An international study has identified that treatment-resistant depression (TRD) has a differentiated biology from common major depression. By analysing the blood of 300 people with major depressive disorder, researchers have discovered more than 5,000 genes that behave differently in patients with treatment-resistant depression compared to those with non-resistant depression. Many of these genes are related to the immune system, gene regulation, and neuroplasticity. This suggests that TRD is not just a more severe form of depression, but a molecular subtype with mechanisms of its own.
The study, led by institutions such as the Hospital del Mar Research Institute, Pompeu Fabra University, the University of Brescia and the Paris Brain Institute, highlights that a reduced immune response could explain why the usual antidepressants often do not work in these cases. This finding opens the door to the development of more specific and personalized treatments for patients with TRD.
The results are part of the European PROMPT project, which uses machine learning tools to predict which patients might develop TRD. The research teams hope that the combination of clinical and molecular data will lead to the creation of precision psychiatry models, algorithms capable of adjusting treatment according to the biology of each patient, avoiding ineffective therapies.
Sirés et al. Blood transcriptomic analysis reveals a distinct molecular subtype of treatment-resistant depression compared to non-treatment resistant depression. Brain, Behavior, and Immunity, November 2025. DOI:10.1016/j.bbi.2025.106103
