Today was a good day for psychiatric criticism. An “Umbrella Review” that essentially declared that serotonin was dead in psychiatric research (1) has essentially been refuted (2). I do not want to mischaracterize the authors conclusion so here it the direct quote from the original paper.
“This review suggests that the huge research effort based
on the serotonin hypothesis has not produced convincing evidence of a biochemical
basis to depression. … We suggest it is
time to acknowledge that the serotonin theory of depression is not empirically
substantiated.” (1)
Ron Pies, MD and I (3) noted several problems with the paper
on a historical and rhetorical basis and penned a response based on those
elements of the paper. The authors used
the terms “serotonin theory” and then “chemical imbalance theory” interchangeably
in the paper. We knew that the former
was a hypothesis at best and the latter really did not exist as either a
hypothesis or theory in the psychiatric literature. We referenced 4 reviews of
the serotonin hypothesis from 1954 to 2017 and the results that the total
evidence was inconclusive or inconsistent.
We included historical quotes to illustrate that researchers investigating
neurochemistry were fully aware of the complexity of psychiatric disorders and
that even clear-cut evidence of a finding implicating a neurotransmitter would
not rule out environmental or psychological factors in the etiology of
depression.
We also discussed the complexity of serotonergic systems in
the brain and the fact that it is an ongoing focus of extensive research and
ongoing publications. The only possible conclusion is that the science around
serotonin is not settled and that needs to be recognized. I put a post on my blog and hoped
to move to a methodological focus on the paper but never got that far.
A group of scientists and psychiatrists was able to do that
in a publication today (2). This paper is
available online and I am not going to repeat their evidence or conclusions
when you can read it yourself at the link below. It is a very brief paper and I highly recommend reading it. This group found substantial methodological
problems with the paper and concluded that there were substantial errors and misinterpretation
of the data in the original paper. Their
conclusion was the errors prevent readers from drawing any “reliable or valid conclusions"
and:
“A more accurate, constructive conclusion would be that
acute tryptophan depletion and decreased plasma tryptophan in depression indicate
a role for 5-HT in those vulnerable to or suffering from depression, and that
molecular imaging suggests the system is perturbed. The proven efficacy of
SSRIs in a proportion of people with depression lends credibility to this
position.”
The most striking aspect of this critique is that it is
authored by 35 scientists – many of whom are also psychiatrists. I have read
papers written by many of them on aspects of the neurobiology of the human
brain in various experimental settings.
There are experts in neuropharmacology and neurobiology. The word brain trust comes to mind
when I think about a group who could have written a response to the umbrella
review or even the original review itself.
In addition to the neuroscience expertise – one of the authors wrote the
reference on rules for conducting an umbrella review (4). There appears to be
no equivalent expertise in the original paper, and in fact very few papers have
that level of expertise. Let me conclude
with some observations based on the current critique:
1: Rhetoric is an important part of both general press and scientific
literature. The authors of the original Moncrieff
review are all on record as supporting positions well outside of mainstream
psychiatric education and practice. To
cite an example, I critiqued a paper by Middleton and Moncrieff on
this blog where I also outlined various examples of philosophical, statistical,
medical, and neuroscience rhetoric that essentially could have predicted the
original umbrella review and both the response by Pies and I as well as the
response by Jauhar, et al. It is probably a good general policy to avoid
entrenched positions when doing systematic reviews and if that is not possible
to stick to clear guidelines for objectivity.
2: The paper today was a welcome return to what psychiatrists everywhere know to be accurate and that is serotonergic systems and the brain in general are complex and the story is incomplete at this point. For the public – proclamations about causes and mechanisms are speculative apart from the evidence reviewed in today’s paper. When you read speculative news stories about psychiatry (they generally all are) maintain a high degree of skepticism – especially if you have found something that is working for you – in this case for depression. Always discuss what you read in the papers with your physician before making any changes.
And for professionals, expertise still means something. With a proliferation of meta-analyses and systematic reviews being published it is evident that many authors have never done research in the field they are attempting to analyze. There is no substitute for experience doing the research and being very familiar with the literature and experimental methods in that field. It is much easier to criticize a clinical trial than to actually do one. That is not just my experience and opinion. Ioannidis has concluded (5): "
3: Several people
today suggested the “damage has been done” by the original paper and there is
certainly some evidence for that. There
were some suggestions that the original paper will be retracted, but I do not
see that happening. Critics of psychiatry always get much more leeway than the
comparatively fewer critics of other specialties. There are many glaring examples, most notably
the Rosenhan paper about psychiatric imposters - even though it was decisively critiqued
at the time of its publication and subsequently shown to have been based on highly
problematic and in some cases false research. That original paper remains in a scientific journal.
4: The profession
and this journal are fortunate for the coordinated efforts by this group of
authors. It will hopefully serve as a
template for responding to similar pieces in the future. I read a lot of papers
in psychiatric journals and the quality of what I read is generally not very
good. Even flagship journals are
publishing articles that are basically opinion pieces that call for significant
modification of the entire profession. These are all typically arguments that
involve author(s) attempting to control the premise of an argument. I have read premises that are either blatantly
false or unprovable and somehow these pieces are published in journals for
psychiatrists. I also read medical literature and apart from the usual pieces claiming
proclaiming the greatness of managed care and administrators in the American
healthcare system – there are no calls for broadly reforming any other specialty.
Like every other psychiatrist out there, I went to work for 35 years and was
able to make a difference by helping people, doing research, and teaching in
very taxing environments. Editing and peer review both need to improve - but in an environment that encourages excessive publishing it is doubtful that either will occur.
5: This is also a teaching and learning moment. Resident and faculty research seminars will benefit from reading both papers and reviewing the implications. Some of those implications include questions about why it is so easy for people both inside and outside of the professional to suggest major departures in the intellectual trajectory and practice of the field and why that does not happen in any other medical specialty.
If someone makes a claim that the field needs an immediate
change in its intellectual focus or practice – there needs to be a compelling
reason. To paraphrase Carl Sagan –
extraordinary demands require extraordinary proof. We are still waiting for the extraordinary proof
for serotonin, but there is some.
Proclaiming serotonin as a dead end was as big a mistake last year as
it was 8 years ago.
George Dawson, MD, DFAPA
1: Moncrieff J, Cooper RE, Stockmann T, Amendola S,
Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic
umbrella review of the evidence. Mol Psychiatry. 2022 Jul 20:1-4.
2: Jauhar S, Arnone D, Baldwin DS, Bloomfield M, Browning
M, Cleare AJ, Corlett P, Deakin JFW, Erritzoe D, Fu C, Fusar-Poli P, Goodwin
GM, Hayes J, Howard R, Howes OD, Juruena MF, Lam RW, Lawrie SM,
McAllister-Williams H, Marwaha S, Matuskey D, McCutcheon RA, Nutt DJ, Pariante
C, Pillinger T, Radhakrishnan R, Rucker J, Selvaraj S, Stokes P, Upthegrove R,
Yalin N, Yatham L, Young AH, Zahn R, Cowen PJ. A leaky umbrella has little
value: evidence clearly indicates the serotonin system is implicated in
depression. Mol Psychiatry. 2023 Jun 16. doi: 10.1038/s41380-023-02095-y.
Epub ahead of print. PMID: 37322065.
3: Pies R, Dawson
G. The Serotonin Fixation: Much Ado
About Nothing New. Psychiatric Times. 2022 Aug 22.
4: Fusar-Poli P, Radua J. Ten simple rules for conducting
umbrella reviews. Evid Based Ment Health. 2018;21:95–100.
5: Ioannidis JP. The mass production of redundant, misleading, and conflicted systematic reviews and meta‐analyses. The Milbank Quarterly. 2016 Sep;94(3):485-514. https://onlinelibrary.wiley.com/doi/abs/10.1111/1468-0009.12210
Supplementary:
To update Ioannidis observations on the systematic reviews (SR) and meta-analyses (MA) versus randomized clinical trials (RCTs) I pulled up searches for those types of studies on PubMed and graphed them below. The 2023 numbers are incomplete and that results in the tailing off of the graph on the right. The numbers of SR + MA compared with RCTs is striking. For the last complete year of data (2022) there were 38,422 RCTs compared with 42,738 SR and 36,614 MA. As you might be able to estimate from the graph the inflection point where the annual production of RCTs were exceeded by SR + MA is relatively recent in about 2017, but the growth of these two groups has been exponential over the past 20 years. That suggests to me that it is easier to talk about research rather than doing it yourself.
