Joint Israeli-U.S. Research Points Way to More Effective Anti-depressants

Scientists cured mice of stress-induced depression using new drugs.

For the last century, research on depression has focused on neurons. But a new study by Israeli and American researchers shows that another type of cell, called the microglia, can cause depression in situations of prolonged stress.

What’s more, they found that using new types of drugs to stimulate the microglia enabled them to cure the depressive symptoms in mice more effectively than could be done using existing anti-depressants.

The researchers from the Hebrew University of Jerusalem and the University of Colorado plan to test the clinical effectiveness of these drugs on human patients in the near future.

The study, which was financed by the National Science Foundation, was published this week in the journal “Molecular Psychiatry.” It was conducted by Hebrew University Prof. Raz Yirmiya and doctoral student Tirzah Kreisel in conjunction with colleagues from the University of Colorado.

That prolonged stress can lead to depression is well known. But the current study, based on experiments conducted in mice, is the first to argue that microglia play a significant role in this process. Specifically, changes in the structure and functioning of microglia can cause depression in situations of prolonged stress, the researchers found.

Microglia, which constitute about 10 percent of all brain cells, are essentially the immune system’s “agents” in the brain. Like immune cells in other parts of the body, they play a role in fighting off bacteria and viruses. But they also play a unique physiological role in brain activity, including in its response to stress situations.

The study involved putting mice in daily situations of moderate but unpredictable stress.

After five weeks of this, the mice developed symptoms of depression: They displayed no interest in pleasurable activity like social play or drinking sweetened beverages, and their production of new brain cells decreased.

In addition, however, they had developed changes in their microglia. During the first week of their exposure to stress, the researchers found, the mice’s microglia underwent an accelerated process of cell division and reproduction that significantly increased the number of microglia. But after that, the opposite occurred.

“This extra activity and proliferation of microglia in the first days of exposure resulted, after another few days, in the death and disappearance of some cells in the area of the hippocampus, which is in the lower part of the forebrain, under the cortex,” Yirmiya told Haaretz. “After several weeks, along with the appearance of depressive symptoms, we saw that some of the microglia had died, and others were undergoing a process of degeneration characterized by changes in their shape – a reduction in their size and a shortening of their branches – and also by a decline in the production of molecules that these cells normally produce.”

To determine whether the changes in the microglia caused the depression or vice versa, the researchers then repaired the degenerated cells by means of chemicals that stimulated the microglia to reproduce and thus raised the quantity of microglia back to normal levels.

“These drugs were administered at a time when the mice were exposed to prolonged stress, displayed depressive symptoms and had already lost many microglia,” Yirmiya noted. “But we found that with the help of these drugs, it’s possible to cure the depressive symptoms and increase the process of producing new nerve cells more quickly and effectively than with most of the pharmaceutical treatments that exist today.”

The researchers plan to conduct clinical tests of the drugs in the near future.

“What’s new here is that until now, biology-based research on depression focused on studying the functioning of neurons, which have been the focus of brain research for the last 100 years,” Yirmiya said. “We’re saying that there’s another type of cell, the microglia, which apparently has a very important causal role in at least some types of depression.”

By 2020, depression is expected to be the second most common cause of illness in the Western world. A national health survey conducted by Israel’s Health Ministry in 2004 found that 7.4 percent of Israeli men and 12 percent of Israeli women are expected to suffer from depression at some point in their lives, and each year, 4.3 percent of women and 7 percent of men are thought to suffer from the disease.

There is currently no agreement in the scientific community as to whether the changes in the brain associated with depression actually cause the illness or are merely a symptom of the illness. According to a paper published by the U.S. National Institute of Mental Health, MRI brain imaging has revealed differences between depressed people and ordinary people in the regions of the brain that process emotions, thought, sleep, appetite and behavior.

Reuters