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Scientists Have Discovered a New Subtype of Depression—and It May Be Harder to Treat

Daniel Z. Lieberman, MD

Written by Daniel Z. Lieberman, MD

Published 08/01/2023

Updated 08/02/2023

Researchers at Stanford University have discovered a new kind of depression. That may sound about as appealing as discovering a new kind of mold in your refrigerator, but it’s actually good news. 

Dr. Lieberman: Hours after you take your first dose of an SSRI, you see increased serotonin activity in the brain. And previously, we had thought that that was the mechanism by which it cures depression: Serotonin is a feel-good neurotransmitter. If you have more of it, you feel better. But that explanation left us stuck with a problem: The serotonin goes up right away, but the actual antidepressant effects are delayed between two, four, maybe even eight weeks. We've been trying to figure out why that is, and this study may shed some light on that. 

The hypothesis of this study was that the way these antidepressants work is by increasing synaptic density. Now, what is synaptic density? The synapse is the basic unit of communication within the brain. 

The brain consists of billions of individual neurons. Those are brain cells, and they’re in constant communication with one another. A huge part of how they communicate with each other is exchanging tiny amounts of chemicals called neurotransmitters. 

When you have two brain cells that are communicating with one another, there are pieces of the brain cells—you can think of them as branches—that are very, very close to one another. One of the brain cells releases the neurotransmitter, and that diffuses across a microscopic, fluid-filled gap, and interacts with receptors on the brain cell receiving the message. That structure, the two brain cells close together, is called a synapse. 

Now, we know that when people get depressed, they lose synapses. They lose these branches, and their neurons start to look like the Charlie Brown Christmas tree. So the question, then, is whether antidepressants such as escitalopram work by replacing those branches and making the brain cells “bushy” again, so to speak. We call that neuroplasticity, which basically means the brain’s capacity to change. 

What this study found was that it seems as though four weeks of treatment with escitalopram led to an increase in that synaptic density. So even though you’re getting more serotonin right away, it takes some time for those branches to fill out before you may start feeling better.

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The first important thing to note is that this was a very small study—only 32 people total, and of those 32, only 17 were in the volunteer group taking escitalopram. The reason the study was so small is because studies that involve brain scanning are expensive.

Another important takeaway is that researchers looked at two regions in the brain: One region was the hippocampus, a very important region in the brain that helps us with memory and with managing negative emotions such as fear. And we find through neuro-imaging studies that people experiencing depression have a shrunken hippocampus. The other area they looked at was the frontal cortex, which is involved in cognition and regulating behavior. 

The researchers’ hypothesis was that after four weeks, participants who’d been taking escitalopram would have increased synaptic density in both of these locations compared to the volunteers in the placebo group. But they did not find a statistically significant increase in the hippocampus, meaning the researchers weren't confident enough that the increase didn't come about simply by chance. 

They did find a statistically significant increase in synaptic density in the frontal cortex. So that was exciting, and it suggests that if maybe they had the patients stay on this medication longer before they measured, or maybe if they had a larger patient group, then the differences in the hippocampus may also have been statistically significant.

Another key limitation is the age-old causation vs. correlation dilemma: What the researchers were able to measure was increased synaptic density, as well as improvement in mood. That doesn't necessarily mean that one caused the other. It’s entirely possible that there was some third factor that responded to the escitalopram that resulted in both the improved mood and the increase in synaptic density.

I'm a clinician, so I really think in terms of helping patients. So for me, the next step is asking, Are there other medications that may increase synaptic density? And are those antidepressants in nature? And most importantly, do they potentially work faster, and on a larger percentage of patients? 

Although SSRIs, including escitalopram, can be miraculously life saving for many, many people, they don't work for everybody. So we do need alternatives, and if we could find something that didn't increase serotonin and then secondarily led to increased synaptic density, but instead targeted synaptic density directly, maybe that would be more effective, because we'd be less dependent on the middleman, so to speak.

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Even though we don’t always know why some people respond well to one medication and not at all to another, the ramifications are clear from a clinical perspective: If you don't respond to one antidepressant, try another one, because there is a good chance that another one is going to work. 

What I find in my practice is that when people don't get better with their first antidepressant, it can lead to pessimism and sometimes despair. But I try to nudge patients away from feeling hopeless, because many times it does take a few tries to find the right one. So people really need to hang in there and keep trying as best they can, because depression is a terrible, terrible illness. And it feels so great when you finally find something that's effective.

5 Sources

  1. Johansen, A., Armand, S., Plavén-Sigray, P., Nasser, A., Ozenne, B., Petersen, I. N., Keller, S. H., Madsen, J., Beliveau, V., Møller, K., Vassilieva, A., Langley, C., Svarer, C., Stenbæk, D. S., Sahakian, B. J., & Knudsen, G. M. (2023). Effects of escitalopram on synaptic density in the healthy human brain: A randomized controlled trial. Molecular Psychiatry. https://doi.org/10.1038/s41380-023-02285-8
  2. Murez, C. (2023, October 12). Some antidepressants take weeks to kick in, and scientists may now know why. HealthDay. https://www.healthday.com/health-news/mental-health/antidepressants-2665851785.html
  3. Chu, A., & Wadhwa, R. (2023, May 1). Selective serotonin reuptake inhibitors. National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK554406/
  4. U.S. Department of Health and Human Services. (n.d.). What are the parts of the nervous system?. Eunice Kennedy Shriver National Institute of Child Health and Human Development. https://www.nichd.nih.gov/health/topics/neuro/conditioninfo/parts
  5. InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Depression: How effective are antidepressants? [Updated 2020 Jun 18]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK361016/
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