Recommendations for the pharmacological management of irritability and aggression in conduct disorder patients

KEYWORDS:

• Aggression
• conduct problems
• stimulants
• antipsychotics
• mood stabilizers
• clonidine

1. Introduction

Conduct Disorder (CD) is characterized by repetitive and persistent patterns of behavior, with violation of the rights of others and societal norms or rules. It is included in the new DSM-5 chapter of Disruptive, Impulse Control and Conduct Disorders, with problems in the self-control of both behavior and emotions. This chapter includes also the Oppositional Defiant Disorder (ODD), often developmentally related to a possible outcome to an early-onset CD. In this developmental pathway, the first disorder to appear is often Attention Deficit Hyperactivity Disorder (ADHD), which affects not only presentation and natural history, but also treatment strategies.

Irritability and/or aggression in CD define subgroups of patients with specific diagnostic and treatment needs. Irritability is a deficit in emotional regulation, and a low threshold to anger in response to frustration [1]. Episodic and chronic irritability are separable presentations, and remain substantially stable over time [2]. Severe irritability, irrespective of its episodicity or chronicity, was firstly considered a possible age-related phenotype of pre-pubertal mania. Subsequent research showed that episodic irritability is mainly related to bipolar disorder (BD), while chronic irritability is associated with ODD or Disruptive Mood Dysregulation Disorder (DMDD) [2,3].

Oppositional Defiant Disorder presents distinct sub-dimensions, irritable, headstrong (rule violations, purposefully annoying others), and hurtful (being spiteful, vindictive behavior), which delineate differential pathways to different negative psychiatric outcomes. The irritable (or affective) sub-dimension is prospectively associated with internalizing problems, and only to a lesser extent, to CD [4], while the behavioral dimensions predict CD [5].

In order to limit the risk of an over-diagnosis of Bipolar Disorder (BD), based on prospective findings, children with chronic irritability, negative mood and temper outbursts were firstly included in a temporary diagnosis of Severe Mood Dysregulation, then in a new DSM-5 diagnostic category, Disruptive Mood Dysregulation Disorder (DMDD), within the chapter of Depressive Disorders. The nosological status of DMDD is still debated, and more recently, according to a different proposal for the next International Classification of Diseases and Related Health Problems (ICD-11), these children have been interpreted as a subtype of Oppositional Defiant Disorder with chronic irritability/anger [5]. When these children evolve to CD, they may present with specific clinical features (i.e. impulsive and emotional aggression, comorbid internalizing symptoms/disorders) and therapeutic needs (i.e. efficacy of early behavioral and psychosocial interventions).

Aggression does not imply a diagnosis of conduct disorder. Other mental disorders (i.e. mood, personality, psychotic or post-traumatic stress disorders) should be ruled out, but they may be also co-morbid to a CD. Aggression can vary according to severity, type (verbal, physical against objects, against self and against other people) and associated emotional state. Two subtypes of aggression have been described, proactive and reactive, with a wide range of mixed conditions. The first is associated with planned, goal-directed, predatory behavior, the expectation of reward or to achieve a goal, callousness and lack of empathy, and antisocial outcomes. The second is associated with impulsive, rule-breaking and risk-taking behavior [6]. When ODD is related to subsequent or associated CD, the headstrong dimension is mostly related to CD with aggression and rule-breaking behaviors, while the hurtful dimension is related to CD with predatory aggression and callousness [7].

Despite extensive research on treatment strategies for irritability and aggression in CD, conclusions are still uncertain. Multi-component psychosocial interventions, including patient-oriented sessions, family sessions, interventions at school, based on cognitive behavioral practices, should be the first-line treatment option [8], namely when the Irritable dimension is prevalent. When psychosocial interventions are not effective [9], or when the patient is persistently not compliant, pharmacotherapy can be considered, as an add-on treatment, even though evidence from studies on pharmacological treatments is far from definitive [9,10].

Several medications have been explored for the treatment of aggression in CD, with varying degrees of efficacy, but the evidence is limited by severe pitfalls. Data support the efficacy of Second-Generation Antipsychotics (SGAs) and Stimulants, with much less robust evidence for Mood Stabilizers and Alpha-Adrenergic Agents. These pharmacological categories will be briefly reviewed here.

1.1. Antipsychotics

Although available research supports the efficacy and effectiveness of SGAs [10,11], significant side effects strongly limit their safety profile. The short-term use of antipsychotics is usually the key to avoid the metabolic side effects. A comprehensive review [10], including 10 trials (2000–2014), with low-to-medium quality, with a total of 896 youths aged 5 to 18 years, reported limited efficacy on aggression and conduct problems in the short term (4–10 weeks).

Risperidone is the most extensively studied SGA for aggression in CD and ODD, as well as in other diagnoses (ADHD, Autism Spectrum Disorders), with a good effect size (weighted mean ES = 0.9) [11]. The TOSCA study [12] found that risperidone added to stimulants (and parent training) was superior to ‘basic therapy’ (stimulants and parent training) in reducing severity of parent-rated peer aggression (p = .02, Cohen’s d = 0.32), with a major effect on physical aggression and on object aggression. Aripiprazole, Quetiapine and Clozapine are supported by low qualitycontrolled trials or open-label studies.

1.2. Stimulant medications

Stimulants are the gold standard in managing not only the core ADHD symptoms, but also aggression in the ADHD+ODD/CD comorbidity, for both overt and covert aggression. The overall weighted mean effect size was 0.84 for overt aggression and 0.69 for covert aggression [13]. A further systematic review and meta-analysis with high-quality evidence [14] including 20 randomized controlled trials indicated that psychostimulants have a moderate-to-large effect on oppositional behavior, conduct problems, and aggression in youth with ADHD, with and without ODD or CD, with an effect size of 0.84 (95% CI 0.59–1.10) on teachers’ measures and of 0.55 (95% CI 0.36–0.73) on parent-rated oppositional/conduct problems and aggression. However, only two of these studies included subjects with a primary diagnosis of CD.

1.3. Other medications

While some limited evidence is available on lithium in episodic irritability and impulsive, affective aggression, no data is available on CD with chronic irritability or predatory aggression. According to a meta-analysis [15], the odd ratio of response or remission was 4.56 (p < 0.001), with a low level of evidence. Data on Divalproex sodium are limited and based on aggression and temper tantrums in mixed populations, prevalently with mood lability, with an odd ratio of responder status of 14.6 (95% CI 3.25 to 65.61; I2 = 33%, p < 0.001), with a low level of evidence [15].

Clonidine in an alpha-adrenergic agent used in ADHD, Tourette syndrome and Post-Traumatic Stress Disorder (PTSD). Very-low-quality evidence shows a small effect on conduct problems in youth with ADHD, with and without ODD or CD [15]. The Standardized Mean Difference between clonidine and placebo for oppositional behavior and conduct problems was 0.27 (95% CI 0.04 to 0.51. p = 0.02).

2. Expert opinion

Keeping in mind the limited and overall low quality of the available evidence, there may be some guidelines for clinical practice that can be gleaned. Behavioral and psychosocial interventions should be the first option, especially when irritability is the main clinical dimension. When psychosocial interventions are ineffective or the patients are persistently uncooperative, pharmacotherapy may be considered.

When ADHD is comorbid, empirical evidence supports a trial with stimulants, given the rate of response and the safety profile. Although some patients (i.e. Autism Spectrum Disorders and/or sub-average IQ) may present poorer response and higher rates of side effects (irritability), they also should firstly receive a stimulant. After an ineffective stimulant trial, an add-on Risperidone may be advised, possibly with short-term treatments, with a careful monitoring of side effects (increased appetite and weight gain, hyperprolactinemia, sedation, extrapyramidal side effects).

In patients with CD as the primary diagnosis, without current ADHD comorbidity, Risperidone may be the first option, namely when physical aggression is prominent; much less evidence supports other SGAs (Aripiprazole, Quetiapine, Clozapine), to be considered when the above-mentioned side effects limit the use of Risperidone.

Adolescents with CD associated with (episodic) irritability, impulsive aggression, suicidal or self-harm ideation or behavior, namely with comorbid BD, may benefit from a treatment with lithium. Patients with CD and comorbid anxiety disorders and emotional dysregulation without severe aggression, rapid-cycling/mixed mood symptoms may benefit from a trial with valproic acid.

Clonidine may be an option when irritability and/or aggression of CD are associated with ADHD, Tourette syndrome, or with PTSD (increased arousal, aggression, irritability and impulsivity, insomnia, and startle reactions).

Scarce information is available on the duration of the treatments, with no clinical guidelines available. In general, the short-term use is recommended with SGAs, namely in the presence of increased weight and metabolic side effects. After 1 year of effective behavioral control, a discontinuation should be always considered, even when medications appear well tolerated.

Declaration of interest

Dr. Masi has served on the advisory boards of Eli Lilly and Company, Shire and Angelini. He has furthermore received research grants from Eli Lilly, Shire, and Lundbeck, and has been a speaker for Eli Lilly, Shire, Lundbeck, FB Health and Otsuka. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.