People react differently to antidepressants. New research is providing us with a better understanding of why some people with depression do not respond to a particular antidepressants.
New research may explain why antidepressants do not always work.
Depression
Depression is a leading cause of disability that affects all ages and contributes in a major way to the “global burden of disease,” according to the World Health Organization (WHO). The United Nations agency estimate that there are around 300 million people worldwide living with this widespread psychiatric condition.
In the United States, the National Institutes of Health (NIH) suggest that in 2017 around 17.3 million adults, or 7.1 percent of all adults, reported having “at least one major depressive episode” in the previous 12 months.
Understanding the Biology of Depression
Our feelings of happiness and well-being are affected by a chemical called Serotonin. Serotonin is a chemical “messenger” that sends “positive” signals from nerve to nerve. Scientists have suspected that a disruption in the messaging ability serotonin is a key factor in major depressive disorder. The major class of drugs used to treat depression – Selective serotonin reuptake inhibitors (SSRIs) – trys to remedy this disruption by increasing serotonin levels between nerves. However, for reasons that we don’t fully understand, SSRIs do not work for around 30 percent of people with major depression.
A new study describes how, by studying cells from hundreds of people with major depression, the team uncovered differences that could explain resistance to SSRIs. For this study, the scientists took skin cells from more than 800 people with major depression and turned the cells into stem cells. They then tried coaxed the stem cells to mature into “serotonergic neurons” – nerve cells that use serotonin. The research team compared serotonergic neurons of “SSRI non-responders” with those of “SSRI responders.” The non-responders were those individuals with depression whose symptoms showed no improvement, while the responders were those whose symptoms showed the most dramatic improvement to treatment with SSRIs.
Structural differences in nerve cells
In previous work, the researchers had demonstrated that cells from SSRI non-responders had more serotonin receptors, causing them to overreact to the chemical messenger. This new study explored a different facet of SSRI non-response at the cell level. While it found no differences between SSRI responder and non-responder cells in terms of how serotonin was handled, it did show some fundamental differences in the cells themselves.
These differences were in the shape and growth of neurites. Neurites are projections that carry serotonin signals to and from nerve cells. We know that the development of the nervous system relies on tight control of neurite growth. Disruption of this process, according to a 2018 study, can lead to “developmental and neurological disorders.” The team found that the nerve cells of SSRI non-responders had much longer neurites than those of SSRI responders.
An analyisis of the non-responder genes also showed a weaker expression of certain genes (PCDHA6 and PCDHA8). These two genes belong to the family of genes that play a key role in the growth and formation of nerve cells and brain circuits. When the researchers “silenced” PCDHA6 and PCDHA8 in healthy serotonergic neurons, these healthy neurons also grew unusually long neurites, just like the nerve cells of SSRI non-responders.
The researcher concluded that having neurites of the wrong length can disrupt communication in serotonin brain circuits with some regions having too much traffic and others not enough. This finding could explain, why SSRIs sometimes fail to treat major depression. The team now intends to look at the role of the two genes in SSRI non-responders. Also important is that the researcher believe that their findings also offer insights into other psychiatric illnesses that involve disruption of the brain’s serotonin system, such as schizophrenia and bipolar disorder.
Leave a Reply