“This could be a primary cause, or at least a major contributing factor, to the signaling abnormalities that lead to depression,” said Ronald S. Duman, professor of psychiatry and pharmacology at Yale and senior author of the study.
Scientists have had a difficult time pinning down the cause of depression, which afflicts almost 16 percent of Americans in any given year and carries an annual economic burden of $100 billion.
Symptoms of depression vary widely among individuals. Most now believe that multiple physiological processes are involved in major depressive disorder. That explains why people respond differently to most commonly prescribed antidepressants, which work by manipulating the uptake of the neurotransmitter serotonin. However, as many as 40 percent of depressed patients do not respond to currently available medications, which take weeks to months to produce a therapeutic response.
Duman’s team did whole genome scans on tissue samples from 21 deceased individuals who had been diagnosed with depression and compared gene expression levels to those of 18 individuals who had not been diagnosed with depression. They found that one gene called MKP-1 was increased more than two-fold in the brain tissues of depressed individuals.
This was particularly exciting, say the researchers, because the gene inactivates a molecular pathway crucial to the survival and function of neurons and its impairment has been implicated in depression as well as other disorders. Duman’s team also found that when the MKP-1 gene is knocked out in mice, the mice become resilient to stress. When the gene is activated, mice exhibit symptoms that mimic depression.
The finding that a negative regulator of a key neuronal signaling pathway is increased in depression also identifies MKP-1 as a potential target for a novel class of therapeutic agents, particularly for treatment resistant depression.
Other Yale authors include Vanja Duric, Mounira Banasr, Pawel Licznerski, Heath D Schmidt, Arthur A Simen and Samuel S Newton.
The work was funded by the U.S. Health Service and State of Connecticut, Connecticut Mental Health Center.