The Path to Somewhere: Moving Toward a Better Biological Understanding of Irritability.

In childmental health, irritability is everywhere and nowhere at once. Irritability is the most common reason children are brought for psychiatric evaluation (.40% of emergency department cases; .20% of outpatients [1–3]). Irritability is an explicit diagnostic criterion or associated symptom for multiple DSM diagnoses affecting children and adults, including mania in bipolar disorder, generalized anxiety disorder, attention deficit hyperactivity disorder (ADHD), oppositional defiantdisorder, autismspectrumdisorder (ASD), and thenew DSM-5disruptivemooddysregulationdisorder (DMDD), plus child-specific modifications to the major depressive episode criteria. Irritability is linked to significant impairment in adulthood, including academic problems, poverty, psychopathology, and suicidality (4–6). Yet there is no reliable marker, measure, or test to help clinicians determine which diagnosis (or diagnoses) involving irritability an individual patient has or which treatment for irritability would work best. Indeed, the lack of such biomarkers is one factor contributing to the overdiagnosis or misdiagnosisof theseconditions.Forexample,upto20%ofchildren discharged from psychiatric hospitalization are diagnosed with bipolar disorder (7); rates of children with ASD increased 78% from 2002 to 2008, accounting for 1 of every 88 children (8); and 28% more children were medicated for ADHD in 2011 than in 2007 (9). There is a clear need to get somewhere along the path toward a greater biological understanding of irritability across the lifespan. The study reported by Roberson-Nay et al. in this issue of the Journal (10) is an important step on that path. This study examined the temporal pattern of genetic and environmental effects of irritability. To achieve this goal, the investigators harnesseddata from the SwedishTwinStudy ofChildren and AdolescentDevelopment,whichassessed twins in fourwaves between ages 8 and 20 (wave 1, ages 8–9; wave 2, ages 13–14; wave 3, ages 16–17; and wave 4, ages 19–20). Altogether, 1,310 twin pairs participated, including 267 female/female monozygotic, 199 female/female dizygotic, 254 male/male monozygotic, 182male/maledizygotic, and408opposite-sexdizygotic twin pairs. Irritability was assessed using the parent-completed Child Behavior Checklist and the twin-completed Youth SelfReport (at waves 2 and 3) and the Adult Behavior Checklist (at wave 4). The study demonstrated that the genetic effects on irritability are strong, are developmentally dynamic frommiddle childhood through young adulthood, and are associated with distinct patterns in males and females. In males, genetic influences on irritability increased with age, while nonshared environmental influences weakened. In contrast, in females, genetic influences on irritabilitywere initially strong, and then declined with age, while nonshared environmental influences were stable throughout development. Notably, shared environmentwasnotaprimary influenceonirritability formalesor females, accounting for only 1%25% of the variability. This study is significant because it moves us closer toward the goal of identifying biobehavioral markers of irritability. From a psychopathology perspective, it suggests biologically determined trajectories of irritability that could improve our classification and diagnosis of irritability. From a treatment perspective, it suggests developmentally salient periods that might be ripe for targeted treatments. The study also serves as a response to a call, made during a 2014 conference sponsoredby theNational Institute of Mental Health (NIMH), for more research on the biological underpinnings of irritability. How do we get to a point where such biobehavioral markers augment clinicians’work with actual patients? Yogi Berra provided important guidance for this journey: “You’ve got to be very careful if you don’t knowwhere you’re going, because you might not get there.” It would be both easy and unfortunate if we gave up on this journey because researching irritability, particularly in children, is complicated. The greatest issue is the lack of a well-accepted definition of irritability. While most clinicians know irritability when they see it (to paraphrase Justice Potter Stewart), we lack consensus about what irritability is and how to differentiate pathological irritability from typical development, or irritability in one disorder from in another. Thanks to work testing potential definitions during the past decade, we are further along the path. Among these efforts include thework of EllenLeibenluft,M.D. (a coauthor on the Roberson-Nay et al.) in relation to children with primary mood disorders. Dr. Leibenluft employed a neuroscience definition of irritability as “markedly increased reactivity This study is significant because it moves us closer toward the goal of identifying biobehavioral markers of irritability.