Contemporary diagnosis and treatment of conduct disorder in youth.

INTRODUCTION: Conduct disorder (CD) is characterized by repetitive and persistent antisocial behaviors, being among the most frequently reported reasons of referral in youth. CD is a highly heterogeneous disorder, with possible specifiers defined according to age at onset, Limited Prosocial Emotions (LPE) otherwise known as Callous-Unemotional (CU) traits, Emotional Dysregulation (ED), and patterns of comorbidity, each with its own specific developmental trajectories. AREAS COVERED: The authors review the evidence from published literature on the clinical presentations, diagnostic procedures, psychotherapeutic and psychoeducational approaches, and pharmacological interventions from RCT and naturalistic studies in youth. Evidence from studies including youths with LPE/CU traits, ED and aggression are also reviewed, as response moderators. EXPERT OPINION: Due to its clinical heterogeneity, relevant subtypes of CD should be carefully characterized to gain reliable information on prognosis and treatments. Thus, disentangling this broad category in subtypes is crucial as a first step in diagnosis. Psychosocial interventions are the first option, possibly improving LPE/CU traits and ED, especially if implemented early during development. Instead, limited information, based on low-quality studies, supports pharmacological options. Second-generation antipsychotics, mood stabilizers, and stimulants are first-line medications, according to different target symptoms, such as aggression and emotional reactivity. Developmental pathways including ADHD suggest a specific role of psychostimulants.

Probable Risperidone-Associated Acute Pancreatitis in a Child with ADHD.

Psychotropic-induced pancreatitis is rare and even rarer in pediatric population. Here, authors report on an interesting case of risperidone-induced pancreatitis in a child with ADHD comorbid with conduct disorder. Clinicians should be mindful of this remote, yet serious, side effect.

Pharmacotherapy of Disruptive Behaviors in Children with Intellectual Disabilities.

Disruptive behaviors are a class of predominantly externalizing behaviors that include physical aggression, property destruction, temper outbursts, verbal aggression, and some forms of self-injurious behaviors. Externalizing behaviors are also major components of disruptive, impulse-control and conduct disorders, disruptive mood dysregulation disorder, trauma-related and stressor-related disorders, intermittent explosive disorder, personality disorders, and other neuropsychiatric and neurodevelopmental disorders. Disruptive behaviors and associated disorders are among the most frequent reasons for child behavioral health referrals and are the most common reason for referrals among children with intellectual disabilities. The focus of this paper is on the adjunctive role of integrated psychopharmacological treatment in the management of children with disruptive behaviors and co-occurring intellectual disabilities. The decision-making process for adding pharmacotherapy to a comprehensive treatment plan incorporates not only a working knowledge of basic behavioral neurobiology of disruptive behaviors but also an understanding of the strengths and weaknesses of various pharmacotherapies. Importantly, there is little evidence to support the use of psychopharmacologic agents in managing difficult behaviors in children with intellectual disabilities, but with that said, risperidone has the strongest evidence base for its use.

Can pediatric bipolar disorder be successfully treated when comorbid with conduct disorder? A secondary analysis of clinical trials of risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

BACKGROUND: Pediatric bipolar disorder (BP) is frequently comorbid with conduct disorder (CD) and its presence adds to the morbidity of BP. While there are no known pharmacological treatments for CD, pediatric BP is responsive to treatment with medications initially indicated for the treatment of psychosis, several of which have Food and Drug Administration (FDA) approval for the treatment of pediatric mania. AIMS: The main aim of this secondary analysis was to examine whether pediatric BP comorbid with CD responds similarly to treatment with such selected medications. Considering the well-documented morbidity of CD, this finding could have important clinical and public health significance. METHODS: We conducted a secondary analysis of six prospective 8-week open-label trials of selected medications (risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) using identical methodology in youth with BP with and without comorbid CD. Results: Of 165 youths with BP, 54% (N = 89) met criteria for comorbid CD. The antimanic effects observed did not significantly differ between BP youths with and without comorbid CD, as measured either by a reduction in Young Mania Rating Scale (YMRS) ⩾ 30% or Clinical Global Impression (CGI)-Improvement ⩽ 2 (p = 0.23), or by the more stringent definition of a reduction in YMRS ⩾ 50% (p = 0.61). CONCLUSION: Pediatric BP can be effectively treated with the abovementioned medications in the context of comorbid CD. Based on previous research showing that remission of BP is associated with remission of CD, if confirmed, these findings raise the possibility that antimanic treatment of youth with BP comorbid with CD could have secondary benefits in mitigating the morbidity associated with CD. This is a pilot scale finding, the results of which are promising and should be confirmed by larger and long-term follow-up studies.

Sensitization-based risk for substance abuse in vulnerable individuals with ADHD: Review and re-examination of evidence.

Evidence of sensitization following stimulants administration in humans is just emerging, which prevents reaching more definitive conclusions in favor or against a purported protective role of stimulant treatments for ADHD for the development of substance use disorders. Existing evidence from both animal and human research suggest that stimulants produce neurophysiological changes in the brain reward system, some of which could be persistent. This could be relevant in choosing optimal treatments for young patients with ADHD who have additional clinical risk factors for substance abuse (e.g. conduct disorder (CD) and/or familial addictions). Here we stipulate that, while the majority of youth with ADHD greatly benefit from treatments with stimulants, there might be a subpopulation of individuals whose neurobiological profiles may confer risk for heightened vulnerability to the effects of stimulants on the responsiveness of the brain reward system. We propose that focused human research is needed to elucidate the unknown effects of prolonged stimulant exposure on the neurophysiology of the brain reward system in young patients with ADHD.

Comparison of thyroid-stimulating hormone levels in adolescents with schizophrenia, bipolar disorder, unipolar depression, conduct disorders, and hyperkinetic disorders.

ABSTRACT: The aim of this study was to retrospectively compare values of thyroid-stimulating hormone (TSH) in adolescent patients diagnosed with schizophrenia, bipolar disorder, unipolar depression (UNI-DEP), conduct disorders (CD), and hyperkinetic disorders.The research involved 1122 patients (718 women, 64%); aged 12 to 18 hospitalized in the Department of Adolescent Psychiatry, Medical University of Lodz. We analyzed TSH levels in the whole study population and compared it between the above-mentioned subgroups of diagnoses.Mean serum TSH concentration in the studied population (n = 1122) was 2.06 µIU/mL. The values of percentiles were as follows: 2.5th - 0.53 µIU/mL, 10th - 0.89 µIU/mL, 25th - 1.31 µIU/mL, 50th - 1.9 µIU/mL, 75th - 2.6 µIU/mL, 90th - 3.43 µIU/mL, 97.5th - 4.72 µIU/mL. TSH values were negatively correlated with patients' age (P = .00001). Patients with bipolar depression had higher TSH levels than patients with CD (P = .002). Also, when male and female groups were examined separately we found that female patients with UNI-DEP and bipolar disorder had higher TSH levels than female patients with CD (P = .001; P = .001).Our results confirm that there may be a higher prevalence of thyroid dysfunctions in bipolar and UNI-DEP subgroups among adolescents and that it is worthy to consider some kind of interventions regarding thyroid function in depressed individuals.

The Importance of Conduct Disorder in the Treatment of Violence in Schizophrenia: Efficacy of Clozapine Compared With Olanzapine and Haloperidol.

OBJECTIVE: Treatment of violence in schizophrenia remains a challenging problem, especially in patients with conduct disorder. Previous clinical studies did not select patients on the basis of violence and did not focus on conduct disorder. This study is a head-to-head comparison of clozapine, olanzapine, and haloperidol in the treatment of violent schizophrenia patients with and without conduct disorder. METHODS: Physically assaultive schizophrenia patients (N=99) were randomly assigned to receive clozapine, olanzapine, or haloperidol in a 12-week double-blind trial. They were characterized on the basis of the presence or absence of conduct disorder before age 15. Assaults were recorded; their frequency and severity were scored on the Modified Overt Aggression Scale. Psychiatric symptoms were evaluated through the Positive and Negative Syndrome Scale. RESULTS: Patients with a history of conduct disorder had more frequent and severe assaults than those without conduct disorder during the 12-week trial. Clozapine was superior to haloperidol and olanzapine in reducing assaults; olanzapine was superior to haloperidol. Clozapine's greater antiaggressive efficacy over haloperidol was substantially more pronounced in patients with conduct disorder than in patients without conduct disorder. In patients with conduct disorder, clozapine was four times more likely than haloperidol to result in lower violence; in patients without conduct disorder, it was three times more likely to do so. Olanzapine's superiority over haloperidol was also more pronounced in patients with conduct disorder. CONCLUSIONS: This study is the first to examine the effect of clozapine in violent schizophrenia patients with conduct disorder. When conduct disorder is present, clozapine is the optimal treatment.

Movement disorders and use of risperidone and methylphenidate: a review of case reports and an analysis of the WHO database in pharmacovigilance.

For patients with attention deficit hyperactivity disorder and comorbid conduct-dissocial disorder, a combination therapy of the psychostimulant methylphenidate and the antipsychotic risperidone may be prescribed. Case reports describe the occurrence of movement disorders under this combination therapy, but clinical trials had limited power to detect these events. This study aimed (1) to summarise published case reports and (2) to analyse pharmacovigilance data consisting of adverse drug event reports to elucidate these reactions. PubMed, Embase, and APA PsycInfo were used to retrieve case reports. For the pharmacovigilance data, aggregated information on individual case safety reports (ICSRs) within the database of suspected adverse drug events by the WHO were analysed. ICSRs were assessed for disproportionality in reporting. Thirteen published case reports (62% male) on movement disorders were identified, with ages between 5 and 15 years. Seven reports (54%) described incidents when risperidone was tapered down or switched to methylphenidate. From the WHO, we identified 25,556 ICSRs (16,118 for methylphenidate, 8,614 for risperidone, and 824 for both). Of these, 953 (5.9%), 1356 (15.7%), and 159 (19.3%) ICSRs reported movement disorders in association with methylphenidate, risperidone or both, respectively. The analyses on disproportionality showed an increased number of ICSRs with movement disorders when the two drugs were coded in combination. The potential of movement disorders as adverse effects might be amplified when methylphenidate and risperidone are used in combination. The results from the literature underline the necessity of caution and patient monitoring when risperidone dosing is modified during methylphenidate therapy.

Frequency and Correlates of Acute Dystonic Reactions After Antipsychotic Initiation in 441 Children and Adolescents.

Objective: To determine the incidence of acute dystonic reactions (ADRs) and risk factors for ADRs in children and adolescents treated with antipsychotics. Methods: This was a retrospective chart review-based cohort study of consecutive patients who attended a university hospital's child and adolescent psychiatry department between 2015 and 2017 and who were treated with antipsychotics and had at least two follow-up visits. Results: Thirty of 441 patients (6.8%) 4-19 years of age who were treated with antipsychotics for conduct disorders (21.5%), attention-deficit/hyperactivity disorder (13.2%) and, irritability and aggression that accompanied intellectual disability (12.9%) and followed for 99.5 ± 223.3 (median: 34) days developed ADRs. ADRs developed in 11/391 patients (2.8%) treated with one antipsychotic and 19/50 patients (38.0%) treated with two antipsychotics (p < 0.001). In patients treated with one antipsychotic that developed ADRs, the time to ADRs was 4.0 ± 4.0 days after antipsychotic initiation and 2.7 ± 2.4 days after an increase in the antipsychotic dose. The time to ADRs in those treated with two antipsychotics was 3.0 ± 2.3 days after the addition of the second antipsychotic and 1.6 ± 0.8 days after a dose increase in the second antipsychotic. The incidence of ADRs during antipsychotic monotherapy was 10.5% with first-generation antipsychotics (FGAs) and 2.2% with second-generation antipsychotics (SGAs; p = 0.037). The antipsychotic was changed due to ADRs in 12/30 (40.0%) of ADR cases. Independent factors associated with ADRs were antipsychotic polypharmacy (p < 0.0001), inpatient treatment (p = 0.013), FGA use (p = 0.015), and diagnoses of schizophrenia (p = 0.039) or bipolar disorder (p < 0.0001). Conclusion: SGAs and low-potency FGA monotherapy in children and adolescents were associated with a relatively low ADR risk, whereas high- and mid-potency FGAs were associated with a high risk. Independent predictors of ADRs were antipsychotic polypharmacy, inpatient treatment, FGAs, and schizophrenia or bipolar disorder diagnoses, which may be related to more aggressive antipsychotic dosing.

The Pharmacoepidemiology of Psychotropic Medication Use in Canadian Children from 2012 to 2016.

Objective: The goal of this study was to characterize the frequency and trends of psychotropic drug prescribing in Canadian children from 2010 to 2016 and to compare these results with a previous study conducted between 2005 and 2009. Methods: Using a national physician panel survey database from IQVIA Canada, aggregated frequencies of written prescriptions and therapeutic indications for antipsychotics, attention-deficit/hyperactivity disorder (ADHD) medications (psychostimulants and nonstimulants), and antidepressants were analyzed in children. Changes in frequency of written prescriptions and therapeutic indications are presented using descriptive statistics. Results: Written prescriptions for antipsychotics decreased by 10% from 2010 to 2016, in contrast to a 114% increase in written prescriptions for antipsychotics observed between 2005 and 2009. Written prescriptions for psychostimulants and antidepressants rose by 35% and 27%, respectively, between 2012 and 2016, comparable with previous results. The most common reasons for recommending an antipsychotic were ADHD and conduct disorder, although there appears to be a downward trend for ADHD compared with other conditions. In contrast, the share of written prescriptions for antipsychotics for autism increased 34% over the study period. Within the second-generation antipsychotics, written prescriptions for aripiprazole increased. An increase in the use of guanfacine extended release for ADHD was also observed. Conclusion: Several factors may be involved in stabilization and small decrease in antipsychotic use in recent years, including physician and patient awareness of adverse effects related to antipsychotic use, knowledge implementation strategies advocating short-term and judicious use of antipsychotics in children, and the approval of guanfacine extended release for use in Canada for ADHD in 2013.

Conduct disorder.

Conduct disorder (CD) is a common and highly impairing psychiatric disorder that usually emerges in childhood or adolescence and is characterized by severe antisocial and aggressive behaviour. It frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD) and often leads to antisocial personality disorder in adulthood. CD affects ~3% of school-aged children and is twice as prevalent in males than in females. This disorder can be subtyped according to age at onset (childhood-onset versus adolescent-onset) and the presence or absence of callous-unemotional traits (deficits in empathy and guilt). The aetiology of CD is complex, with contributions of both genetic and environmental risk factors and different forms of interplay among the two (gene-environment interaction and correlation). In addition, CD is associated with neurocognitive impairments; smaller grey matter volume in limbic regions such as the amygdala, insula and orbitofrontal cortex, and functional abnormalities in overlapping brain circuits responsible for emotion processing, emotion regulation and reinforcement-based decision-making have been reported. Lower hypothalamic-pituitary-adrenal axis and autonomic reactivity to stress has also been reported. Management of CD primarily involves parent-based or family-based psychosocial interventions, although stimulants and atypical antipsychotics are sometimes used, especially in individuals with comorbid ADHD.

Methylphenidate administration promotes sociability and reduces aggression in a mouse model of callousness.

RATIONALE: Deficits in empathy constitute a distinctive feature of several psychopathologies, including conduct disorder (CD). The co-occurrence of callous-unemotional (CU) traits, excess rates of aggression and violation of societal norms confers specific risk for adult psychopathy. To date, the off-label use of methylphenidate (MPH) constitutes the drug treatment of choice. OBJECTIVES: Herein, we tested the therapeutic potential of MPH in a recently devised mouse model recapitulating the core phenotypic abnormalities of CD. METHODS: Two subgroups of BALB/cJ male mice exhibiting opposite profiles of emotional contagion (i.e. socially transmitted adoption of another's emotional states) were investigated for reactive aggression, sociability, attention control, anxiety-related behaviours and locomotor activity, in response to MPH administration (0.0, 3.0 or 6.0 mg/kg). RESULTS: Our data indicate that mice selected for excess callousness exhibit phenotypic abnormalities isomorphic to the symptoms of CD: stability of the low emotional contagion trait, increased aggression and reduced sociability. In accordance with our predictions, MPH reduced aggression and increased sociability in callous mice; yet, it failed to restore the low responsiveness to the emotions of a conspecific in pain, isomorphic to CU traits. CONCLUSIONS: Although our data support the notion that MPH may contribute to the management of excess aggression in CD patients, additional studies shall identify specific treatments to target the callousness domain. The latter, unaffected by MPH in our experimental model, demands focused consideration whereby it constitutes a specifier associated with a worse prognosis.

Current pharmacotherapy options for conduct disorders in adolescents and children.

INTRODUCTION: Conduct disorder (CD) is a common mental health disorder of childhood and adolescence. CD's complexity, with its heterogenous clinical manifestations and overlapping comorbidities makes the application of evidence-based management approaches challenging. This article aims to combine a systematic review of the available literature, with a consensus opinion from both child and adolescent psychiatrists and developmental pediatricians on the clinical and pharmacological management of children and adolescents with conduct disorder (CD). AREAS COVERED: The authors review the CD population and provide a systematic review and meta-analysis of the effectiveness and safety of pharmacotherapies using preferred reporting items for systematic review and meta-analysis (PRISMA) and strength of evidence recommendation taxonomy (SORT) guidelines. The authors then provide an expert clinical opinion for the use of different pharmacotherapies to address aggressive and disruptive behavior in children. EXPERT OPINION: Atypical antipsychotics (e.g. risperidone) demonstrate evidence for efficacy in CD. Other pharmacotherapies (e.g. mood stabilizers, anticonvulsants, psychostimulants and selective norepinephrine reuptake inhibitors) have a low level of evidence for CD alone, however, can sometimes be effective in managing the symptoms of CD when other psychiatric disorders are also present.

Psychotropic Treatment Pattern in Medicaid Pediatric Patients With Concomitant ADHD and ODD/CD.

OBJECTIVE: To describe psychotropic treatment pattern and evaluate the association of socio-demographic factors and psychotropic combination therapy in children with ADHD and oppositional defiant disorder/conduct disorder (ODD/CD). METHOD: This is a cross-sectional drug utilization study based on Medicaid fee-for-service programs in 26 U.S. states (1999-2006). Children aged 4 to 18 with concomitant ADHD and ODD/CD were included. We calculated the prevalence of psychotropic drugs and used logistic regression to evaluate the role of socio-demographic factors in psychotropic combination therapy. RESULTS: We identified 121,740 children with ADHD and ODD/CD (140,777 person-years). The period prevalence of "no psychotropic therapy," psychotropic monotherapy, and psychotropic dual therapy was 38.1%, 44.7%, and 9.0%, respectively. The most common drug class was stimulants. Whites, males, and children in foster care were more likely to use psychotropic combination therapy. State-level variation was observed. CONCLUSION: "No psychotropic therapy" and stimulants dominate treatment choices in children with ADHD and ODD/CD. Socio-demographic characteristics are associated with combination psychotropic therapy.

Attendance and Engagement in Parent Training Predict Child Behavioral Outcomes in Children Pharmacologically Treated for Attention-Deficit/Hyperactivity Disorder and Severe Aggression.

OBJECTIVES: We examined the association of parent training (PT)-related factors with therapeutic success in the Treatment of Severe Childhood Aggression (TOSCA) study. Our aims were (1) to evaluate demographic and clinical characteristics as predictors of parent attendance and engagement in PT and (2) to examine the associations of parent attendance and engagement in PT with study-targeted child behavior outcomes (i.e., attention-deficit/hyperactivity disorder [ADHD] and disruptive behavior symptoms). TOSCA was a randomized clinical trial evaluating the effect of placebo versus risperidone when added to PT and psychostimulant for childhood ADHD with severe aggression. METHODS: Data for 167 parents and children 6-12 years old with ADHD, oppositional defiant disorder (ODD) or conduct disorder, and severe physical aggression were examined. Analyses used generalized linear models. RESULTS: Most parents (72%) attended seven or more of nine sessions. The average parental engagement, that is, the percentage of PT elements fully achieved across participants and sessions, was 85%. The average therapist rating of goal completion was 92%. Parents of non-white and/or Hispanic children (p = 0.01) and children with lower intelligence quotient (p = 0.02) had lower PT attendance; parents with lower family incomes (p = 0.01) were less engaged. Attendance and engagement predicted better scores on the primary child behavior outcomes of disruptive behavior (Nisonger Child Behavior Rating Form Disruptive Behavior Total) and ADHD and ODD symptoms, adjusting for baseline severity. CONCLUSIONS: When the clinical picture is sufficiently severe to warrant prescribing an atypical antipsychotic, PT is feasible for families of children with ADHD and co-occurring severe aggression. The promotion of attendance and engagement in PT is important to enhance clinical outcomes among this challenging population. Methods for overcoming barriers to participation in PT deserve vigorous investigation, particularly for those with low family income, non-white race, Hispanic ethnicity, or when children have lower cognitive level.

Intranasal oxytocin administration promotes emotional contagion and reduces aggression in a mouse model of callousness.

Deficits in empathy, the ability to share an emotion of another individual, constitute a hallmark of several psychopathological conditions, including conduct disorder. The co-occurrence of excess rates of aggression, general violation of societal norms and callous-unemotional traits confers specific risk for adult psychopathy. In the present study, we relied on a recently devised experimental model of conduct disorder in mice to test the potential efficacy of intranasal oxytocin administration. Two subgroups of BALB/cJ male mice exhibiting opposite profiles in emotional contagion (i.e. socially transmitted adoption of another's emotional states) underwent a series of tests mapping onto reactive aggression, information processing, perseverative behaviour, punishment-related emotional memory, physiological arousal and hormonal stress reactivity, with or without intranasal oxytocin administration (5.0 or 20.0 µg/kg). Collectively, our data indicate that a trait of markedly reduced emotional contagion is associated with a behavioural syndrome of sensorimotor gating deficits, impaired emotional memory, increased aggression and stereotyped behaviours, dysregulations in the circadian rhythms of activity and body temperature and dampened physiological reactivity to external stressors. Moreover, in the absence of changes in oxytocin receptor density in the neural network involved in empathy-like behaviour, we showed that oxytocin administration normalised emotional contagion, aggression and behavioural stereotypies, thereby ameliorating the phenotype of mice characterised by deficient empathy-like behaviour. Besides, oxytocin led to a lower, more prolonged neuroendocrine response of the HPA-axis to stress in all mice. Ultimately, current data support the notion that oxytocin may constitute a valid therapeutic approach in disturbances characterised by abnormal aggression and excess callousness.

Impact of Drug Adherence on Oppositional Defiant Disorder and Conduct Disorder Among Patients With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) may be a predecessor of oppositional defiant disorder (ODD) and conduct disorder (CD), and medication is an effective treatment option for ADHD. This study aims to examine whether adherence to medication treatment is associated with developing ODD and CD among youths with ADHD. METHODS: A total of 33,835 youths (4 years ≤ age of diagnosis ≤ 18 years) with ADHD (ICD-9-CM code 314.X) undergoing medication treatment for at least 90 days were selected from Taiwan's National Health Insurance Research Database during the period of January 2000 through December 2009. Patients' medical records were monitored through December 31, 2011, or until they had a diagnosis of ODD or CD. We categorized participants as compliant or noncompliant on the basis of a medication possession ratio (MPR) of 50%. RESULTS: The patients with better drug adherence (MPR ≥ 50%) exhibited a significantly decreased probability of developing ODD (53% reduction, P < .001) or CD (58% reduction, P < .001) when compared to the patients with poor drug adherence (MPR < 50%). The results in our sensitivity analyses showed that good drug adherence consistently exerted protective effects on ODD or CD, irrespective of patients' characteristics. Moreover, the patients with the best drug adherence (MPR ≥ 75%) had the lowest risks of developing ODD or CD. CONCLUSION: Among patients with ADHD undergoing drug therapy, a better drug adherence is associated with a lower likelihood of their developing ODD or CD in later life.