When neurons are not fit, antidepressants may not work

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed drug for major depressive disorder (MDD), but scientists still do not understand why treatment does not work in nearly thirty percent of patients with of CT. Researchers at the Salk Institute have discovered differences in the growth patterns of neurons in SSRI-resistant patients. The work, published in Molecular Psychiatry on March 22, 2019, has implications for depression as well as for other psychiatric conditions such as bipolar disorder and schizophrenia, presumably involving abnormalities of the serotonin system in the brain.

"With each new study, we are getting closer to a more complete understanding of the complex neural circuits that underlie neuropsychiatric diseases, including major depression," says Professor Salk Rusty Gage, lead author of the study. Study, President of the Institute and President of Vi and John Adler for research on age-related neurodegenerative diseases. "This paper, as well as another that we recently published, not only provides information on this common treatment, but also suggests that other drugs, such as serotonergic antagonists, might constitute additional options for some patients. "

The cause of depression is still unknown, but scientists believe that the disease is partly related to the serotonergic circuit in the brain. This is largely due to the fact that SSRIs, which increase neurotransmitter levels, serotonin at the level of neuronal connections, help to alleviate the symptoms of many people with depression. However, the mechanism that explains why some people respond to SSRIs, while others do not, remains a mystery. It has been difficult to solve the problem of SSRI resistance because it requires studying the 300,000 neurons that use the neurotransmitter, serotonin, for communication in a brain of 100 billion neurons in total. Scientists have recently overcome this obstacle by generating these serotonergic neurons in the laboratory.

The previous article of the team in Molecular Psychiatry showed that non-responders SSRIs had an increase in serotonin receptors, which made the neurons hyperactive in response to serotonin. The current paper wanted to look at non-respondents from SSRIs in a different light.

"We wanted to know if biochemistry, gene expression and serotonin circuits were altered in non-responders SSRIs compared to responders using serotonin neurons derived from TDM patients," says Krishna Vadodaria, researcher in Salk and first author of this article. "The use of neurons derived from TDM patients provides a new representation of how SSRI responders compare to non-responders."

From a large-scale clinical study involving 800 patients with MDD, the researchers selected the most extreme SSRI response cases: patients who improved significantly when taking SSRIs and patients who observed no effect. The team took skin samples from these patients and reprogrammed them into induced pluripotent stem cells (iPSCs) to create serotonergic neurons that they could study.

The scientists examined the serotonin targets in the patient 's serotonergic neurons, including the enzyme that makes serotonin, the protein that carries it, and the enzyme that breaks it down, but found no difference in biochemical interactions between groups. Instead, the researchers observed a difference in how neurons responded to their shape.

The neurons of the non-responders SSRIs had neuronal projections longer than those of the responders. Gene analysis revealed that non-responders SSRIs also had low levels of key genes (protocadherins PCDHA6 and PCDHA8) involved in the formation of neuronal circuits. When these genes were rendered non-functional in serotoninergic neurons (mimicking the low levels of previously observed genes), neurons developed the same exceptionally long projections in non-responders SSRIs. These abnormal features could lead to excessive neuronal communication in some areas of the brain and insufficiently in others, which would alter communication within the serotonergic circuit and explain why SSRIs do not always treat CT.

"These findings contribute to a new way of looking at, understanding and treating depression," Gage said.

The next step is to examine the protocadherin genes to better understand the genetics of non-responders SSRIs.

Provided by
Salk Institute