A Delphi-method-based consensus for clinical domains and assessment of the inflammatory subtype of major depressive disorder from the ASPIRE study

Background: Elevated inflammatory biomarkers have been consistently associated with a subset of depressive symptoms, particularly atypical and energy-related features, as well as antidepressant treatment resistance. This evidence has supported the definition of an inflammatory subtype of major depressive disorder (ISMDD), characterized by immune-inflammatory dysregulation and reduced response to first- and second-line antidepressants. However, a lack of consensus on its definition and assessment tools limits research and treatment development. Methods: Using a Delphi approach, international experts from the ASPIRE consortium (Advanced Stratification of People with Depression based on Inflammation, n = 25) identified ISMDD symptom domains, which were then evaluated by the European College of Neuropsychopharmacology Immuno-Neuropsychiatry Network (INPN-ECNP, n = 12). Using the same consensus structure, the coverage of these domains by depression rating scales was then assessed. People with lived experience (PWLE, n = 11) provided perspectives on the clinical relevance and impact of the emerged symptoms. Results: ASPIRE consensus identified ten ISMDD symptom domains: fatigue/low energy, hypersomnia, increased weight/appetite, cognitive difficulties, lack of motivation, anhedonia, diminished interest, leaden paralysis, psychomotor retardation, and insomnia, with the first five being also confirmed by INPN-ECNP consensus. Except for increased weight/appetite, PWLE identified these domains as negatively affecting quality of life; most of them were also reported as not extensively assessed in clinical care. Among rating scales, the Inventory of Depressive Symptomatology tools, including their Quick versions, were the only instruments covering all or almost all the ISMDD domains. Conclusion: These findings support a framework for ISMDD and highlight the importance of symptom assessment to improve clinical evaluation, research, and personalized immunopsychiatric treatment.