A blood test harnessing a brain-enriched circular RNA could predict whether a patient will respond to SSRI antidepressants, according to findings described in two independent clinical trials. The biomarker, a molecule known as CDR1as, was identified as a potential predictor of sertraline response and was associated with class-wide SSRI outcomes in the research published in Molecular Psychiatry. The work was led by Grigorios Papageorgiou, Eleni T. Tzavara and Nikolaos Mellios of Circular Genomics, with collaborators from US and French institutions, and Madhukar H. Trivedi of the University of Texas Southwestern Medical Center.
Major depressive disorder affects millions globally, and doctors often begin treatment with selective serotonin reuptake inhibitors, or SSRIs. These drugs work by increasing serotonin availability in the brain, but fewer than half of patients experience relief after their first prescription. The result is a lengthy period of trial and error, with substantial personal and healthcare costs attached.
The focus of the study is a circular RNA called CDR1as. Circular RNAs are unusually stable loop-shaped genetic molecules that can survive in the body longer than typical RNA. They are concentrated in the brain and can cross the blood-brain barrier, allowing brain-derived molecules to appear in the bloodstream where they can be measured by a standard blood test.
Researchers analysed baseline blood samples from patients diagnosed with major depressive disorder who were about to begin sertraline treatment. They measured the starting levels of CDR1as and tracked responses over eight weeks of therapy.
The team found that patients who did not respond to sertraline by eight weeks had notably higher baseline levels of CDR1as in their blood. By contrast, those who experienced symptom relief began with lower CDR1as levels, and unaffected control subjects also showed comparatively low levels.
Using the clinical trial design, researchers also tracked CDR1as after treatment began. They observed that responders tended to show an increase in CDR1as following the start of sertraline, whereas non-responders did not exhibit a rise in the molecule’s concentration.
To determine whether the biomarker was specific to SSRIs, the researchers looked at other treatment groups. Baseline CDR1as levels did not predict improvement for patients given a placebo, and they did not forecast remission for patients who switched to bupropion, a different class of antidepressant. This suggested the biomarker’s predictive power is linked to SSRI mechanisms rather than general mood improvement.
The team then assessed whether the biomarker applied to the broader SSRI drug class. They analysed samples from patients taking fluoxetine, citalopram or escitalopram, and found that CDR1as levels did identify patients doing well on various SSRIs, not just sertraline. However, with other medication types, the molecule did not predict relief.
In a series of animal experiments, mice were used to explore how CDR1as is produced in the brain. When researchers blocked the serotonin 5-HT2A receptor, Cdr1as levels fell across three brain regions. Blocking dopamine or glutamate receptors did not yield the same effect, establishing a direct link between serotonin system activity and the production of the circular RNA.
Further experiments on cultured human and mouse nerve cells showed that inhibiting brain-derived neurotrophic factor receptors led to lower CDR1as production, implying a connection between this growth-factor pathway and the circular RNA.
The researchers noted certain conditions could affect the test’s accuracy. For example, high baseline CDR1as levels were less predictive in patients with a family history of mania, a possible sign of undiagnosed bipolar disorder. They also cautioned that events that disrupt the blood-brain barrier, such as severe head injury or stroke, could alter circulating levels of the molecule. Future work will need to clarify these effects.
Beyond the biomarker itself, the study linked higher baseline CDR1as with specific depressive symptoms, including anhedonia and social withdrawal—features often associated with a depression subtype historically harder to treat with SSRIs.
The study is titled “A brain-enriched circRNA blood biomarker can predict response to SSRI antidepressants” and lists authors Grigorios Papageorgiou, El Chérif Ibrahim, Victor Gorgievski, Gabriella Maxson, Evelyn Lozano, Eric Gordon, Antoine Lefrere, Marie-Julie Toupet, Philippe Courtet, Raoul Belzeaux, Jane Foster, Thomas Carmody, Roy H. Perlis, Madhukar H. Trivedi, Eleni T. Tzavara and Nikolaos Mellios.
