12/10/2010 08:10 am ET Updated May 25, 2011

Advances in How to Think About and Treat Depression

Did you know that there are almost twice as many suicides each year in the United States as there are murders? I was surprised to find out that in 2007, the most recent year on which the CDC provides data, there were almost 35,000 suicides in the Unites States and more than 18,000 murders. These statistics are important because many people still write off psychiatric illness as less important than diseases of the rest of the body, like heart disease and cancer, with the false assumption that psychiatric disease is not fatal. As you can see from these CDC stats, this is just not true. We spend a lot of effort and a lot of money trying to reduce the murder rate, so we should be spending even more trying to treat the central cause of suicide: major depressive disorder.

The good news for depression is that we do have medications that work for some patients. Unfortunately, these medicines do not work for everyone. In fact, STAR*D, a large study funded by the National Institutes for Mental Health, found that less than half of patients got completely well after a single antidepressant was taken, and although more patients got well once they were switched to another medicine, the proportion of those who got better decreased each time a person had to switch to another medication. Since most of the medicines used for depression target similar mechanisms, there is still urgent need for new medications.

Luckily, there have been real advances in what we know about depression and how to treat it. Some of this new research was highlighted at the recent Annual Meeting of the Society for Neuroscience.

One exciting avenue of research has been the identification of interactions between the immune system and depression. Sickness behavior has some common features with depression; for example, both result in fatigue and loss of interest in usually fun activities, and some people become depressed due to an immune response to illness or stress. Scientists have found that blocking the immune system's chemical interleukin-6 (IL-6) can increase motivation for a pleasurable activity in mice that have been sick.

Humans with depression can show increased levels of IL-6. But also people who are not depressed, but are treated for other illnesses with medicines that increase immune function, and therefore levels of chemicals like IL-6, often become depressed. This provides a new way to think about treating depression through actions on both the body and the brain. While studies of agents related to interleukin-6 function are still at the pre-clinical stage, clinical trials are still actively investigating the link between circulating cytokines and depression, particularly in cancer patients.

A number of other studies have found new molecules that are required for antidepressants to work. Both p11 and cdk5 could be new targets for development of medications to treat depression. Depressed patients have lower levels of p11 and this protein seems to be critical for the ability of animals to respond to antidepressants. Animals without cdk5 look like animals treated with an antidepressant, so blocking this protein may be a new way to treat depression.

This year there has also been excitement about speeding up the action of antidepressants. Normally, a patient has to take an antidepressant medicine for several weeks before they start to recover. A medicine called ketamine is exceptional in that people given ketamine are less depressed almost immediately. New research shows that the reason for this response is that ketamine changes communication between nerve cells by activating mTOR that helps make new connections between nerve cells. Ketamine is currently in Phase I clinical trials for rapid treatment of major depression.

Another new approach to depression has been to use drugs that block the action of acetylcholine in the brain. Most antidepressants used today increase the action of serotonin or norepinephrine in the brain. Adding a blocker of acetylcholine can decrease the symptoms of depression in patients who don't respond to existing antidepressants.

Some of these new avenues for treating depression are already close to the clinic and others still need more research before they can be used in humans. A new way to identify medicines that might make it into the clinic is to use fish to screen rapidly through chemicals that act like existing antidepressants. When placed in stressful situations, zebrafish (with a mutation in a receptor important in stress management) displayed depression-like behavior, which was reversed when the fish were given Prozac. This finding not only shows that stress can lead to depression even in fish, it provides a new model to test antidepressants.

It is clear that there is a need for new ways to help patients with depression. Basic research into the causes of depression and the mechanisms of antidepressant effects has provided new targets for developing treatments for depression, but this is just the beginning. Research into the causes and treatments of depressive illness provides hope that patients will not have to suffer with this disease, and perhaps we can hope for the day that death from depression in the United States is no longer more likely than death by murder.