Irritability in Mood Disorders: Neurobiological Underpinnings and Implications for Pharmacological Intervention

Feeling irritable is a common experience, both in health and disease. In the context of psychiatric illnesses, it is a transdiagnostic phenomenon that features across all ages, and often causes significant distress and impairment. In mood disorders, irritability is near ubiquitous and plays a central role in diagnosis and yet, despite its prevalence, it remains poorly understood. A neurobiological model of irritability posits that, in children and adolescents, it is consequent upon deficits in reward and threat processing, involving regions such as the amygdala and frontal cortices. In comparison, in adults with mood disorders, the few studies that have been conducted implicate the amygdala, orbitofrontal cortices, and hypothalamus; however, the patterns of activity in these areas are at variance with the findings in youth. These age-related differences seem to extend to the neurochemistry of irritability, with links between increased monoamine transmission and irritability evident in adults, but aberrant levels of, and responses to, dopamine in youth. Presently, there are no specific treatments that have significant efficacy in reducing irritability in mood disorders. However, treatments that hold some potential and warrant further exploration include agents that act on serotonergic and dopaminergic systems, especially as irritability may serve as a prognostic indicator for overall clinical responsiveness to specific medications. Therefore, for understanding and treatment of irritability to advance meaningfully, it is imperative that an accurate definition and means of measuring irritability are developed. To achieve this, it is necessary that the subjective experience of irritability, both in health and illness, is better understood. These insights will inform an accurate, comprehensive, and valid interrogation of the qualities of irritability in health and illness, and allow not only a clinical appreciation of the phenomenon, but also a deeper understanding of its important role within the development and manifestation of mood disorders.