Studies of Susceptibility and Resilience in Depression Point the Way to New Antidepressant Treatment

Studies of Susceptibility and Resilience in Depression Point the Way to New Antidepressant Treatment

Posted: May 1, 2010

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Half of people diagnosed with major depression are not helped by current antidepressant medication; and while depression is believed to have a large genetic component, the genes involved have not been found. Current research seeks to discover the brain pathways and genetic activity that underlie depression, thus opening the way to new forms of antidepressant treatment.

Specific use of animal models of depression and a mouse model that exhibits “chronic social defeat” are important parts of this research. These mice, frightened by exposure to larger, more aggressive animals, show reduced interest in eating, drinking and sex. They have increased stress hormone levels, disrupted circadian rhythms, metabolic changes and avoid social contact. Importantly, as models of depression, they respond to antidepressant drugs. Also important, some of the mice exposed to the stressors don’t display symptoms of social defeat; they are resilient.

The behavioral changes in these model mice result from changes in gene expression. In the nucleus accumbens, a reward region in the brain, DNA is normally loosely packed in nerve cells so as to be available for action — through machinery of the cell that “expresses” certain genes in certain situations. In the stressed mice, the DNA becomes more tightly packed, hampering gene expression. The research hypothesis was that the effect could be reversed with HDAC (histone deacetylase) inhibitors, molecules that promote a more open, and hence expressable, DNA state — and this was ultimately demonstrated. This dramatic antidepressant-like effect has provided the basis for clinical studies to try to adapt HDAC inhibitors as a fundamentally new type of antidepressant treatment.

In order to learn which genes are affected in the nucleus accumbens, data from gene expression studies have been carefully analyzed. (Humans, like mice, have about 22,000 genes.) To date, the lab has identified a few hundred genes that are “upregulated” — more actively expressed — after chronic social defeat. Genes that persist in that state may be related to symptoms that persist. Also of interest are the genes affected by fluoxetine (Prozac).

One of the most interesting findings of this research is that resilience involves unique changes in gene expression that do not occur in susceptible mice, suggesting that resilience itself is an active process.

After mimicking these changes in susceptible mice and reversing depression symptoms, this method may offer a totally new approach to treating depression.

Eric J. Nestler, M.D., Ph.D.

NARSAD Scientific Council Member

Nash Family Professor and Chairman, Department of Neuroscience

Director, Brain Institute

Mount Sinai School of Medicine

In partnership with University of California, Davis, The M.I.N.D. Institute, UC Davis Health System



Discovery to Recovery through Science

More than 40 institutions across the United States and Canada partnered with NARSAD in presenting its “Healthy Minds Across America” series of public talks. Each event helped to bring science to families seeking hope for better treatments of a broad range of mental illnesses.