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Early life stress may result in a serotonin deficiency


If you have experienced — or are experiencing — mood disorders like anxiety or depression, you know about SSRI’s and chances are they didn’t do much for you. In fact studies indicate that the majority of people with mood and anxiety disorders who receive Selective Serotonin Reuptake Inhibitors (SSRI’s) are not helped by these medications. Sadly, they are the most commonly prescribed class of antidepressant medications, this is because SSRIs are designed to increase serotonin levels, a neurotransmitter in the brain that is key to maintenance of mood.

Researchers have published data suggesting an explanation for the longstanding puzzle as to why low serotonin could not be detected in depression without suicidal intent, even though many antidepressant treatments work by increasing serotonin in areas key for mood regulation, such as the hippocampus. Utilizing the variable foraging demand (VFD) macaque model; where the macaque are placed in a situation which causes artificially induced early life stress, a known cause of mood disorders such as depression and anxiety in both animals and humans.

“We have shown that serotonin is too high near the serotonin brain cells, reducing firing of the serotonin nerve cells through a well-documented negative feedback mechanism in the raphe nucleus. The result is that the hippocampus and other critical brain structures needed for mood maintenance do not get enough serotonin,”Jeremy D. Coplan, MD explains.

“We can see this because the hippocampus is shrunken and the white matter loses integrity. By the time serotonin metabolites are measured in a lumbar spinal tap, the usual way serotonin levels have been measured, the high serotonin has mixed with the low serotonin and you have no difference from people who are healthy.”

“We have hypothesized in an earlier paper that this is a plausible reason why SSRIs may not work in a majority of people, because SSRIs will tend to make the high serotonin even higher in the raphe nucleus. The serotonin neuron may not be able to adapt and restore its firing, inducing a presumed serotonin deficit in terminal fields, evidenced by shrinkage of the hippocampus.”

“We cannot say categorically, in our pre-clinical model, that high serotonin in the raphe nucleus leads to low serotonin in the hippocampus, but studies have shown that people who committed suicide exhibited high serotonin in the raphe nucleus and low serotonin in another area of the brain critical for mood maintenance, the prefrontal cortex. Additional studies should be performed, especially since better understanding of the serotonin system will significantly improve future treatment options.”

In the earlier paper, Dr. Coplan proposed augmentation therapies in treatment-resistant patients, including stacking one medication upon another in the most difficult cases.

“This is what physicians do for hypertension, diabetes, and congestive heart failure,” said Dr. Coplan. “But in psychiatry, we sometimes act as if our medications are so effective that we are exempt from how the rest of medicine deals with difficult-to-treat cases.”

Other approaches to bypass the high midbrain serotonin impasse, are shutting glutamate input into the raphe nucleus, a portion of the brain that controls the release of serotonin, and utilizing drugs that block noradrenergic input into the dorsal raphe.

A recent large-scale study showed only a minority of patients do well on SSRIs, and of those, many lose response in a year or two.

“There is an epidemic of inadequately treated depression and psychiatrists are not well trained to deal with this challenge,” Dr. Coplan observed.

“What they often do is change from one antidepressant to another when there is a lack of response. Eventually the patient becomes non-compliant and the patient, rather than the treatment, is blamed for the non-efficacy.”

“These two papers provide possible insights as to why our treatments are ineffective and what we should be doing to treat patients effectively,” Dr. Coplan said.

“Many academic researchers currently do not practice clinically, so they are out of touch with real-life patients and their struggles. In the meantime, suicide rates have not budged in decades.”

Depression and anxiety are very real and have very real (and measurable) effects on the brain. If you are reading this you may already know that and take comfort that despite what some think — that it is all in your head — science says, and in fact can show conclusively, that this could not be further from the truth. So please, if you feel depressed or suicidal, there is free anonymous (if needed) help, it does get better, and — while it may not feel like it — you are not alone. Suicide is never the only option, regardless of what it may feel like at the time.

Coplan, J., Fulton, S., Reiner, W., Jackowski, A., Panthangi, V., Perera, T., Gorman, J., Huang, Y., Tang, C., Hof, P., Kaffman, A., Dwork, A., Mathew, S., Kaufman, J., & Mann, J. (2014). Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders Frontiers in Behavioral Neuroscience, 8 DOI: 10.3389/fnbeh.2014.00440

Coplan, J., Gopinath, S., Abdallah, C., & Berry, B. (2014). A Neurobiological Hypothesis of Treatment-Resistant Depression — Mechanisms for Selective Serotonin Reuptake Inhibitor Non-Efficacy Frontiers in Behavioral Neuroscience, 8 DOI: 10.3389/fnbeh.2014.00189

4 responses

  1. ano

    Why does the title mention early life stress, but the article only discusses serotonin and medication?


    March 3, 2015 at 12:12 pm

    • Look at the name of the paper:

      Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume

      Early life stress may cause excess serotonin release resulting in a serotonin deficit later on. I guess I should have made that more clear, however this whole article is based on that premise. When there is a trauma (stress) early in life you see high serotonin near the raphe nucleus which causes lower levels in other parts of the brain. This is why SSRI’s don’t work, because you have high levels of serotonin in the area that controls the negative feedback loop for serotonin levels (like if your home thermometer was near the stove where it was really warm, it could cause the rest of the house to be colder because you have a spot of really high warmth and turning up the heat would have little value because the stove already makes the thermometer read a much higher temp.

      Then we get into why you can see normal levels from a lumbar spinal tap, the high levels of serotonin in certain parts of the brain mix with the low serotonin and “you have no difference from people who are healthy”

      I have also updated the article to be more explicit about the connection. Given your confusion, I am assuming others would have the same questions.


      March 3, 2015 at 12:40 pm

  2. ano

    I really appreciate the clarification. Someone close to me had a very stressful childhood and has endured recurring bouts of deep depression throughout their life. So, I was curious to what extent childhood stress induced depression differs from others in terms of treatment (like SSRI) or illness trajectory.

    Particularly the comment response does seem to imply this raphe nucleus concentration is more common in childhood stress induced depression. I found your writings on the subject very informative overall, thank you!


    March 17, 2015 at 10:42 am

    • Thank you and I’m really sorry to hear that your friend had a stressful childhood, I hope they find some peace.


      March 17, 2015 at 2:15 pm

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