Immune System May Hold Key to New Depression Treatments

The results “open a whole new set of molecular targets” for possible treatments, said Sternberg. “This is the most exciting area of research into depression.”

The research grew out of Schwartz's earlier work on spinal-cord damage, in which she observed that sensitized T cells generated by injury could either damage or protect neurons, depending on when they were activated.

Still other work indicated that auto-reactive T cells help protect injured central nervous system tissue, maintain hippocampal neurogenesis, and increase expression of brain-derived neurotrophic factor (BDNF).

The researchers vaccinated rats with altered myelin basic protein peptide (A91), chosen because it was already known to activate T cells.

Just as vaccines that prevent infectious diseases use attenuated viruses to stimulate the body's defenses, Schwartz and colleagues used this weakened agonist to stimulate T cells but not make the immune system overreact and cause autoimmune disease in brain neurons.

To begin with, immunization proved to have no effect on naïve, unstressed rats.

Next, Lewis rats (a type frequently used to study autoimmune diseases) were stressed with a varying mix of strobe lights, intermittent white noise, food or water deprivation, a cage tilt of 45 degrees, and other stimuli. This chronic mild stress caused a reduction in two measures of behavior analogous to depressive symptoms: sucrose preference—considered a measure of anhedonia—and reduced mobility in the forced swim test—a test of motivation.

Control rats were injected with a saline solution. Immunized Lewis rats showed a higher sucrose preference compared with that of controls, but no improvement in the forced swim test.

Since Lewis rats have a blunted HPA-axis response to stress, the researchers then repeated the experiment with Sprague-Dawley rats, more commonly used in tests of chronic mild stress. In this group, immunized animals had significantly better scores on both the sucrose preference and forced swim tests than did control rats. However, both groups did equally well on other tests of movement in the home-cage or a novel environment, indicating lessened motivation by the saline-injected control animals but not reduced basic locomotor activity, Schwartz said.

The researchers also examined the rats' brains to observe the levels of BDNF in the dentate gyrus of the hippocampus. Hippocampal BDNF and neurogenesis are known to decrease following chronic mild stress, but stressed rats immunized with A91 had significantly higher levels of BDNF and more cell proliferation than controls.

This finding may further explain the observation in humans that antidepressant drugs take several weeks to work because their effect depends on growth of new neurons in the hippocampus.

Both Schwartz and colleagues and Sternberg acknowledged that a good deal of refinement will be needed to turn these initial results into therapy.

“In terms of a proof-of-principle, it is a well-designed trial,” said Sternberg. “The question is not if it works. It does, but a lot more work needs to be done before immunization could be used for patients.”

“Further studies are necessary to identify the best antigen, regimen, timing, and carrier capable of providing the most effective and risk-free therapeutic vaccination for the protection against chronic stress that often leads to depression,” the authors concluded.

An abstract of “Vaccination as a Novel Approach for Treating Depressive Behavior” is posted at<www.journals.elsevierhealth.com/periodicals/bps/article/S0006-3223(08)00832-9/abstract>.▪