In stressed animals, inhibition of SGK1 may prevent depressive and suicidal behaviors by increasing the number of new neurons (pink) created in the brain's hippocampus. Photo: Anacker lab, Columbia University Irving Medical Center
Neuroscientists at Columbia and McGill have discovered that high levels of a brain chemical cause depression and suicidal thoughts in people who experienced trauma or adversity during childhood.
The discovery paves the way for a new type of antidepressant that inhibits the chemical, SGK1, which may be a better way to help people who were neglected or abused as children. About 60% of American adults diagnosed with major depression and two-thirds of those who attempt suicide had childhood adversity or trauma.
"Current antidepressants are often less effective for people with a history of childhood adversity, who represent a large proportion of adults with depression," says the study's leader, Christoph Anacker, assistant professor of clinical neurobiology in the Department of Psychiatry at Columbia University Vagelos College of Physicians and Surgeons. "What's exciting about our study is that it raises the prospect of quickly developing new treatments, as SGK1 inhibitors are in development for other conditions, and gives us a screening tool to identify people at greatest risk."
Depression triggered by early life adversity is different
Childhood adversity-from growing up in a dysfunctional family to physical abuse-is one of the strongest predictors of depression later in life.
While SSRI antidepressants are effective for many people with anxiety and depression, they often fail to help patients who experienced childhood trauma. "This suggested to us that the biological processes that lead to depression and suicidality in general may differ from those with less stressful childhoods," Anacker says.
About ten years ago, while searching for potential mechanisms, Anacker and his colleagues found high levels of SGK1, a protein produced in response to stress, in the blood of unmedicated patients with depression.
In the new study, the researchers found high levels of the chemical in the brains of adults who died by suicide, with the highest levels (up to twice as much as other patients who died by suicide) in those who had experienced childhood trauma. They also found that children exposed to early life adversity who possessed gene variants that increase SGK1 in the brain were more likely to develop depression as teenagers, suggesting that the chemical is a catalyst for depression and suicidal behavior.
A new antidepressant?
Anacker says drugs that inhibit SGK1 may have the potential to prevent or treat depression in people exposed to childhood trauma, based on the study's findings in mice. In those experiments, an SGK1 inhibitor injected into the bloodstream prevented the development of depressive behaviors in mice experiencing chronic stress.
SGK1 inhibitors are being tested in people with atrial fibrillation and other conditions, and Anacker's team is now looking to begin testing SGK1 inhibitors in people with depression and a history of childhood adversity. The study also suggests that individuals with depression and early life trauma could undergo genetic screening to determine if they may be most likely to benefit from an SGK1 antidepressant.
"There's an urgent need to identify and treat people with the greatest risk of depression and suicide after exposure to early life adversity and SGK1 is a promising avenue to explore," Anacker says.
References
Additional information
The study, titled "Hippocampal SGK1 promotes vulnerability to depression: the role of early life adversity, stress, and genetic risk," was published in Molecular Psychiatry.
All authors: Amira Millette (Columbia), Milena T. van Dijk (Columbia), Irina Pokhvisneva (McGill), Yifei Li (Columbia), Rory Thompson (Columbia), Sachin Patel (McGill), Rosemary C. Bagot (McGill), Aniko Naray-Fejes-Toth (Dartmouth), Geja Fejes-Toth (Dartmouth), Patricia Palufo-Silveira (McGill), Gustavo Turecki (McGill), Juan Pablo Lopez (Karolinksa Institute), and Christoph Anacker (Columbia).
The study was supported by a NARSAD Young Investigator award from the Brain & Behavior Research Foundation and the Columbia University Department of Psychiatry.
