Irritability is the most common reason children are brought for psychiatric evaluation. It is a diagnostic criterion or associated symptom for multiple diagnoses listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
Over the past 20 years, much has been learned about brain and behavior mechanisms that involve irritability, but published reports are often marred by excessive jargon.
To help clinicians overcome this problem, so they can understand this important research and begin to consider how to apply it to their patients, Daniel P. Dickstein, MD, FAAP, chief of McLean Hospital’s Nancy and Richard Simches Division of Child and Adolescent Psychiatry and director of the PediMIND Program at McLean Hospital, and colleagues published their review in Child and Adolescent Psychiatric Clinics of North America.
Tools of the Trade
The paper begins with a clear discussion of the various magnetic resonance imaging (MRI) techniques used to study brain structure and function in people with mental health problems.
It also explains how computerized games can be used to assess cognitive and emotional processes related to irritability:
- Cognitive flexibility (the ability to adapt to changing rewards and punishments)
- Reward processing/frustrative non-reward (the response stemming from blocked goal attainment)
- Response inhibition (the ability to stop a dominant, natural reaction)
- Emotional face processing (the ability to identify what emotion someone else’s face is showing)
The article then reviews what’s known about irritability in four major psychiatric disorders.
Bipolar Disorder (BD)
Youth with bipolar disorder (BD) show dysfunction in the prefrontal cortex striatal-amygdala circuit, which mediates all four processes listed above. These deficits have been observed during euthymia (normal mood), so they aren’t byproducts of mania itself, and they persist when individuals with prospectively documented childhood-onset BD become adults.
The deficits have also been found in youth at risk of BD because they have first-degree relatives with the disorder. That suggests these may be trait deficits distinct from those seen in children with chronic irritability who meet research criteria for severe mood dysregulation.
This research may explain why BD youth become irritable when they can’t adapt to life situations or when things don’t work out as expected. Furthermore, it suggests why some forms of psychotherapy don’t work well for BD youth:
- Behavior modification requires an intact reward processing system so the child can desire/anticipate rewards and adapt their behavior to obtain rewards
- Cognitive behavior therapy requires recognizing the negative consequences of automatic thoughts/behaviors, such as losing out on rewarding relationships due to mind reading
Ongoing research at McLean is investigating whether computer games designed to enhance cognitive flexibility can reduce BD symptoms in children.
Disruptive Mood Dysregulation Disorder (DMDD)
Disruptive mood dysregulation disorder, DMDD, introduced in DSM-5, involves prefrontal cortex striatal dysfunction during reward processing and emotional face processing. Unlike BD that involves distinct episodes of mania characterized by elevated, expansive mood (aka euphoria) and often irritability, DMDD requires chronic, non-episodic severe irritability occurring nearly daily out of proportion to specific triggers.
Studies suggest chronic irritability in childhood is more likely to progress to depression in adulthood rather than mania. Clinical translation into potential treatments is underway. For example, one group developed a computer game to train youth on emotional face processing, and participants showed less irritability afterward.
Attention-Deficit/Hyperactivity Disorder (ADHD)
Irritability is not a DSM-5 diagnostic criterion for ADHD but an associated feature. It seems to be mediated by alterations in frontostriatal circuits that mediate reward processing and executive control/planning, including response inhibition.
These findings can help patients, parents, teachers, and clinicians understand why:
- Children with ADHD struggle to complete tasks, pay attention to schoolwork for prolonged periods, or inhibit their responses to “look before they leap”
- Certain psychosocial treatments are less successful for ADHD, such as behavior modification and parent training, which require individuals to adapt their behavior to earn rewards—a system that’s impaired in ADHD
- ADHD psychostimulants are useful—they increase synaptic dopamine levels and improve reward-related behavior, including response inhibition and learning
Longitudinal studies show children with ADHD have an approximate five-year lag, but not a permanent deficit, in the maturation of frontostriatal circuits compared with typically developing children. This suggests a biological reason why many patients no longer need treatment in young adulthood.
Autism Spectrum Disorder (ASD)
As with ADHD, irritability is not a diagnostic criterion for autism spectrum disorder (ASD) but rather an associated feature. Irritability often results when ASD diagnostic core features (e.g., deficits in social relationships, communication, or restricted repetitive behaviors and interests) cannot be accommodated, such as when preferred food, clothing, people, or schedules are unavailable or must change.
Unlike the other disorders discussed here, ASD involves brain changes in all four lobes and the cerebellum. That information may help clinicians explain to patients and parents the profound nature of ASD impairments.
Examples of treatments under investigation are:
- Citalopram, which in a double-blind, placebo-controlled functional MRI study, was associated with normalized aberrant inferior frontal activation in adults with ASD during a response inhibition task
- Oxytocin, which is being studied in a double-blind, randomized trial to evaluate whether it enhances reward processing and social skills in people with ASD
The FDA has already approved certain atypical neuroleptics to treat ASD-associated irritability.
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