2016 NETP Investigator Vignette

Title: New P11 Biomarker Predicts Clinical Effectiveness of Antidepressant Drugs

Investigator: Paul Greengard, PhD; Rockefeller University

The work we've done has enabled a new way of viewing brain function in which nerve cells communicate with each other through very complicated signaling pathways involving cascades of proteins inhibiting or exciting each other. So instead of being a single ion channel in the plasma membrane, and we call that pathway today fast synaptic transmission, we found that in the vast majority of cases these signaling pathways we found carried out this cascade of biochemical steps which is referred today as slow synaptic transmission. And you can look at it as a fast synaptic transmission being analogous to the hardware in a computer and the slow synaptic transmission as being the software.

The fast synaptic transmission is true and it's-with the way the major excitatory, the major inhibitory neurotransmitters work, but it didn't really elucidate how the brain is working. The software controls everything. It provides mechanisms for input from many different nerve cell types into a single nerve cell. All that information is integrated into these slow pathways. And so it had this dramatic effect of opening up new opportunities for drug development.

I think one very important area of research in the-in the area of depression is to elucidate these slow synaptic transmission pathways which underlie the malfunction of the cells that are involved in depression. We know empirically to a certain extent, which cell types are involved and by studying the biochemistry of those nerve cells and the signaling pathways that are involved in making them function-it should be possible to develop many new antidepressant drugs.

In the case of Parkinsonism we have obtained data, which indicates that P11 in a certain sub-class of neurons regulates the function of those nerve cells involved in Parkinsonism. In other words, there's certain nerve cells which behave in an abberant fashion in patients with Parkinson's compared to normal patients and P11 is also involved in the function of those cells so we're anticipating that understanding the signaling pathways that evolve around P11 that it should be possible to develop new anti-Parkinson's drugs.

As a result of our research, we have developed a biomarker namely measurement of P11 levels in a certain sub-class of white blood cells which act as a very good predictor of the efficacy of a new drug towards the treatment of major depressive disorder.

We did a collaboration with the National Institute of Mental Health in Bethesda, Maryland and a group at the University of Texas Southwestern in Dallas where we studied levels of P11 in the plasma of normal and depressed people on the baseline conditions and after being given an antidepressant. And we found a correlation between the ability to respond to the antidepressant and the ability to manifest certain changes in P11 in certain sub-classes of white blood cells. We were able to predict, for example, with greater than 95-percent accuracy whether a given drug is going to be clinically effective. This is terribly important because people that are undergoing severe depressive episodes are suicidal and have many other unwanted behaviors. And so we were able to show that there's one class of blood cells where changes in P11 predict with a high-degree of accuracy whether that drug is going to be therapeutically effective in that patient. This means instead of waiting six weeks to know whether this new drug on trial will be effective, you know within a week. And this enables the psychiatrist to switch to another drug very quickly. So you can screen a lot more antidepressants that way at a greatly reduced cost.

One of the reasons that I'm excited about our work on P11 is that it is beginning to unravel the molecular mechanisms to control our mood whether we're happy or depressed. Until this work you could say well, how do these antidepressants work? And the answer would be limited to, well they prevent the reuptake of serotonin so there's more serotonin to activate the post-synaptic cell, and then something happens. We're finding out what that something is. We're elucidating the molecular pathways underlying depression and so I'm very, very excited about it.

The work supported by the DoD program has been of great value in enabling us to make the discoveries that I've been talking about. Hopefully those results that we've gotten will greatly strengthen our chances of getting support from other private and government foundations.