NARSAD Researcher Discoveries Shed Important Light on Why Antidepressants Can Be Limited in their Long-Term Efficacys

NARSAD Researcher Discoveries Shed Important Light on Why Antidepressants Can Be Limited in their Long-Term Efficacys

Posted: December 1, 2010

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Lynette Daws, Ph.D., is a NARSAD Independent Investigator whose discoveries over the last five years represent not only new knowledge, but seem to be overturning a way of thinking about depression that has been widely accepted for decades.

Depression has long been associated with not enough serotonin in the brain being available to carry nerve messages from cell to cell. Selective Serotonin Reuptake Inhibitor (SSRI)-class antidepressants have been developed to block what is called the serotonin transporter molecule so that more serotonin is available in the brain.

Without this blockage, serotonin is cleared away or ‘vacuumed up’ by these serotonin transporters from the synapse and taken back into the cell that emitted them, before a nerve message can be conveyed successfully to the next cell.

Dr. Daws has focused her research on understanding neurotransmitter and transporter biology, work that has shed light on how SSRIs work and, in many cases, fail to work after they are taken by patients over an extended period.

Motivated by research showing that depression was more likely to occur in people who had a deletion in a gene that controls the manufacture of the serotonin transporter (ST), Dr. Daws sought to discover more about the role of STs and their link to depression. STs are one of many “transporters” in the brain that vacuum up neurotransmitters emitted from nerve cells and carry their “messages” to adjacent nerve cells across tiny gaps called synapses.

The genetic deletion resulting in much less of the serotonin transporter molecule being available to vacuum up serotonin between nerve cells indicates there should have been more than normal amounts of serotonin left in the synapse. But depression has long been associated with not enough serotonin being available. What was going on? This is what Dr. Daws has been dedicated to understanding.

A first NARSAD Young Investigator grant in 2000 started the ball rolling. But it was a NARSAD Independent Investigator grant in 2007 that produced Dr. Daws’ first truly surprising results. In her grant-funded experiments, she subjected mice to “repeated swim,” a stressful regimen that resulted in over-production of corticosterone, a major stress hormone. High levels of this hormone correlate with depression. Yet in the stressed mice, Dr. Daws also observed high levels of serotonin in the synaptic gaps between cells rather than there not being enough serotonin.

This high level of serotonin in the synapse is an effect similar to that produced by SSRI-class antidepressants, which block the serotonin transporter molecule. But these experiments showed the excess of serotonin wasn’t related to the activity, or lack thereof, of the serotonin transporter at all. Dr. Daws discovered that an alternative transporter was being blocked by the stress hormone. Corticosterone is a potent blocker of a naturally occurring molecule called the organic cation transporter, type 3, or OCT3, which is also capable of sweeping up serotonin between cells.

This finding is exciting because it provides a plausible explanation for why SSRIs like Prozac often become less effective over time in some people, and don’t tend to work well at all in people with the short variation of the ST gene. In both cases, Dr. Daws proposes, the OCT3 transporters will sweep up the serotonin in the same way STs do, leaving an insufficient amount of serotonin available.

So a patient takes an SSRI to have more serotonin available, but the body “in its amazing ability to adapt, finds an alternate transporter molecule, OCT3, to do the work that the blocked serotonin transporter is unable to do,” Dr. Daws explains. She now proposes that if  OCT3 can also be inhibited, thus blocking serotonin uptake at least to some degree, people with the short variant of the ST gene might maintain more sufficient levels of serotonin, thus deriving greater benefit from SSRI antidepressants.  Dr. Daws’ current NARSAD-funded work will probe that possibility, while continuing to reveal new information about the function of critical transporter molecules in the synapses between nerve cells in the brain.