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Researchers at the Salk Institute have discovered differences in neuron growth patterns of SSRI-resistant patients. The work has implications for depression as well as for other psychiatric conditions such as bipolar disorder and schizophrenia, which probably also involve abnormalities of the serotonin system in the brain.
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.
"With each new study, we are getting closer to a more complete understanding of the complex neural circuits underlying neuropsychiatric diseases, including major depression. This paper, along with another that we have recently published, not only provides information on this common treatment, but also suggests that other drugs, such as serotonergic antagonists, might provide additional options for some patients,
According to Professor Salk, Rusty Gage, lead author of the study, chair of the Institute, and Vi and John Adler Chair for research on age-related neurodegenerative diseases.
The serotonergic circuit
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.
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 the biochemistry of serotonin, gene expression and circuits were altered in non-responders SSRIs compared to responders using serotonin neurons derived from patients with CT. The use of neurons derived from TDM patients offers a new representation of how SSRI responders compare to non-responders ",
says Krishna Vadodaria, research scientist at Salk and first author of the new article.
Differences of form
From a large-scale clinical study of 800 patients with MDD, the researchers selected the most extreme cases of SSRI response; patients who have significantly improved under SSRIs, and patients who have seen 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 badysis revealed that non-responders SSRIs also had low levels of key genes (protocadherins PCDHA6 and PCDHA8) involved in the formation of neuronal circuits.
SSRI resistance
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,"
said Gage.
The next step is to examine the protocadherin genes to better understand the genetics of non-responders SSRIs.
The research was funded by the Robert and Mary Jane Engman Foundation, Lynn and Edward Streim, an innovation alliance grant program of the Takeda-Sanford consortium (Takeda Pharmaceutical Company), the Swiss National Science Foundation (SNSF), the Minnesota Partnership Award for Biotechnology and Medical. Genomics, the Mayo Clinic's Center for Regenerative Medicine, the NIK-Mayo Clinic KL2 Mentored Career Development Award, the Gerstner Family Mayo Career Development Award in Individualized Medicine, and the National Institutes of Health.
Krishna C. Vadodaria, Yuan Ji, Michelle Skime, Apua C. Paquola, Timothy Nelson, Daniel Hall-Flavin, Kelly J. Heard, Callie Fredlender, Yalin Deng, James Elkins, Komal Dani, Amy T. The, Maria C. Marchetto , Richard Weinshilboum and Fred H. Gage
Altered serotoninergic circuits in neurons derived from patients with major SSRI-resistant depressive disorder
Molecular Psychiatry (2019) DOI – https://doi.org/10.1038/s41380-019-0377-5
Image: Salk Institute.
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