Depression impacts over 300 million people worldwide, and and it’s thought that about 6.7 percent of Americans experienced a major depressive episode in 2016. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant, but they don’t work for about a third of the people that take them. Salk Institute researchers have found a potential explanation for that; in some people, SSRIs cause neurons to become hyperactive. The findings have been reported in Molecular Psychiatry.
"This is a promising step toward understanding why some patients don't respond to SSRIs and letting us better personalize treatments for depression," said the senior author of the study, Salk Professor Rusty Gage, president of the Institute, and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.
Major depressive disorder (MDD) has been connected to problems with a signaling chemical in the brain - a neurotransmitter called serotonin. A neuron releases serotonin, which can then bind to receptors on nearby neurons. SSRIs raise the amount of serotonin that’s available for binding; the drug blocks a transporting molecule that carries serotonin back inside the cells and away from the receptors - stopping reuptake.
Scientists at Salk and the Mayo Clinic looked at how 803 patients with MDD responded to SSRIs. Three patients that were successfully treated for depressive symptoms with SSRIs were selected, along with three that had not seen any improvement in symptoms after eight weeks of SSRI treatment. The researchers used skin cells from these patients to first create pluripotent stem cells and then neurons.
"What's exciting is that we could look directly at human cells, neurons that are not usually accessible in living patients," explained the first author of the report Krishna Vadodaria, a Salk staff scientist. "We can finally tap into the potential of looking at neurons from individuals whose medication histories, genetics and response profiles we know."
The team was able to explore how SSRIs impacted these neurons by exposing them to varying levels of serotonin. Neurons from patients that did not respond to SSRIs had a significantly higher average activity when serotonin was present compared to neurons from SSRI responders or healthy people.
Two serotonin receptors were implicated by additional studies, 5-HT2A and 5-HT7. After blocking these receptors with a chemical, the hyperactivity in the neurons from SSRI non-responders was reduced. Those receptors may, therefore, be a good therapeutic target for depression patients that don’t respond to SSRIs.
"I hope this opens the door to many more studies of individuals who are extreme cases in terms of how they respond to treatments," said Vadodaria. "In turn, that will help us understand major depression in the broader population."
The video above from the Atlantic and by visual artists Emma Allen and clinical neuroscientist Dr. Daisy Thompson-Lake explores the neuroscience of depression with an artistic flare.