A New Approach to the Diagnosis and Treatment of Depression

Although textbooks and pharmaceutical company literature often claim that the biological component of depression has been clearly defined, the fact is that we still have no certain knowledge about the molecular and biochemical disturbances in depressive disorders. Furthermore, our theories of how antidepressants are constantly being revised, and it is now thought likely that these drugs have several mechanisms of action.

There is an interesting study from the University of Illinois at Chicago College of Medicine and Maryland Psychiatric Research Center in Baltimore in today’s issue of the Journal of Neuroscience.

They have discovered that a change in the location of a protein in the brain could serve as a biomarker for depression. This is exceptionally important, since it may give us a simple and rapid laboratory test to identify patients with depression and, more importantly, to predict clinical response to specific antidepressants.

Over the last few years this same team of researchers, and others around the globe, have been examining a protein named Gs alpha that activates adenylyl cyclase. Adenylyl cyclase is a link in signal transduction that is in part responsible for the action of neurotransmitters including serotonin. Instead of just looking at the biochemical properties of the protein, they have also been looking at the way that it moves in the cell membrane, which in turn impacts the way in which neurotransmitters act on cells.

In both rats and cultured brain cells, Gs alpha changes its location in response to antidepressants, moving out of lipid “rafts” in the cell membrane, to areas of the membrane that allow more efficient communication among membrane components responsible for the action of neurotransmitters. Both antidepressant and antipsychotic drugs have been shown to concentrate in these lipid rafts.

In this new study, brain samples from depressed people who had committed suicide were compared with controls who had no history of psychiatric disorders. Although the total amount of Gs alpha was the same in the depressed and non-depressed, in people with depression, Gs alpha was stuck in these lipid “rafts.” Therefore the protein is unable to do its job of mediating the action of neurotransmitters. Antidepressants have the opposite effect, moving it to regions of the membrane where it can do its work. The localization of other G proteins was not different.

This is such a robust finding, that identifying the location of Gs alpha in the cell membrane may provide an objective diagnosis of depression and second, whether someone is responding to the chosen antidepressant therapy.

The senior author in this research is Mark Rasenick, who is distinguished university professor of physiology and biophysics and psychiatry at the University of Illinois. He described the lipid “rafts” and the importance of the findings like this:

“These “rafts” are thick, viscous, almost gluey areas, that either facilitate or impede communication between membrane molecules… When Gs alpha is caught in these lipid raft domains, its ability to couple with and activate adenylyl cyclase is markedly reduced. Antidepressants help to move the Gs alpha out of these rafts and facilitate the action of certain neurotransmitters.”

He goes on to say,

“This test could serve to predict the efficacy of antidepressant therapy quickly, within four to five days, sparing patients the agony of waiting a month or more to find out if they are on the correct therapeutic regimen.”

The findings may also help explain two old puzzles:

• Why do antidepressants take so long to work?
• Why do such chemically different compounds produce similar clinical effects?

We are going to need a load of further studies to confirm and expand these findings, and to examine the clinical utility of the test. But it’s a great start.