29, 95%CI 0.62–2.70, k=13). However, this beneficial effect did not persist at follow-up (SMD=-0.36, 95%CI 0.06 to -0.78, k=10). Family format was the most effective variable. No other clinically significant moderator was found. Conclusion Psychosocial interventions involving the families of DBD adolescents are effective and acceptable in the short term. Future studies should focus on strategies to achieve their long-term efficacy.
... risperidone) treatments showed significant effects on comorbid aggression in ADHD patients. Nevertheless, pharmacotherapy of aggression is limited by quality, the existing literature and serious adverse effects (Pappadopulos et al., 2006), therefore first-line treatment should be psychosocial interventions, which are supported by substantial evidence and have low risks for adverse effects (Wilkes & Nixon, 2015). ...
Thesis
The present thesis focused on specificity and long-term effects of slow-cortical potential neurofeedback (SCP-NF) treatment for children with ADHD in a large multicenter randomized controlled trial, on its relation to aggressive behaviors as a common comorbidity of ADHD, and on neuroimaging and psychophysiological subtypes of aggression. We assessed clinical efficacy on ADHD and comorbid aggression in comparison to a semi-active control group which controlled for unspecific effects. The role of self-regulation and learning of SCPs was systematically evaluated. Additionally, we investigated amygdala-specific activity in aggression subtypes in a large multicenter cohort, which might provide a possible putative NF target. The first two studies assessed 150 children aged 7–9 years diagnosed with ADHD which were randomized to 25 sessions of feedback of SCPs (NF) or feedback of coordination of the supraspinatus muscles (EMG). The primary outcome was the change in ADHD symptoms rated by parents four weeks and six-month after treatment end. Slow-cortical potential neurofeedback showed significant superiority over the semi-active control condition with medium effect sizes four weeks after treatment. This superiority of SCP-NF over the semi-active control group became non-significant 6 months after treatment end. However, taking together all assessments, SCP-NF showed a stable improvement with large effect sizes following treatment and EMG-BF showed worsening of symptoms one month after treatment, with subsequent remission at follow-up, leading to non-significant group differences six months after treatment end. Assessment of self-regulation showed significant ability to self-regulate slow-cortical potential when direct feedback is given and improvement of self-regulation skills indicate specificity of SCP-NF for selected subscales after training, but not at follow-up. In sum, these findings suggest shared specific and unspecific effects contributing to this clinical outcome. The third study aimed to disentangle aggression-related subtypes at a neural level. In total 177 participants (n=108 cases with aggression-related disorders and n= 69 typically developing peers), aged 8-18 years were assessed across nine sites in Europa during a well-established emotional face-matching fMRI task. Additionally, simultaneous skin conductance recordings were acquired in a subsample (n=64). Children and adolescents with aggression-related problems showed higher amygdala activity in response to negative faces compared to typically developing peers. Further, we showed distinct amygdala activity for subtypes of aggression. Callous-unemotional traits showed to moderate both central (amygdala) and peripheral (SC) responses. These findings increase insights which could be used for personalized diagnostics and treatments.
... The utilization of psychotropic medication in youth may be influenced by a number of complex contextual factors: recognition of serious mental health disorders, higher rates of emergency department visits and hospitalization, or an overemphasis on pharmacotherapy as a first-line treatment. 22 Choosing Wisely Canada recommendations highlight the need for clinicians to be aware of the evidence relevant to prescribing and, where appropriate, consider psychosocial modalities and evidence-based therapies such as cognitive behavioural therapy and family interventions as a first-line approach. ...
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Available evidence indicates that the use of antipsychotics, especially second-generation antipsychotics (SGAs), for children with mental health disorders has increased dramatically. Given the demonstrated metabolic and neurological adverse effects seen in adult patients on these medications, detailed evaluation of the risk for these adverse effects in children is appropriate. The aim of the study was to assess the evidence for specific metabolic and neurological adverse effects associated with the use of SGAs in children. MEDLINE (1996-May 2010) and EMBASE (1996-May 2010) databases were searched using highly sensitive search strategies for clinical trials in a paediatric population (children up to age 18 years). We included any double-blind, randomized controlled trial (RCT) of SGA medications conducted specifically in a paediatric population for the treatment of a mental health disorder. This included the medications risperidone, olanzapine, quetiapine, aripiprazole, clozapine, ziprasidone and paliperidone. The primary outcomes assessed for this review were metabolic and neurological adverse effects, as measured using physical examination manoeuvres, rating scales or laboratory tests. A total of 35 RCTs were included in the analysis, but not all studies had data that could be used in the meta-analysis. Abstracts retrieved from the searches were reviewed independently by two different reviewers for potential relevant articles. Full-text articles were then read in detail independently by two different reviewers to see if inclusion criteria were fulfilled. Data were extracted independently by two review authors from included studies and entered onto pre-designed summary forms. Clinical trials were evaluated for methodological quality using quality criteria developed by the US Preventive Services Task Force. Based on the fulfilment of quality criteria, studies were rated as good, fair or poor. Meta-analysis was performed on the data for synthesis, and was carried out for commonly reported outcomes for each medication individually, in comparison with placebo or another drug. Odds ratios (ORs) with 95% confidence intervals for binary outcomes were used. For continuous outcomes, mean differences were used to analyze the data. Meta-analysis revealed that mean weight gain compared with placebo was highest for olanzapine at 3.47 kg (95% CI 2.94, 3.99) followed by risperidone at 1.72 kg (95% CI 1.17, 2.26), quetiapine at 1.41 kg (95% CI 1.10, 1.81) and aripiprazole at 0.85 kg (95% CI 0.58, 1.13). Olanzapine and clozapine treatment were associated with the highest rate of metabolic laboratory abnormalities in cholesterol and triglycerides. Prolactin elevation occurred with risperidone and olanzapine therapy. Higher odds of extrapyramidal symptoms compared with placebo were seen in children treated with risperidone (OR 3.55; 95% CI 2.04, 5.48) and aripiprazole (OR 3.70; 95% CI 2.37, 5.77). Elevated rates of extrapyramidal symptoms were also experienced with olanzapine use. There is good evidence to support the existence of both metabolic and neurological adverse effects in children treated with these medications. Proper attention and vigilance to potential metabolic and neurological adverse effects is necessary, and should be considered part of the standard of care.
Article
Background: Available evidence indicates that the use of antipsychotics, especially second-generation antipsychotics (SGAs), for children with mental health disorders has increased dramatically. Given the demonstrated metabolic and neurological adverse effects seen in adult patients on these medications, detailed evaluation of the risk for these adverse effects in children is appropriate. Objective: The aim of the study was to assess the evidence for specific metabolic and neurological adverse effects associated with the use of SGAs in children. Data Sources: MEDLINE (1996 May 2010) and EMBASE (1996 May 2010) databases were searched using highly sensitive search strategies for clinical trials in a paediatric population (children up to age 18 years). Study Selection: We included any double-blind, randomized controlled trial (RCT) of SGA medications conducted specifically in a paediatric population for the treatment of a mental health disorder. This included the medications risperidone, olanzapine, quetiapine, aripiprazole, clozapine, ziprasidone and paliperidone. The primary outcomes assessed for this review were metabolic and neurological adverse effects, as measured using physical examination manoeuvres, rating scales or laboratory tests. A total of 35 RCTs were included in the analysis, but not all studies had data that could be used in the meta-analysis. Data Extraction: Abstracts retrieved from the searches were reviewed independently by two different reviewers for potential relevant articles. Full-text articles were then read in detail independently by two different reviewers to see if inclusion criteria were fulfilled. Data were extracted independently by two review authors from included studies and entered onto pre-designed summary forms. Clinical trials were evaluated for methodological quality using quality criteria developed by the US Preventive Services Task Force. Based on the fulfilment of quality criteria, studies were rated as good, fair or poor. Data Synthesis: Meta-analysis was performed on the data for synthesis, and was carried out for commonly reported outcomes for each medication individually, in comparison with placebo or another drug. Odds ratios (ORs) with 95% confidence intervals for binary outcomes were used. For continuous outcomes, mean differences were used to analyze the data. Meta-analysis revealed that mean weight gain compared with placebo was highest for olanzapine at 3.47 kg (95% CI 2.94, 3.99) followed by risperidone at 1.72 kg (95% CI 1.17, 2.26), quetiapine at 1.41 kg (95% CI 1.10, 1.81) and aripiprazole at 0.85 kg (95% Cl 0.58, 1.13). Olanzapine and clozapine treatment were associated with the highest rate of metabolic laboratory abnormalities in cholesterol and triglycerides. Prolactin elevation occurred with risperidone and olanzapine therapy. Higher odds of extrapyramidal symptoms compared with placebo were seen in children treated with risperidone (OR 3.55; 95% CI 2.04, 5.48) and aripiprazole (OR 3.70; 95% Cl 2.37, 5.77). Elevated rates of extrapyramidal symptoms were also experienced with olanzapine use. Conclusions: There is good evidence to support the existence of both metabolic and neurological adverse effects in children treated with these medications. Proper attention and vigilance to potential metabolic and neurological adverse effects is necessary, and should be considered part of the standard of care.
Article
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. 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 (↓↓). 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. 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.
Article
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. 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. 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. 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.
Article
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. 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. 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. With the exception of risperidone, the evidence to support the use of antipsychotics and mood stabilizers is of low quality.
Article
Neuroleptic malignant syndrome (NMS) is a severe iatrogenic complication of treatment with antipsychotic medication. The purpose of this report is to examine the published cases of NMS in children and adolescents receiving atypical antipsychotic medication and review early warning symptoms, risk factors, and treatment in this population. An extensive review of the literature from 1990 to 2008 was conducted via computerized searches (PubMed and Ovid) to identify case reports. Descriptive statistics were employed to describe our findings. There were 23 episodes in 20 subjects, with ages ranging from 11 to 18 years. Increased creatine phosphokinase (CPK) was the most common finding (100%), followed by fever (78%), tachycardia (74%), rigidity (70%), and altered mental status (61%). The number of NMS symptoms ranged from 1 to 11 (mean 4.7 +/- 2.4) and positive laboratory findings ranged from 1 to 4 (2.2 +/- 1). The duration of NMS (mean 6.1 +/- 6.4 days) was one third of the duration associated with typical antipsychotics. Patients treated with bromocriptine had a shorter duration of illness, whereas the same was not true for those receiving dantrolene. In all cases, the NMS symptoms eventually resolved and there were no reported deaths or permanent sequelae. NMS is a serious condition. Symptom presentation related to atypical agents differs from that seen with older antipsychotic medications.