Why Do Some People Not Respond to SSRIs?


Serotonin refers to a chemical messenger that has a huge impact on your feelings of wellbeing and happiness.

Scientists have been suspecting for a long time how disruption in the brain circuits of serotonin can be a key factor in causing the major depressive disorder. This disruption can be controlled by selective serotonin reuptake inhibitors (SSRIs) which help increase the levels of serotonin at the nerve junctions. But a growing resistance has been reported towards SSRIs.

A recent research paper has intended to unravel the mystery behind this resistance.

Depression and Response to SSRI

Depression is among the leading causes of disability that can affect people of all ages. It also significantly contributes to the global burden of disease. It has been estimated that there are currently 300 million people living with depression.

For this research study, the researchers took the skin cells from over 800 people suffering from depression and converted them into stem cells. These stem cells were then coaxed to mature into the serotonergic neurons i.e. the nerve cells that produce the brain circuitry for generating and using serotonin.

The team then made comparisons between the serotonergic neurons of SSRI non-responders and the ones of SSRI responders. The non-responders referred to the individuals whose depressive symptoms showed no improvement. On the other hand, there were responders whose symptoms had drastic improvements.

In their previous work, the researchers also demonstrated that the cells coming from SSRI non-responders contained a higher number of serotonin receptors making them overreact to this chemical messenger.

The Difference in Structure of Nerve Cells

The new study checked a different facet for the SSRI non-response on a cell level. No difference could be found between the responder and the non-responder cells in the context of serotonin biochemistry. However, it was able to reveal certain fundamental structural differences in cells.

The differences were found in the growth and shape of neuritis, even in the projections that are responsible for carrying signals towards and away from nerve cells.

Tight control of the neurite growth is what the development of your entire nervous system relies on. Any disruption in this process may lead to neurological or developmental disorders.

The team found out that the nerve cells taken from the SSRI non-responders were found to have longer neuritis as compared to those of the responders. A genetic analysis was performed which showed a weaker expression of PCDHA8 and PCDHA6 in the non-responders.

These two genes are a part of the protocadherin family and play a major role in the formation and growth of brain cells and nerve cells.

When the PCDHA6 and PCDHA8 were silenced in healthy neurons, they also grew unusually long neuritis, similar to the ones found in the cells of the non-responders.

Having abnormally long neuritis often lead to a disruption of communication in the brain circuits of serotonin. This makes some of the regions have too much traffic while others may not be enough. This explains why SSRIs are not able to treat depression in all cases.


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Samantha Issac
Samantha is a graduate of Medicine with masters in Public Health. Most of her writings are in medicinal tools, technology, and treatments. In addition to that, she is a freelance healthcare writer based in the USA.


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