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The most commonly prescribed antidepressants, selective serotonin reuptake inhibitors (SSRIs), raise the fog of depression in many people. But for about a third of people with major depressive disorder, SSRIs do not make a big difference. Researchers at the Salk Institute have identified a possible reason: neurons in at least some of the brains of these patients can become hyperactive in the presence of drugs. The study appeared in Molecular Psychiatry January 30, 2019.
"This is a promising step in understanding why some patients do not respond to SSRIs and allow us to better customize treatments for depression," says Professor Salk, Rusty Gage, lead author of the study, chair of the Institute. and president of Vi and John Adler. for research on age-related neurodegenerative diseases.
Depression affects 300 million people worldwide and more than 6% of the US population is living a major depressive disorder (MDD) episode in a given year. DMD has been linked to an imbalance in serotonin signaling, although the exact mechanism is not well understood.
When the brain cells emit a signal with serotonin, the neurotransmitter is released from one cell, binds to neighboring cell receptors, and then is transported into the first cell. SSRIs increase the levels of serotonin available for signaling by blocking the transporter that normally moves serotonin into cells, according to a process called reuptake.
Gage and colleagues from Salk, along with Mayo Clinic staff, investigated the range of SSRI responses in 803 patients with MDD. In this group, they selected three patients who achieved complete remission of their symptoms of depression with SSRIs, as well as three patients with no improvement in their depression after taking SSRIs for eight weeks. The researchers isolated cutaneous cells from all these patients and three healthy control subjects. They used stem cell reprogramming techniques to transform skin cells into induced pluripotent stem cells (iPSCs) and neurons.
"What's exciting is that we could look directly at human cells, neurons that are generally not accessible to living patients," said Krishna Vadodaria, research scientist at Salk and first author of the new article. "We can finally harness the research potential on the neurons of individuals whose treatment histories, genetics, and response patterns we know."
The researchers studied how the neurons derived from each person responded to an increase in serotonin levels, mimicking the effect of SSRIs. When serotonin was present, some neurons derived from non-responders SSRIs had significantly higher activity on average compared to neurons of healthy individuals or SSRI respondents.
Other experiments have directed the team to two particular serotonin receptors (5 out of 7 known in the human brain), 5-HT2A and 5-HT7. When these receptors were blocked by a chemical compound, non-responder neurons were more hyperactive in the presence of serotonin, suggesting that drugs targeting these receptors might be effective alternatives to SSRIs in some patients, but additional research is needed.
The researchers explain that the methods used in the new document may be more widely applied to other subsets of patients with depression.
"I hope this will open the door to many more studies on individuals who represent extreme cases in terms of treatment response," Vadodaria said. "This will help us understand major depression in the general population."
Apua Paquola, Callie Fredlender, Kelly Heard, Yalin Deng, Amy Le, Sonia Dave, Lianna Fung, Li Xinyi and Maria Machetto of the Salk Institute; and Yuan Ji, Michelle Skime, Timothy Nelson, Daniel Hall-Flavin and Richard Weinshilboum of the Mayo Clinic.
The works and researchers involved have been supported by grants from the Robert and Mary Jane Engman Foundation, Lynn and Edward Streim, the Takeda-Sanford Consortium's Innovation Alliance Grants Program, an outgoing postdoctoral fellowship from the Swiss National Science Foundation (SNSF). ), a Minnesota Partnership Award for Biotechnology and Medical Genomics, a Career Development Award mentored by the NIH-Mayo KL2 Clinic (NCAT UL1TR000135) and a Gerstner Family Mayo Career Development Award in Individualized Medicine.
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