Aggressive behaviour in children and adolescents with Conduct Disorder or Oppositional Defiant Disorder: neuropsychological characterization and drug treatments. Preliminary analysis of data from the European MATRICS project

Oppositional Defiant Disorder (ODD) and Conduct Disorder (CD) have significant long-term implications and pose a serious public health problem, nevertheless efficacy of therapeutic intervention, including medications, remains unclear. Recently there has been rapid progress in understanding the neuropsychological characterization and the neurobiology of CD and of Callous-Unemotional (CU) traits, including the physiological and neuroanatomical functioning. Evidence are controversial but it is likely that different etiological pathways lead to either a CD with CU traits with predominant instrumental aggression (low emotional reactivity, dysfunction in emotional empathy, lower amygdala reactivity), or to a CD with reactive aggression (exaggerated affective response, deficit in the processing of social stimuli-affective, increased amygdala responsiveness). With the aim of implementing the knowledge on CDs and identifying new targets of potential pharmacological therapies, withn the FP7, the European Commission funded the MATRICS project (Multidisciplinary Approaches to Translational Research In Conduct Syndromes), including studies finalized to identify neural, genetic and molecular factors involved in the pathogenesis of aggression/antisocial behaviour in preclinical models and clinical samples. The main objectives of the clinical study (MATRICS_WP6-1) were to characterize the neuropsychological/autonomic profiles of aggressive children and adolescents with CD/ODD compared to typical development controls (TDC), to highlight features associated with CU traits, and to identify the neuropsychological/physiological mechanisms underlying the acute responses to different drugs. In order to accurately select the drugs to be included into the trial, a systematic review and meta-analysis was conducted on the evidence of effectiveness of the treatments for aggression in CD: methylphenidate (MPH) and risperidone showed the largest effects on aggression in randomized controlled trials; other antipsychotics showed clinical efficacy on CD, but this was mainly revealed by open-label studies; only few studies included patients with CD as a primary diagnosis and/or discriminated between different types of aggression or reported measures of CU traits. The clinical study was designed on the assumption that gaining a deeper definition of the neuropsychological/physiological characteristics underlying CD and of the profile of acute responses to drugs would help identify the potential mechanisms of action of these substances and facilitate the development of new pharmacological treatments. It incorporated a case-control study followed by a randomized, single-dose, cross-over, placebo-controlled, single-blind study including the CD/ODD cohort only. The assessment implied a set of neuropsychological tests from the CANTAB battery and the new EMOTICOM battery (for “cold” and "hot" executive functions), the recording of autonomic measures such as heart rate and skin conductance, and the collection of serial saliva samples for cortisol levels. For the single-dose trial patients were re-evaluated after being randomized to take a single dose of placebo and two of the four study drugs (MPH or atomoxetine, and aripiprazole or risperidone). The main preliminary results reveal that aggressive CD/ODD subjects show: deficit in sustained attention and memory skills; difficulties in recognizing emotions and in affective attentional control; anomalies in decision-making, risk assessment (reduced response to rewards and punishments) and moral judgment. Higher CU traits seem associated with more impaired emotion processing (particularly negative ones). Single doses of MPH and atomoxetine improve accuracy in measures of affective attentional control; limited evidence of effects of aripiprazole and risperidone were detected. No drug led to significant impairment in cognitive performance. CU traits do not seem to predict different responses to medications.