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

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Abstract

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.

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(adapted from Brotman et al. [26]).

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Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine and Health, Northern Clinical School, The University of Sydney, Sydney, NSW, Australia

    Erica Bell & Gin S. Malhi

  2. Academic Department of Psychiatry, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia

    Erica Bell & Gin S. Malhi

  3. Department of Psychiatry, CADE Clinic, Royal North Shore Hospital, Level 3, Main Hospital Building, Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia

    Erica Bell & Gin S. Malhi

  4. Department of Psychiatry, Westmead Hospital and the Westmead Clinical School, Wentworthville, NSW, 2145, Australia

    Phil Boyce

  5. Discipline of Psychiatry, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

    Phil Boyce

  6. Department of Psychological Medicine, University of Otago, Christchurch, New Zealand

    Richard J. Porter

  7. School of Psychology, University of New South Wales, Sydney, NSW, Australia

    Richard A. Bryant

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Correspondence to Erica Bell.

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This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.

Conflict of interest

E. Bell has nothing to disclose. R.A. Bryant has nothing to disclose. P. Boyce has received research support from the National Health and Medical Research Council, speaker fees from Servier and the Australian Medical Forum, educational support from Servier and Lundbeck, has been a consultant for Servier, served on an advisory board for Lundbeck and has served as DSMC Chair for Douglas Pharmaceuticals. R.J. Porter reports non-financial support from CBT-pro, personal fees from Lundbeck, and from Servier, outside the submitted work. G.S. Malhi reports grants from NHMRC, grants from NSW Agency for Clinical Innovation and NSW Ministry of Health, grants from Australian Rotary Health, grants from Ramsay Research and Teaching Fund, grants from American Foundation for Suicide Prevention, personal fees from Elsevier, personal fees from Lundbeck, personal fees from Otsuka, personal fees from Astrazeneca, personal fees from Janssen-Cilag, and personal fees from Servier, outside the submitted work.

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Conceptualisation and original draft by EB. Conceptualisation and reviewing by GM, RAB, PB, and RJP. All authors conducted critical revision for important intellectual content and approved the final manuscript.

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Bell, E., Boyce, P., Porter, R.J. et al. Irritability in Mood Disorders: Neurobiological Underpinnings and Implications for Pharmacological Intervention. CNS Drugs 35, 619–641 (2021). https://doi.org/10.1007/s40263-021-00823-y

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