Scientists find brain chemical tied to trauma and depression

The researchers found that high levels of a stress-related protein called SGK1 are closely associated with depression among people who endured early-life adversity. This discovery opens the door to a new type of antidepressant that blocks SGK1 activity and may be more effective for people who were neglected or abused as children.

Studies show that about 60% of adults in the United States diagnosed with major depression and roughly two-thirds of those who attempt suicide experienced some form of trauma or adversity during childhood.

"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 lead author, 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."

Why Depression After Early Trauma May Be Different

Childhood adversity (such as physical abuse or growing up in a dysfunctional family) is one of the strongest predictors of depression in adulthood.

While common antidepressants like SSRIs are helpful for many people, they are less effective for those who experienced early 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 explains.

Around ten years ago, Anacker's team discovered unusually high levels of SGK1 -- a stress-responsive protein -- in the blood of unmedicated patients with depression.

Evidence of SGK1's Role in Depression and Suicide

In the latest research, the scientists examined the brains of adults who had died by suicide and found elevated SGK1 levels. Those who had suffered childhood trauma showed the highest concentrations, up to twice as much as others who had also died by suicide.

The researchers also studied children exposed to early adversity and discovered that those carrying genetic variants that increase SGK1 production were more likely to experience depression as teenagers. These findings point to SGK1 as a biological driver of depression and suicidal behavior, particularly among people affected by trauma early in life.

Developing a New Kind of Antidepressant

Based on these results, Anacker and his colleagues suggest that drugs designed to block SGK1 might help prevent or treat depression in individuals with a history of trauma. In experiments with mice, SGK1 inhibitors delivered into the bloodstream prevented the animals from developing depressive-like behaviors during chronic stress.

SGK1 inhibitors are already being evaluated for use in other conditions, including atrial fibrillation. Anacker's team now hopes to begin clinical trials in people who have depression and a background of early life adversity. The researchers also propose that genetic screening could identify individuals most likely to benefit from an SGK1-targeted 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.

The research, titled "Hippocampal SGK1 promotes vulnerability to depression: the role of early life adversity, stress, and genetic risk," was published in Molecular Psychiatry.

Authors include 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 funded by a NARSAD Young Investigator award from the Brain & Behavior Research Foundation and the Columbia University Department of Psychiatry.