Neuroscientists from Columbia University and McGill University have discovered that high levels of the stress-related protein SGK1 are associated with depression and suicidal behavior in people who experienced childhood adversity. This finding suggests potential for new antidepressants targeting SGK1, particularly for those resistant to current treatments. The research highlights how early trauma alters brain chemistry differently from other forms of depression.
Childhood adversity, such as physical abuse or growing up in a dysfunctional family, is a strong predictor of depression in adulthood. Common antidepressants like SSRIs help many patients but are less effective for those with a history of early trauma. About 60% of U.S. adults with major depression and two-thirds of suicide attempters experienced such adversity.
Researchers led by Christoph Anacker, assistant professor of clinical neurobiology at Columbia University Vagelos College of Physicians and Surgeons, identified SGK1—a stress-responsive protein—as a key factor. Around ten years ago, Anacker's team found elevated SGK1 in the blood of unmedicated depression patients. In the latest study, they examined brains of suicide victims and detected high SGK1 levels, with concentrations up to twice as high in those who suffered childhood trauma compared to others.
The team also studied children exposed to early adversity, finding that genetic variants increasing SGK1 production raised the risk of teenage depression. '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 explained.
In mouse experiments, SGK1 inhibitors prevented depressive-like behaviors under chronic stress. These drugs are already in development for conditions like atrial fibrillation. Anacker's group proposes clinical trials for depression patients with trauma histories and genetic screening to identify suitable candidates.
'Current antidepressants are often less effective for people with a history of childhood adversity, who represent a large proportion of adults with depression,' Anacker said. '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.'
The study, titled 'Hippocampal SGK1 promotes vulnerability to depression: the role of early life adversity, stress, and genetic risk,' was published in Molecular Psychiatry.