Aggression in attention-deficit/hyperactivity disorder children: diagnostic or comorbid symptom?

Is aggression a comorbid symptom of attention-deficit/hyperactivity disorder (ADHD) or a common developmental trajectory more frequently expressed in children who already suffer from a psychiatric disorder such as ADHD?

Diagnosing the disease

ADHD is a serious neuropsychiatric disorder that greatly affects the afflicted children and their families with negative medical, occupational and psychosocial consequences lasting a lifetime. It is also one of the most common diagnoses among children referred clinically for aggression. ADHD is described as the most common neurobehavioral condition of childhood. The definition of the ‘core symptoms’ of ADHD are ‘inattentiveness, impulsivity and hyperactivity’ as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM)–IV; however these criteria are not sufficient to describe the variety of emotional and psychological symptoms and/or learning problems associated with this disease. Therefore, it is important to recognize that during the course of treatment, the core symptoms of ADHD may improve and changes may also be observed in frequently associated behaviors, such as irritability, aggression or oppositional behavior. The partial unlinking of symptoms and impairment has implications for decisions regarding the diagnostic process as well as research criteria and evaluation of treatment effects.

Since patients with a diagnosis of ADHD often express symptoms of aggression, anger or emotional outburst, it is, as yet, unclear whether this is part of an underlying comorbid disorder, such as oppositional defiant disorder, conduct disorder or bipolar disorder, or a comorbid symptom that does not reach diagnostic criteria for any of those conditions. It is possible that it may be a side effect of treatment or a manifestation of a developmental trajectory in a population highly susceptible to sensory overload and irritability. There is evidence that, in particular, the relationship between impulsivity and aggression might be related to the presence of comorbid psychiatric diagnoses, such as oppositional defiant disorder or conduct disorder [1], rather than ADHD alone. Several underlying factors are related to impulsive aggression, including genetics, environment (i.e. childhood experiences of aggression or parental dysfunction), structural brain abnormalities and neurotransmitter dysfunction. In addition, children with both ADHD, particularly hyperactivity type, and aggressive behavior have worse outcomes than those with either problem alone [2].

Individuals with severe mental illness display a significantly higher rate of aggression than the general population. Comorbid conditions seem to significantly increase the risk of expression of aggressive symptoms [3]. This finding has shown to apply particularly to substance abuse and antisocial personality disorder, but aggression has also been found to be associated with various other pediatric psychiatric disorders, developmental disorders and certain medical conditions [4].

Childhood physical aggression is of particular concern as it is viewed as a precursor of physical and mental health problems such as, higher risk of alcohol and drug abuse, depression, suicide attempts, violent crimes and neglectful and abusive parenting [5,6]. Furthermore, aggressive behavior in children and adolescents has been identified as a current major public health concern ranging from frequent bullying to violence and delinquency [7,8]. In general, risk factors for displaying physical aggression were having young siblings, mothers with high levels of antisocial behavior before the end of high school, mothers who had their children early, families with low income and mothers who smoked during pregnancy [8]. In general, aggressive behavior is associated with a wide range of social problems, which can be identified early on in preschool years [9,10].

The lack of standard methods to specifically assess and categorize aggression or hostility makes it difficult to understand the potential relationship between the use of psychotropic medications and aggression/hostility. Structured assessment by using symptom-specific rating scales might be helpful in monitoring aggression in terms of changes during the course of treatment, such as to differentiate between verbal and physical aggression [11]. There is evidence that further differentiation of behavioral dimensions (for example, reactive versus proactive types of aggressive behavior) might assist in acknowledging the individual behavior changes of a pediatric patient treated for ADHD in different environments, such as social functioning in peer groups, school or home [12].

Aggression takes many forms and, therefore, comparisons between studies may be difficult. Verbal aggression may be the focus of some studies, whereas other researchers examine physical acts of violence. A recent review of psychiatric adverse events undertaken by the US FDA with drugs approved for ADHD attempted to shed light on the frequency and severity of behaviors, including aggression, associated with the treatment of ADHD [101]. The data analyses yielded results from 100 separate clinical trials in the development programs for these products. The findings are subject to the usual limitations of such safety analyses, which include potential lack of consistency of ascertainment of adverse events across the various trials, the possibility of misclassification of cases and statistical power limitations imposed by the sample sizes. Aggressive events were evident within all clinical trials for ADHD, with none of the drugs indicated for ADHD reaching levels of statistical significance according to this analysis. In this review of aggression events, there was little evidence that drug treatment reduced the frequency of aggression events relative to placebo to a statistically significant extent. This might be due to the fact that the level of sensitivity for qualifying an adverse event by different investigators, and in different trials, varies. Some investigators may consider particularly aggressive behavior as features of the disease based on their level of experience with this patient population and individual clinical judgment. Further limitations are that the data presented were based on each sponsor’s adverse event classifications, but the methods employed to produce these classifications varied across sponsors. Thirdly, the statistical power of such safety analyses are always limited by the sample sizes of the trials considered.

Despite the extent and seriousness of the problem of aggression, a wide variety of agents not indicated for use in children have been used to accommodate the severity of these symptoms in some patients. Often, treatment of the underlying condition helps to ameliorate problems with aggression. However, aggressive symptoms sometimes remain and affect the outcome of treatment for ADHD and these must be specifically targeted and treated. When aggression is treated comprehensively, the care of the individual with a psychiatric disorder is more effective.

Side effects of treatment for attention–deficit/ hyperactivity disorder

Considering the co-occurrence of ADHD and aggressive behavior in some patients, it may be difficult to separate disease-related behaviors from treatment-emergent adverse drug reactions. In general, treatment indicated for ADHD has been proven to show significant symptom reduction [101] and improvement of social and academic functioning. Children who demonstrate dysphoria, outbursts or limited response to a medication trial are sometimes thought to need adjustment of dose, a different type of drug or an add-on medication [13,14]. Although the potential bodily side effects of psychotropic medications are well known and usually monitored, the mental and emotional side effects are less commonly discussed and are not considered an indication to discontinue medication. Optimal treatment for ADHD attempts to effectively reduce the symptoms of the illness, while not increasing undesirable behaviors such as aggression or hostility.

The practice parameters of the American Academy of Child and Adolescent Psychiatry include a list of minor side effects with stimulants such as mild anxiety, depression and irritability, feeling dull/tired/listless, mild picking at skin/nail biting, and fleeting tics [15]. Whether these side effects are tolerable to the child is not known; studies that evaluate this question have not been performed.

Conclusion

ADHD is a collection of symptoms, namely inattention, impulsivity and hyperactivity, that can occur in conjunction with other major and minor mental health conditions. Aggression is a common symptom in pediatric psychiatric disorders and is more frequently expressed if one or more comorbid psychiatric diagnoses and/or social stressors are apparent. There is evidence that aggressive behavior probably reflects a common developmental trajectory more frequently expressed in children who are diagnosed with any psychiatric disorder, rather than being a specific symptom of ADHD. Treatment for ADHD is effective in reducing symptoms in most patients and often ameliorates problems with aggression.

The Multimodal Treatment Study of Children with ADHD showed that medication treatment for ADHD was generally superior to nonmedication treatments, such as intensive behavioral therapy [16]. However, the individual benefit from treatment might differ in this highly sensitive population, which undergoes constant physical and emotional changes during development and maturation. Monitoring of symptoms beyond the core symptoms of ADHD during treatment is warranted to better acknowledge the individual benefit risk profiles of patients.

Disclaimer

This editorial reflects the personal opinion of Dr Sitra Tauscher–Wisniewski. The views expressed herein are not those of Eli Lilly and Company.