New Frontiers in Irritability Research—From Cradle to Grave and Bench to Bedside. Neir Eshel, Ellen Leibenluft. JAMA Psychiatry. 2020;77(3):227-228, December 4, 2019. doi:10.1001/jamapsychiatry.2019.3686
We all know what it’s like to be irritable. Our partners walk on eggshells around us. The slightest trigger sets us off. If there’s a punching bag nearby, it had better watch out. Irritability, defined as a low threshold for experiencing frustration or anger, is common. In the right context, irritability can be adaptive, motivating us to overcome barriers or dominate our environment. When prolonged or disproportionate, however, irritability can be counterproductive, causing us to waste our energy on maladaptive behavior.
In recent years, there has been an increase in research on irritability in childhood, with an emerging literature on its neurobiology, genetics, and epidemiology.1 There is even a new diagnosis focused on this symptom, disruptive mood dysregulation disorder (DMDD). However, there is a dearth of irritability research in adults. This is regrettable, because irritability is an important clinical symptom in multiple mental illnesses throughout the life span. From depression to posttraumatic stress disorder, dementia to premenstrual dysphoric disorder, traumatic brain injury to borderline personality disorder, irritability is associated with extensive burdens on individuals, their families, and the general public.
In this Viewpoint we suggest that studying the brain basis for irritability across development and disorder could have substantial clinical benefits. Furthermore, we propose that irritability, like addiction or anxiety, is an evolutionarily conserved focus ready for translational neuroscience.
Diagnosis and Treatment Across the Life Span
Despite its clinical toll, there are few evidence-based
treatments for irritability. The only US Food and Drug
Administration–approved medications for irritability are risperidone and
aripiprazole, which are approved only in the context of autism and are
associated with adverse effects that limit their utility. Stimulants,
serotonin reuptake inhibitors, and variants of cognitive behavioral
therapy and parent management training show promise for different
populations, but overall there is a shortage of options, leading many
health care professionals to try off-label drug cocktails with unclear
efficacy. This situation results in part from our primitive
understanding of the phenomenology and brain mechanisms of irritability
throughout the life span.
An emerging body of work focuses on measuring
irritability in children and adolescents, determining comorbid
disorders, and tracking related functional impairment.
1
Multiple studies, for example, report that chronically irritable youth
are at elevated risk for suicidality, depression, and anxiety in
adulthood.
2,3
But what are the clinical characteristics and longitudinal course of
irritability in adults? Irritability diminishes from toddlerhood through
school age, but does it continue to decrease monotonically with age
into adulthood? What about the end of life? Irritability and aggression
are common in patients with neurodegenerative disorders, but are these
symptoms similar to those in a child with DMDD? There has been limited
systematic study of irritability in adulthood, and studies that mention
irritability in adulthood operationalize the construct in different
ways. One study counted 21 definitions and 11 measures of irritability
in the psychiatric literature, all of which overlapped with anger and
aggression.
4
This lack of clarity diminishes our ability to identify biomarkers or
track treatment success. Even studies that use childhood irritability to
predict adult impairment do not typically measure irritability in
adults, thereby obscuring the natural history of irritability as a
symptom.
5
For the field to progress, it will be crucial to establish standard
definitions and measurements spanning childhood through adulthood.
Beyond phenomenology, we need to identify brain
signatures associated with the emergence, recurrence, and remission of
irritability across the life span and during treatment. Irritability is a
prototypical transdiagnostic symptom, but it remains unclear to what
extent its brain mechanisms overlap across disorders. For example, in
children, data suggest that the brain mechanisms mediating irritability
in DMDD, anxiety disorders, and attention-deficit/hyperactivity disorder
are similar but differ from those mediating irritability in childhood
bipolar disorder.
1,6 The frequency of irritable outbursts appears to diminish in step with the maturity of prefrontal regions during childhood.
1
Could degeneration in the same structures predict reemergence of
irritable outbursts in patients with dementia? Could developmental
differences in these regions increase the likelihood of irritability
when individuals are sleep deprived or intoxicated later in adolescence
or adulthood? Only through fine-grained neuroscientific studies can we
disentangle what is unique to the symptom (ie, irritability) and to the
disorder (eg, bipolar disorder vs DMDD vs dementia), and develop
treatments tailored to an individual’s brain pathology.
Translational Neuroscience and Irritability
In addition to their clinical relevance, neuroscientific
studies of irritability can address fundamental questions about brain
dysfunction and recovery. Over the past 2 decades, studies have revealed
the circuits underlying reward processing, and in particular prediction
error, the mismatch between expected and actual reward.
7
The neuroscience of aggression has also advanced through the discovery
of cells in the amygdala and hypothalamus that form a final common
pathway for aggressive behavior.
8 Irritability and the concept of frustrative nonreward can tie these 2 fields together.
Frustrative nonreward is the behavioral and emotional
state that occurs in response to a negative prediction error, ie, the
failure to receive an expected reward. In the classic study by Azrin et
al,
9
pigeons were trained to peck a key for food reward. After pigeons
learned the task, the experimenters removed the reward; then when the
pigeons pecked, nothing happened. For the next several minutes, there
were 2 changes in the pigeons’ behavior. First, they pecked the key at a
higher rate. Second, they became unusually aggressive, damaging the
cage and attacking another pigeon nearby. In other words, a negative
prediction error led to a state of frustration, which then induced
increased motor activity and aggression. Such responses to frustration
have been replicated in many species, including chimpanzees, cockerels,
salmon, and human children and adults.
10
Frustrative nonreward therefore provides an evolutionarily conserved
behavioral association between prediction error and aggression. Apart
from studies in children,
1,6
however, little has been done to probe the neural circuits of
frustrative nonreward or of irritability, which can be defined as a low
threshold for experiencing frustrative nonreward.
We know, for example, that negative prediction errors
cause phasic decreases in dopamine neuron firing, which help mediate
learning by reducing the valuation of a stimulus. Does this dip in
dopamine level also increase the likelihood of aggression and if so how?
The same optogenetic techniques that have demonstrated a causal role
for dopamine prediction errors in reward learning could be used to test
their role in aggressive behavior. Likewise, multiple nodes in the
reward circuit encode the value of environmental stimuli. Could these
values modulate the propensity for aggression? Environments of plenty,
for instance, may protect against aggressive outbursts, because if there
is always more reward available, the missing out factor may not be
salient. Conversely, scarcity could make individuals more likely to be
aggressive, because if there are few rewards to be had, achieving
dominance may be necessary for survival.
Exploring the bidirectional associations between the
reward processing and aggression circuits would help us understand state
changes in the brain and how environmental context determines our
behavior. At the same time, understanding these circuits will lay the
groundwork for mechanism-based treatments for irritability.
The neuroscience of irritability is in its infancy and
research has focused almost exclusively on children. We now have an
opportunity to expand this field to adults, across disorders, and to
animal models for more precise mechanistic studies. Through better
measurement, careful experimental design, input from theorists and
computational psychiatrists, and coordinated efforts across experts in
multiple disorders, we can guide the field to maturity.
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