Genetics Underlying Antidepressant Treatment Response
Post by Anastasia Sares
What's the science?
Depression is one of the most common psychiatric diseases in the world, and is growing in prevalence: major depressive disorder currently affects about 7% of adults in the USA and around 264 million people worldwide. A large percentage of people go untreated, and of those who do receive medication, not everyone responds to it. We still don’t fully understand how SSRIs, one of the most common depression medications, act to relieve depression in some people. We know SSRIs change the levels of the neurotransmitter serotonin in the brain, but how they relieve symptoms remains poorly understood. Advances in genetic research may help us better understand how they work and predict which people will respond to SSRI treatment. This week in Molecular Psychiatry, Liu and colleagues investigated a gene called ERICH3, showing that it plays a role in serotonin transport and storage, and could be involved in the brain’s response to SSRIs.
How did they do it?
The authors had identified ERICH3 as a gene of interest in a previous genome-wide study in individuals with depression. They found that expression of this gene correlated with levels of serotonin in these individuals, and that it was also associated with their responsiveness to SSRI treatment. They wanted to characterize this gene in more detail, see what kinds of proteins it codes for, and describe how these proteins behave. When a gene is being turned into a protein that can act in the body, not all of the material in the gene is used. Sections of the gene are transcribed into messenger RNA in the nucleus of the cell, and these messenger RNAs leave the nucleus and are translated into proteins. More than one sequence of messenger RNA can be created by reading different sections of the gene. So, the first step to characterizing a gene is to figure out what messenger RNAs are being made. The authors used published data— RNA material collected directly from individual brain cells during surgery— to see which messenger RNAs were present in the human brain.
The next step was to look at the proteins—the functional molecules—coded for by these RNA sequences. For this step, the authors used cell culture: they inserted genetic material derived from their RNA into a dish of living cells. The cells translated this material into proteins, which could then be isolated and analyzed. The authors also decided to knock out the ERICH3 gene in a different set of cells and monitor the effects on serotonin production. The final step was to verify that specific variants of this gene actually affected people’s response to antidepressants in an independent sample. Since the gene had been originally identified by a similar correlation, it was important to show that it could be replicated in a new group of people, and wasn’t due to random chance.
What did they find?
There were 3 predominant sequences of RNA produced by the ERICH3 gene, and these were most prevalent in neurons. The proteins created from the RNAs were located in the cytosol (outside the cell’s nucleus), and associated with vesicle-like structures (vesicles are little packets of chemicals, including neurotransmitters, surrounded by a spherical membrane). The authors discovered that ERICH3 proteins would also bind to other molecules known to interact with vesicles. This finding suggests that ERICH3 might be involved in releasing and recycling serotonin—a process that SSRI drugs interfere with. When ERICH3 function was blocked, serotonin levels did indeed decrease. Finally, in an independent sample, the authors found that an individual’s genetic sequence in the ERICH3 gene was associated with their SSRI response.
What's the impact?
This work is crucial for our understanding of SSRIs and will help us understand which people are likely to respond to them, making it easier for psychiatrists to find the right medication for their patients sooner. That being said, medication is not the only way to tackle depression; psychotherapy and other lifestyle changes like regular exercise may also help, and combining approaches may be even more beneficial.
If you think you are experiencing symptoms of depression, don’t be afraid to reach out and get help. Do a quick internet search for mental health resources in your area, or try the following links:
Liu et al. ERICH3: vesicular association and antidepressant treatment response. Molecular Psychiatry (2020). Access the original scientific publication here.