Atypical depression: state of the art and future perspectives

Atypical depression was first described in the 1950s, but after a surge of interest and publications in the 1980s, this construct appears to have fallen out of focus, with comparatively less literature produced over recent decades. Despite different conceptualisations proposed by different authors, atypical depression is considered by current nosographic classification systems to be characterised by mood reactivity, reversed neurovegetative symptoms such as hyperphagia or hypersomnia, marked fatigue and rejection sensitivity. Core features described in historical accounts also include prominent anxiety symptoms, reversed diurnal variation of mood, and a specific response to monoamine oxidase inhibitors (MAOIs). Many authors have reported latent or future bipolarity in subjects presenting with this depressive subtype, while others have explored a broader spectrum encompassing bipolar spectrum conditions and certain presentations of borderline personality disorder. From a pathophysiological perspective, current evidence suggests that atypical depression represents a biologically and clinically meaningful depressive phenotype, characterised by converging neuroendocrine, immuno-inflammatory, and metabolic alterations, including specific hypothalamic-pituitary-adrenal axis dysregulation and associations with obesity and type 2 diabetes. Additionally, the frequent overlap with the bipolar spectrum has implications for diagnostic formulation and treatment planning in at least a subset of patients. Notably, alongside the classically identified efficacy of MAOIs, a wide range of treatments appears also to be effective in the management of atypical depression, and emerging options like GLP-1 receptor agonists may theoretically prove preferentially efficacious in this depressive subtype.