Trajectories, cognitive mechanisms, and treatment response of irritability in children and adolescents

Irritability is one of the most common reasons for referral to child and adolescent mental health services and is a strong predictor of current and future functional impairment. Furthermore, irritability is one of the few psychiatric symptoms that is present in both internalising and externalising disorders. In children, irritability is part of the diagnostic criteria of every mood disorder described in the DSM-5, as well as of oppositional defiant disorder (ODD). It is also listed as an associated symptom for conduct disorder (CD), attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). Recently, irritability as a disorder itself has been introduced in the DSM under the term disruptive mood dysregulation disorder (DMDD). Despite the omnipresence of irritability across distinct psychiatric disorders, we still know little about its predictors, longitudinal outcomes, mechanisms, and, most importantly, effective treatment approaches. In this thesis, I examine the predictors and longitudinal correlates of irritability in young people. I also test candidate cognitive mechanisms and treatments for irritability driven by results of previous research. Specifically, I examine the potential mechanisms that might explain the specific association between irritability and depression found in longitudinal studies and test a new treatment approach motivated by this association. First, I present a systematic review and meta-analysis of the longitudinal correlates of chronic severe irritability. I searched for studies in PubMed and Web of Science that investigated DMDD or the irritability dimension of ODD as a predictor of future psychiatric disorders and symptoms. The findings from this study highlight the specific association between chronic severe irritability and future depressive and anxiety disorders. 4 Second, I examine early predictors of irritability that might explain its specific association with depression. Using a large community-based sample, I tested whether an infant’s sex and variation in physiological stress reactivity (i.e., two known risk factors for depression) interact to predict different patterns of ODD symptom dimensions, including headstrong and irritability, in the pre-school age. We predicted that girls would be at higher risk for irritability whereas boys would be at higher risk for headstrong symptoms. The results show that stress reactivity predicts ODD symptoms in opposite directions in boys and girls. However, this pattern was the same for both ODD dimensions, without specific risk for girls and boys. Third, using both cross-sectional and longitudinal analyses, I test whether deficits in emotion recognition, commonly seen in youth with irritability and youth with depression, are associated with an increase in the risk of depressive symptoms in children and adolescents with DMDD. The results show that emotion recognition deficits in youth with DMDD are associated with co-occurring depressive symptoms and predict these symptoms at follow-up. Fourth, I provide the results of the first-ever randomised controlled pharmacological trial (RCT) that has used irritability as a primary outcome in youth with severe mood dysregulation (SMD), the precursor of DMDD. Given the specific association between irritability and depression/anxiety, I examine whether adding citalopram to methylphenidate improves irritability to a greater extent than adding placebo. The results of the RCT show that add-on citalopram improves irritability in youth with SMD. However, improvements of irritability are not accompanied by improvements in functional impairment, depressive symptoms or anxiety symptoms. 5 Finally, I propose a model to explain the association between irritability and future depressive disorder. To do so, I refer to both findings reported in this thesis and results from previous works. The model also includes aspects that are hypothesised to play a role in this transition but still need to be tested. The hypothesised model is based on a shared factors model, in which factors contributing to irritability are shared with those contributing to depression. I discuss genetic, environmental and early life factors, as well as aberrant responses to reward and emotional stimuli. I conclude this thesis by proposing some directions for future research