Over the past week a review was published in Molecular Psychiatry that claimed to discredit nearly all of the previous work on serotonin hypotheses of depression (there are far more than one). Ron W. Pies, MD, and I wrote a rejoinder to this review. Whenever you consider a commentary about a published paper the level needs to be considered. For example, if the paper is a polemic – responding to the rhetoric is one approach. For those not familiar with the rhetoric around this issue take a look at this previous post on Chemical Imbalance Theory and you will be brought up to speed. If you need additional information here is a second, more recent post. If the paper is primarily scientific then responding to the science and measurements in the paper is another. These days, responding to the statistics is a third option and in the case of specialized reviews like an “umbrella review” commentary on the methodology is a third. For our initial effort we made a conscious decision not to go “to far into the weeds” of science or statistics.
On that basis, we respond to a fair amount of rhetoric and
science. I refer interested readers to our paper published this morning on the Psychiatric
Times. On that page the study I am
referring to is reference 1, The serotonin theory of depression: a systematic
umbrella review of the evidence. The serotonin
theory of depression is just like Fight Club – there is no serotonin theory
of depression and that is one of the first points we make in the paper.
As far as the science of serotonin goes – it is fairly
intense. Since 1957 when there were only 2 known serotonin receptors types, we
have developed a lot of knowledge about this system. With that knowledge there has been a mind-boggling
amount of system complexity that nobody has been able to explain to date. We
are basically getting glimpse of how the entire system works. It is highly
likely that there are behavioral, cognitive, and autonomic correlates of these
systems – but we have a way to go. Back in the day when I was a research fellow in neuroendocrinology I tried (in vain) to find out how serotonin signaling affected the HPA axis. Practically all researchers at the time considered monoaminergic hypotheses of mood disorders to have heuristic value (see the quote below). The intervening 30 years of advanced research proved them correct. The authors of the umbrella review conclude
that it is time to acknowledge that the serotonin theory of depression is
unsubstantiated despite a large research effort and that this should be
acknowledged. That is difficult to do
when they seem to be the only people promoting this theory.
For those interested in excellent summaries of current
serotonin research I suggest the following volumes written by 41 and 128
scientists respectively.
At some point, I will take a much closer look at the methodology used in this study. Just looking at the PRISMA diagram and 360 reviews being pared down to 17 with just a few in some categories – suggests that the umbrella has collapsed.
George Dawson, MD, DFAPA
Reference:
Ron W. Pies, George Dawson. The Serotonin Fixation: Much Ado About Nothing New, Psychiatric Times. August 3, 2022
https://www.psychiatrictimes.com/view/the-serotonin-fixation-much-ado-about-nothing-new
Supplementary Graphic:
When I first started to respond to the chemical imbalance theory rhetoric - I took all of the psychopharmacology books off my shelves from the past 35 years to illustrate that in all of those texts on the subject there were no references to a chemical imbalance theory and that I had never been taught such a theory by my professors (many of whom were leading psychopharmacologists). Since the original photo, my stack of psychopharmacology journals has increased about 3/4 of a foot and that would bring the stack up to about 5 feet. I am not going to pull them all down to remeasure so I just made this graphic.
Graphics Credit:
The iceberg graphic at the top of this post was done by the following authors and I added the text only. Full credit is listed below per Wikimedia and CC licensing:
Created by Uwe Kils (iceberg) and User:Wiska Bodo (sky)., CC BY-SA 3.0
I enjoyed reading the Psychiatric Times article by you and Ron Pies. In general, it reminded me of my former department chair’s (Bob Robinson) recommendation to use the book The Perspectives of Psychiatry by McHugh and Slavney, which recommended an essentially biopsychosocial approach: disease, dimensional, behavior, and life story. It was later developed into the more explicit guide, Systematic Psychiatric Evaluation, by Chisolm and Lyketsos (2012).
ReplyDeleteThanks!
DeleteBoth are excellent books. What I find most interesting is that researchers in the 1960s to the 1980s were very cautious about interpreting any biological findings as theories (it basically never happened) and many of their quotes capture the complexity of the systems involved. I was a research fellow for one of those years doing neuroendocrine research and I recall trying in vain to figure out serotonergic signaling involved in the HPA axis. The term "heuristic value" was ever present as the raison d'être for biological research and very few people give a tip of the cap to the scientific thought involved.
A quote from those times - Harvard Guide to Psychiatry (1988 version) off my reserve shelves in the Biochemistry of Depression chapter written by Green, Mooney, and Schildkraudt (p. 136):
Delete"For over 20 years the catecholamine hypothesis of affective disorders proved to be a model of heuristic value; it provided both investigators and clinicians with a frame of reference for understanding much of the available data about depression and mania while it stimulated new research on their biochemistry."