Doctors warn patients starting on antidepressants that they will have to wait weeks for the effects to kick in. Marketing materials for the drugs claim that the medications correct imbalances of neurotransmitters in the brain. So why must patients wait?

That lag time sparked the curiosity of Ronald S. Duman, Ph.D., the Elizabeth Mears and House Jameson Professor of Psychiatry and Pharmacology. It was clear, he said, that the drugs’ effects on neurotransmitter levels cannot fully explain why the drugs can help relieve depression. “You have to wait for something else to happen,” says Duman.

Duman and graduate student Jennifer L. Warner-Schmidt have now shown that the “something else” can be attributed in part to a growth-inducing protein called vascular endothelial growth factor (VEGF). In a March 13 article in the Proceedings of the National Academy of Sciences, they reported that the neurotrophin VEGF is necessary for antidepressants to work in preclinical models.

In previous rodent studies, Duman had found that sustained use of antidepressants and electroconvulsive therapy (ECT) causes new cells to proliferate in the hippocampus, a brain structure that plays a vital role in memory, emotion and learning. The hippocampus shrinks under long-term stress, and Duman showed that by spurring the growth of new neurons, antidepressant drugs reverse or block the effects of stress on the hippocampus.

Duman and Warner-Schmidt have now linked VEGF to neurogenesis in the hippocampus. They showed that two classes of antidepressants and ECT increase the levels of VEGF, while blocking the effects of VEGF thwarted neurogenesis in the hippocampus.

“Neurogenesis has become very interesting,” said Duman. “Even the idea that you can make new neurons is exciting, and we think that neurotrophins contribute to the effects of antidepressants.”

Duman said that VEGF and at least one other neuronal growth factor, brain-derived neurotrophic factor, are necessary not only to allow neurogenesis but also to support the function of mature neurons. “Trophic factors are not just necessary for survival,” he said. “They are also required for growth, and closely involved in normal function.”

Still, Duman said, his discovery of the role of neurotrophins “is probably not the whole story. You can’t explain the entire action of antidepressants through neurotrophins and neurogenesis.” In the meantime, this new information about VEGF might provide new pathways for antidepressant therapies.