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Study links treatment-resistant depression to body mass index
Last reviewed: 02.07.2025
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Genetic factors are a small but significant contributor to severe depression that doesn't respond to standard treatment, according to a study from Vanderbilt Medical Center and Massachusetts General Hospital.
The heritability of treatment-resistant depression (TRD) has significant genetic overlap with schizophrenia, attention deficit disorder, cognitive performance, alcohol and tobacco habits, and body mass index (BMI), suggesting shared biology and potential new avenues for treatment.
The report, published in the American Journal of Psychiatry, provides insights into the genetics and biology underlying TRD, supports the utility of estimating disease probability from clinical data for genomic studies, and "lays the foundation for future efforts to apply genomic data to biomarker and drug development."
"Despite the large number of patients with TRD, the biology remains poorly understood. Our work here provides genetic support for new biological directions to investigate this problem," said Douglas Ruderfer, Ph.D., associate professor of medicine (genetic medicine), psychiatry, and biomedical informatics.
"This work finally gives us new directions rather than just inventing the same antidepressants over and over again for a condition that is extremely common," said Roy Perlis, MD, professor of psychiatry at Harvard Medical School and director of the MGH Center for Experimental Drugs and Diagnostics.
Nearly 2 in 10 people in the United States experience major depression, and about a third of them do not respond to antidepressant medications and therapies. TRD is associated with a significantly increased risk of suicide.
Despite evidence that treatment resistance may be a heritable trait, the "genetic architecture" of this condition remains unclear, largely due to the lack of an agreed upon and rigorous definition of treatment resistance and the difficulty of recruiting sufficient numbers of study subjects.
To overcome these obstacles, the researchers chose a surrogate condition—whether a person diagnosed with major depressive disorder had received electroconvulsive therapy (ECT).
ECT applies low voltage to the head to induce a generalized seizure without muscle twitching. About half of TRD patients respond to ECT, which is thought to improve symptoms by stimulating "reprogramming" of brain circuits after they are disrupted by electrical current.
To ensure the study had sufficient "power," or enough patients, to produce reliable results, the researchers developed a machine learning model to predict, based on clinical information recorded in electronic health records (EHRs), which patients were most likely to receive ECT.
The researchers applied the model to EHRs and biobanks from Mass General Brigham and VUMC and validated the results by comparing predicted cases with actual ECT cases identified through the Geisinger Health System in Pennsylvania and the U.S. Department of Veterans Affairs' Million Veteran Program.
More than 154,000 patients from four health systems with medical records and genotypes, or sequences of their DNA samples, were included in a genome-wide association study that can identify genetic associations with health conditions (in this case, a marker for TRD).
The study identified genes clustered at two loci on different chromosomes that were significantly correlated with the probability of ECT predicted by the model. The first locus overlapped with a previously reported chromosomal region associated with body mass index (BMI).
The ECT-BMI association was inverse, with lower weight patients having a higher risk of treatment resistance.
This finding is supported by research that has shown that patients with anorexia nervosa, an eating disorder characterized by extremely low weight, are more likely than those with a higher BMI to be resistant to treatment for comorbid depression.
Another locus linked to ECT points to a gene that is highly expressed in brain regions that regulate body weight and appetite. This gene has also recently been linked to bipolar disorder, a major psychiatric disorder.
Large studies are currently underway to collect tens of thousands of ECT cases for case-control studies.
Confirming the link between the ECT marker for TRD and complex metabolic pathways underlying food intake, weight maintenance and energy balance could open the door to new, more effective treatments for major depressive disorder, the researchers say.