Why some people respond to antidepressants when others don’t.

So, it is not quite like learning that the sun is not carried on the back of a turtle but seeing the sun continue to rise, but it is similar.

Over the years patients have come to me saying they think they have or have been told they have a chemical imbalance of neurotransmitters. I would try not to roll my eyes but when really irritated I would ask which neurotransmitter was out of balance and how was it measured. In reality, it was a metaphor and not a biological assay, and although they did not know the details of how this worked, it at least gave it a medical, biological reason they were depressed instead of it being due to poor choices and moral ineptitude. They were referring to what is called the serotonin hypothesis of depression that has been around for 50 years based on the observation that when medications, like the old antihypertensive medicine reserpine, depleted amines in the brain, depression ensued. Later, tricyclic antidepressants and monoamine oxidase inhibitors were found to increase the effects of serotonin and other monoamines in the space where two cells communicate, the synapse, and the theory has been that depression can be caused by a decrease in serotonin and depression can be treated by medicines that increase serotonin.

Antidepressants are our first line of treatment for depression and they have brought relief to millions of patients but not everyone responds to medications as about 30% of patients do not respond to antidepressants. A study just published in Molecular Psychiatry described some novel research techniques that led to some fascinating results that may provide some of the answers as to why some people respond to antidepressants and others don??. And it raises questions about some of our old beliefs.

Selective serotonin reuptake inhibitors (SSRI??) are most prescribed antidepressants so the researchers chose to investigate the neural mechanism responsible for the success and failure of the neurotransmitter, serotonin. Initially, they took 803 patients and placed them on an SSRI antidepressant for eight weeks. They then chose 3 patients who were excellent responders and 3 patients who very poor responders and took blood samples from them and then did some very complicated analyses.

According to the serotonin hypothesis one would expect to find a greater amount of serotonin in the blood of the responders and a higher rate of response to the SSRI??. But they found no difference in blood concentration between responders and non-responders and there were no correlations between blood concentration of serotonin and therapeutic outcome.

Then they did something I did not know could be done. They grew serotonergic neurons (brain cells) from responders and non-responders by using dermal fibroblast cells that underwent complex processing to become these two lines of neurons. When they isolated and compared the neurons between the two groups, an incredibly difficult procedure, they found that the non-responding serotonergic neurons were longer and had more branch points than neurons of the responders. They then did a gene analysis and found that the non-responders had lower amounts of 2 genes, protocadherins PCDHA6 and PCDHA8, which are genes thought to be predominantly expressed in the developing nervous system that may provide a synaptic-address code for neuronal connectivity. Further analysis indicated that there was a reverse correlation between the level of PCDHA6 and PCDHA8 and the length of the neuron in non-responders. Lower levels of PCDHA6 and PCDHA8 resulted in longer neurons and higher levels of these genes produced normal length neurons suggesting that this longer, cellular phenotype may be associated with SSRI treatment resistance


What does this mean?

Depression is a very complex condition and seems to have many subtypes. There is a fairly constant barrage of research into factors like proteins, receptors, cellular membrane channels, genes and other factors that seem impact causes of depression and whether a person is a responder or non-responder. Sometimes there are so many factors posited for influencing depression I am surprised any of our medicines work but we have a 50-year history of patients??depressions responding to serotonergic antidepressants (as well as other antidepressants). This research is another insight into the actual mechanism of what possibly causes depression and why some people respond to antidepressants when others don??. So, in the future patients may come in with depression complaining that their neurons are too long instead of having a chemical imbalance.

What are the alternatives?

TMS Solutions was created seven years ago with new technology as its basis. It is FDA cleared as a process and as a device. Several million treatments have been given using this technology. While there will continue to be medications developed and prescribed, TMS Solutions provides a safe, drug-free, non-systemic solution that is covered by most insurance providers. If the medications you are taking aren?? providing the outcome you expect, if you??e tried and failed four medication treatments, then it may be worth talking to your health provider about TMS Therapy.

If you live in Colorado, Washington or Wyoming  — and coming soon in Utah, you may speak with a TMS Solutions Patient Advocate to see if TMS Therapy is right for you.




Vadodaria, K. C., Ji, Y., Skime, M., Paquola, A. C., Nelson, T., Hall-Flavin, D., … & Dani, K. (2019). Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons. Molecular psychiatry, 1.