Depression and mood disorders can seem universal. But recent research has revealed that some people — specifically those with a smaller-than-normal hippocampus — are more likely to suffer than others. Staff reporter DIVYA SUBRAHMANYAM reports how understanding the genetic link between brain size and mood may help scientists create more effective treatments for depression and bipolar disorder in the future.

There is indeed a biological reason for depression, and it lies much deeper than a series of bad breakups or a miserably dead-end job.

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Scientists have long recognized a link between mood disorders, such as depression and bipolar disorder, and the size of one particular region in the brain, the hippocampus, without understanding the reason for the relationship.

But a recent School of Medicine study has identified a seemingly unrelated growth factor gene — which controls blood vessel growth — whose variations correlate with differences in the size of the hippocampus. A smaller hippocampus volume has been linked in past studies with mood disorders like depression and bipolar disorder, medical school psychiatrist and lead author of the study Hilary Blumberg said. The new discovery could therefore lead to research with dual benefits: more accurate diagnoses of depression and more efficacious anti-depressant drugs.

Blumberg said the study was performed by scanning the brains of subjects with MRI and then analyzing their DNA to detect variation in the gene, known as vascular endothelial growth factor, or VEGF. Only healthy patients without mood disorders were analyzed in the study, she said.

“We were trying to investigate which genetic mechanisms might contribute to differences in the development of emotional brain circuitry in individuals with mood disorders,” Blumberg said. She explained that the researchers compared individuals with similar variations in the gene to see if they could find similarities in brain physiology. And they did — the correlation with hippocampus size.

Blumberg said the link between the gene and hippocampus size can be attributed to the fact that VEGF is neurotrophic, meaning that it contributes to the growth of neurons in the brain.

VEGF at work

VEGF has been studied in numerous biological contexts, including its relationship to asthma, cancer, macular degeneration and cardiovascular disease. Prior to Blumberg’s work, other Yale researchers had also worked on VEGF and hippocampus size.

Psychiatry professor Ronald Duman conducted a study in 2000 that found that some antidepressant drugs encourage neuron growth in the brain. VEGF, he discovered, was the gene underlying this stimulated neurogenesis. Based on Duman’s studies, Blumberg began her own research into the effects of VEGF.

Duman said Blumberg’s new evidence is consistent with his earlier research in that both studies point to increased neuron growth as an effect of VEGF.

“The real key thing will be to determine whether or not there’s also a greater prevalence of that polymorphism in depression and whether or not there’s a correlation,” Duman said. “The hypothesis is that patients with that particular polymorphism would correlate with their depressive symptoms.”

This hypothesis, he said, is currently being tested by Blumberg. Vetting it, Duman said, could allow scientists to develop more effective drugs that would act through the VEGF pathway.

Treating Depression

Current treatments for depression include transcranial magnetic stimulation, electroconvulsive treatment, behavioral therapies and antidepressant drugs, said Yale psychiatrist George Heninger, who was not involved in the study.

He said pharmacological treatments target monoamines in the brain. The treatments inhibit the degradation of chemicals such as serotonin, dopamine and norephinephrine, which help control mood.

Such drugs do not yet specifically target VEGF, Blumberg said, but it is possible that VEGF might act as a mediator of their antidepressant effects.

Further investigation of VEGF’s mediating effects could allow the gene and its function to be harnessed pharmacologically, several researchers said — but the discovery could also have far-reaching effects in the diagnosis of depression.

With a new molecular mechanism to start to look at, we can start to think of new ways to detect vulnerability to a disorder,” she said of potential further work on VEGF.

But the next step will be to further investigate the brain circuitry involved in mood disorders and clarify its relationship to VEGF, Blumberg said.

Joel Gelernter, a Yale psychiatrist who has studied drug dependence genetics and is working with Blumberg on imaging genetics, also said that studying VEGF could allow scientists to better understand brain function and develop better therapies for depression.

“It’s something to bring us to a closer understanding of the relationship between genetic polymorphism [DNA variation among individuals] and brain function,” he said. “And secondly in knowing how specific chains relate to function, which relates to targets of pharmacology.”

Another direction for the future, Blumberg hypothesized, would be to study individual variations in the VEGF gene and in hippocampus size to gain a better understanding of individual biology. This, in turn, could allow doctors to better predict how patients will respond to treatment by various antidepressant medications.

There are currently no biological markers by which doctors can identify patients with depression.

Contact Divya Subrahmanyam at