An analysis of 84 post-mortem brains found that gene activity and protein levels did not move in step in people with major depression or schizophrenia. Researchers at the Complutense University of Madrid and CIBERSAM led the study.
The 84 samples came from the dorsolateral prefrontal cortex: 28 from people with major depression, 28 from people with schizophrenia and 28 from controls without a psychiatric diagnosis. This brain region supports executive functions. It also plays a role in emotion regulation and stress responses. Across the samples, changes in gene activity did not consistently match the levels of the proteins measured.
Led by the Complutense University of Madrid and CIBERSAM, the research examined mechanisms linked to cellular stress. The team studied inflammation and autophagy, the cell’s system for clearing and recycling damaged components. Researchers also assessed how the endoplasmic reticulum responds to misfolded proteins. The findings appeared in Molecular Biomedicine in 2026. Cristina Ulecia-Morón, a CIBERSAM researcher and the study’s first author, said RNA levels of IRE1α rose significantly in both diagnostic groups.
The mismatch is central to the findings. Some genes showed increased expression, while several measured proteins were generally lower in both disorders. Gene activity alone, then, may not reveal how much of a given protein is present. The authors say more work on post-transcriptional regulation, the processes that act after RNA is produced, is needed to explain the gap.
Differences also emerged between groups. Gene-expression changes were more prominent among men with major depression. Women with schizophrenia showed a greater number of changes. Age-related effects appeared mainly in gene expression, especially among genes linked to autophagy. Researchers also accounted for cause of death.
IRE1α participates in the cell’s response to misfolded proteins in the endoplasmic reticulum. Its RNA levels were higher in both the major-depression and schizophrenia groups, pointing to a shared change in a cellular stress-response mechanism.
Among people with schizophrenia who had died by suicide, researchers found higher expression of IL18 and caspase-5. IRE1α expression was also higher, alongside higher levels of the caspase-8 protein. This pattern is associated with inflammatory processes and cellular stress. The post-mortem findings do not show that these changes caused the deaths or establish their functional effects.
The study examines biological mechanisms, rather than the day-to-day pressures people face. A separate report on household costs covered a different issue affecting people across Europe.
Researchers from the University of the Basque Country also took part. The authors say more studies are needed to establish the findings’ functional consequences and assess their possible use in research into biological mechanisms and future therapeutic targets. This was an observational analysis of post-mortem tissue, not a clinical trial or a basis for changing treatment for depression or schizophrenia.
