New research reveals that severe childhood hardships may increase levels of the protein SGK1 in the brain, potentially explaining lifelong mental health issues like depression. Scientists found higher SGK1 activity in the hippocampus of individuals with trauma histories, and inhibiting the protein in mice reduced stress effects. This discovery could lead to targeted treatments, though human applications remain distant.
Experiencing severe hardship early in life, such as abuse, neglect, homelessness, or parental death, affects about 1 in 5 US teenagers, who report at least four such events. These traumas can alter brain development and elevate risks for adult mental health conditions, including depression. "We still don’t really understand the mechanisms by which adversity or stress that is experienced early on in life can have such lasting effects," says Christoph Anacker at Columbia University in New York. People with childhood trauma also tend to respond less to existing antidepressants.
Previous studies link depression to elevated SGK1, or serum and glucocorticoid-regulated kinase 1, in the blood, a protein that influences brain cell communication. Anacker's team examined postmortem brains from 50 men, 36 of whom died by suicide; all had reported on physical or sexual abuse before age 16. In the hippocampus—a region key to stress and memory—genetic material for SGK1 was 33% higher on average in suicide victims compared to others, with even greater increases among those with childhood adversity.
The study also analyzed over 8,500 children aged 9 to 10, finding that those with depression showed heightened SGK1 gene activity, tied to early hardships. In mice experiments, 10 adult males received daily injections of an SGK1-inhibiting drug for 10 days, followed by 5-minute exposures to an aggressive mouse to induce stress. Compared to saltwater-injected controls, treated mice displayed reduced anxiety and depression signs, spending more than twice as long in the center of an open cage.
"When we reduce levels of SGK1 in this brain region, the hippocampus, mice are more resilient to the effects of stress," Anacker explains. SGK1 may impair hippocampal neuron formation, worsening mental health. While the experimental drug is unapproved for humans, other SGK1 inhibitors are in heart disease trials and could be repurposed if safe. However, "this kind of basic research in rodents is many, many steps from the kind of evidence that would be needed to say we have [an] actionable drug target in humans," cautions Katie McLaughlin at Harvard University. The findings appear in Molecular Psychiatry (DOI: 10.1038/s41380-025-03269-6).