New Frontiers in Irritability Research

New Frontiers in Irritability Research—From Cradle to Grave and Bench to Bedside. Neir Eshel, Ellen Leibenluft. JAMA Psychiatry, December 4, 2019. https://doi.org/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.

Conclusions
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.