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Childhood Chronic Irritability and the Pathophysiology of Mental Illness


Location: Rockville, MD

Sponsored by: Division of Developmental Translational Research, National Institute of Mental Health (NIMH)

Chronic irritability is one of the most common reasons children present to psychiatric clinics for evaluation and treatment, yet there is a notable gap between the public health importance of the symptom and our knowledge of its underlying mechanisms and pathways to psychiatric illness. On February 27-28, 2014, the Division of Developmental Translational Research, NIMH, convened a multidisciplinary group of researchers—representing expertise in development, genomics, neural circuitry, pathophysiology, behavior, risk, and intervention—to summarize the state of the science and discuss future directions for the study of chronic irritability in youth. The workshop was intended to act as an impetus for coordinated and collaborative research efforts, consistent with the Research Domain Criteria (RDoC) project; to enhance understanding of shared etiology among childhood psychopathologies; speed progress toward understanding root causes of mental illness; and, identify targets for novel interventions that can be implemented early in the disease trajectory.

Definition and Measurement

Session 1 provided an overview of the working definitions, measureable components, and assessment of irritability in humans and animals. The discussion focused specifically on chronic irritability. Although episodic irritability (e.g., in the context of a manic or depressive episode) is clinically relevant, the topic was left to future discussions because of differences in longitudinal course between episodic and chronic irritability, and because of likely differences in pathophysiology.

Irritability can be classified as a mood state, clinical symptom, or temperamental trait. Irritability is variably defined and measured in terms of anger, response to frustration, and reactive aggression. One formulation suggests that irritability is a trait presentation of chronic anger, and that irritability is characterized by a decreased threshold for, and aberrant responses to frustration, where frustration is the emotional response to blocked goal attainment. In addition, irritability can also be conceptualized in terms of aberrant approach responses to threat; by definition, then, reactive aggression (i.e., aggressive responses to threat) is characteristic of irritable people. Frustrative nonreward, a relevant construct, is included under the negative valence system in the NIMH RDoC matrix. There is debate about whether irritability is a homogenous construct.

The group discussed the need to create a typology of irritability to organize and advance the field (see Definition and Measurement Framework, below). Group members suggested that an important distinction may exist between two types of chronic irritability: tonic and phasic. Tonic irritability may be defined as persistently angry, grumpy, or grouchy mood, while phasic irritability may be defined as the tendency to have developmentally inappropriate outbursts of intense anger. Whether these two constructs are distinct forms of chronic irritability is an open, empirical question. Additional key themes raised during discussion included a need to discriminate irritability from other negative valence constructs and behaviors (e.g., aggression); the need for common measures and paradigms to be used across studies (see below); and the need to incorporate threshold (individual differences), duration (trait vs. state), context, normative developmental responses, and developmental timing into definitions and assessments/paradigms. The group also discussed the challenges of developing paradigms that could be used in animals and across the developmental spectrum to model key psychological processes mediating irritability. It is not clear how best to evoke irritability across species, i.e., how to evoke and measure frustration or aberrant approach responses to threat in animals.

Neurobiology of Irritability

The second session focused on the state of the science on the heritability, neural circuitry, and HPA function associated with irritability and highlighted the gap areas and general issues for future investigation. Genetic studies of irritability have been limited, with twin data suggesting moderate heritability, and sex and age differences in the developmental time course of genetic effects. Many questions remain, including whether different types of irritability (e.g., phasic versus tonic) are differentially heritable; the key molecular pathways of interest; and the role of gene-environment interaction and correlation (e.g., maternal irritability may be associated with both genetic and environmental risk, with genetic risk possibly shared between irritability and depression). HPA axis dysregulation, particularly HPA axis response to stress, is another mechanism through which irritability may increase risk for disorder, but is understudied.

Limited data exist on brain structure and function associated with irritability. Furthermore, for functional neuroimaging, the processes tapped, the paradigms used, and the regions of interest studied vary widely across studies. For example, elicitation of frustration typically involves rigged tasks, and studies comparing brain function in irritable vs. non-irritable youth show differences in activation during frustration in regions mediating attention, emotion salience, reward processing, and emotion regulation. Studies that evaluate reactive aggression examine threat circuitry, including amygdala, ventromedial prefrontal cortex, anterior cingulate cortex, and the anterior insular cortex.

Key themes during this session included a need for developing an assessment battery than can be shared across studies and used to define the cognitive and affective processes that mediate irritability (e.g., baseline responsivity to blocked goal or threat, attentional redirecting, suppression of affect, and decision making). Many questions were raised about the significance of irritability in the context of other disorders. For example, is irritability a non-specific severity marker? Is it a prognostic marker? Other questions concerned the utility of studying irritability across disorders (consistent with RDoC approaches). That is, is irritability heterogeneous? Is the neural circuitry mediating irritability the same across mental disorders? Other issues for future investigation include incorporating context into studies of irritability, examining age and sex differences, incorporating developmentally appropriate measures, and considering the extent to which a low threshold for anger may be functional or adaptive in some contexts. The group discussed the value of using model animals for elucidating the neurobiology of irritability—i.e., to evaluate mechanism, flesh out issues of context, duration, and developmental timing, and identify downstream and upstream effects—and the challenges associated with these models.

Developmental Trajectories of Irritability and Psychiatric Illness

The third session provided an overview of research on the developmental trajectories of irritability and links to psychopathology. Irritability is often conceptualized as a symptom of early disruptive behavior or externalizing disorders (i.e., oppositional defiant disorder, and attention deficit hyperactivity disorder), but is also a criterion for the diagnosis of several internalizing disorders that typically onset in the second decade of life, including major depression, bipolar disorder, generalized anxiety disorder, and borderline personality disorder. There is evidence suggesting chronic irritability may subside somewhat with age but that early childhood irritability predicts major depression, generalized anxiety disorder, suicidality, and functional impairment in adolescence and adulthood. However, the normal-abnormal spectrum of irritability has not yet been fully characterized, and the extant literature linking irritability to psychopathology is based on studies that vary widely in their assessment of irritability. The role of contextual factors such as family environment, medical illness, sleep, diet, and puberty may be informative. The panel highlighted the importance of a neurodevelopmental framework, starting early in life before illness onset, to address current gaps in knowledge.

Treating Irritability

The fourth session focused on current treatment approaches and promising intervention targets. Second generation antipsychotics are the most commonly used pharmacologic treatments for chronic irritability as well as the irritability associated with Autism and other disorders. Ongoing, hypothesis-driven trials are evaluating the efficacy of stimulants and selective serotonin re-uptake inhibitors to reduce chronic irritability. At present, there are no widely available, evidence-based psychosocial interventions designed to address severe irritability in children and adolescents, although several existing interventions are being adapted or combined to target emotional dysregulation, anger, heightened arousal, poor inhibitory control, and other constructs associated with irritability. Evidence suggests that interventions involving parents may be particularly effective.

Consistent with an experimental medicine approach and NIMH intervention funding priorities, there is an immediate need to identify and test promising intervention targets that are specific to irritability. There was discussion about the best approaches to identifying these pathophysiologic targets: studying naturally occurring individual differences versus viable compensatory mechanisms (e.g., if the child does not have the ‘hardware’ for regulation, then there may be a need to focus on ways to compensate for the poor regulation). Questions of appropriate timing of interventions were also discussed. While all participants recognized that early intervention is a priority for preempting mental illness onset, most also agreed that treatment decisions need to take into account the possibility that symptoms might diminish as systems and functions mature—i.e., an older child with better executive functioning may be better able to regulate irritability and compute the possible consequences of irritable behavior.

Next steps

  1. Elucidate heterogeneity of chronic irritability to allow for future investigations of narrowly and well-defined circuit-based subtypes, across species and levels of analyses (see below). Examine the stability and normal variation of well-defined subtypes of irritability.
  2. Characterize the normal-abnormal spectrum of irritability, and identify early pathways beginning in infancy and toddlerhood that lead to psychopathology in childhood and adolescence. Elucidate mechanisms underlying chronic irritability and identify biomarkers that predict these pathways.
  3. Develop taxonomy to encourage common definitions and measures across studies. Incorporate threshold (individual differences), duration (trait vs. state), context, normative developmental responses, and developmental timing into definition and assessments/paradigms. Define thresholds of irritable mood and behavior.
  4. Create reliable and valid measures of irritable mood and behavior, along with paradigms that can be used in both the clinic and scanner to elucidate the pathophysiological mechanisms mediating irritability.
  5. Identify plausible targets and mechanisms for intervention development at different developmental and disease stages.

Definition and Measurement Framework – A Starting Point

For the purpose of accomplishing the goals highlighted during the workshop through coordinated and collaborative research efforts, the group discussed and proposed the following definition and measurement framework. This framework is suggested as a starting point that may be refined with further investigation.

Neuroscience-based definition of irritability

  • Aberrant responses to frustration (i.e., blocked goal attainment) or aberrant approach responses to threat

Clinical/behavioral dimensions of chronic irritability

  • Tonic Irritability: Persistently angry, grumpy, grouchy mood
  • Phasic Irritability: Tendency to have developmentally inappropriate outbursts of intense anger
  • Frequency, duration (trait vs. state), and severity of irritability, variability of irritability within context, and developmental stage of the individual

Measures for shared assessment battery

  • Clinical self/parent report: The Affective Reactivity Index (ARI, 6 items). Future investigations may also want to adapt the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB).
  • Clinician-based report: Clinician-based ARI (under development)
  • Neuroimaging paradigms: Ideally include 4 tasks, 15 minutes each: 1-2 reward tasks, at least one frustration task, an approach response to threat task, and a cognitive control task. Participants acknowledged the challenges this paradigm presents for event-related designs.