Scientists from the Salk Institute say they uncovered a possible reason why the neurons in some patients’ brains may become hyperactive in the presence of the antidepressant drugs, selective serotonin reuptake inhibitors. Their study (“Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons”) appears in Molecular Psychiatry.

“Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters,” wrote the investigators.

“We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.”

“This is a promising step toward understanding why some patients don’t respond to SSRIs and letting us better personalize treatments for depression,” said Salk professor Rusty Gage, PhD, the study’s senior author, president of the Institute, and the Vi and John Adler chair for research on age-related neurodegenerative disease.

Gage and his colleagues at Salk, along with collaborators at the Mayo Clinic, studied the range of responses to SSRIs in 803 patients with MDD. From this group, they selected three patients who achieved complete remission of their depression symptoms with SSRIs, as well as three patients with no improvement in their depression after taking SSRIs for eight weeks. The researchers isolated skin cells from all of these patients and from three healthy control subjects. They used stem cell reprogramming techniques to turn the skin cells into induced pluripotent stem cells (iPSCs), and from there into neurons.

“What’s exciting is that we could look directly at human cells, neurons that are not usually accessible in living patients,” said Krishna Vadodaria, PhD, a Salk staff scientist and first author of the new paper. “We can finally tap into the potential of looking at neurons from individuals whose medication histories, genetics, and response profiles we know.”

The researchers studied how the neurons derived from each person responded to increased levels of serotonin, mimicking the effect of SSRIs. When serotonin was present, some neurons derived from SSRI non-responders had significantly higher activity on average compared to the neurons of healthy individuals or SSRI responders.

Further experiments pointed the team toward two particular serotonin receptors (out of seven known in the human brain), 5-HT2A and 5-HT7. When these receptors were blocked with a chemical compound, the neurons of nonresponders were no longer hyperactive in the presence of serotonin, suggesting that drugs targeting these receptors may be effective alternates to SSRIs in some patients, but more research is needed.

The methods used in the new paper can be more broadly applied to other subsets of patients with depression, the researchers said.

“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.”

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