Biogenic amine hypotheses of depression date back 60 years
at this point. Ron Pies and I reviewed a
couple of the key papers by Kety, Schildkraut and others that were some of the
first to apply what was known about biogenic amine neurotransmitters to
depression. These papers were elegantly written, keenly aware of the dangers of
biological reductionism, and very clear that much more study needed to be done
to either accept or reject the biogenic amine hypotheses. Those hypotheses eventually
extended to the specific neurotransmitters - norepinephrine, serotonin, and dopamine. Much
has been written about the Chemical Imbalance Theory and more recently a Serotonin Theory of depression even though they do not
exist.
I decided to study the transition in hypotheses over the
course of my career by looking at major psychiatric diagnosis and counting the
number of hypotheses in the literature for each diagnosis. For the purpose of this post I will be
posting a list of hypotheses about depression and discussing the implications.
In general, there are many hypotheses about disorders that seem to
linger in the literature. I have not found any solid evidence that hypotheses
are accepted or rejected. There is also the possibility that they can be
combined to produce new comprehensive hypotheses. At this point I have not been able to
identify any solid theories based on the development of hypotheses. But before I get into that a brief discussion
of definitions is in order to add some consistency to the rest of this
essay.
I will be using definitions from a book written in 1986 (1) because
I think they are the clearest. The logical place to start is with a definition
of a theory. Theory is commonly
mistaken for a hypothesis. The best case
in point that I can think of is the Serotonin Theory or Chemical Imbalance
Theory. By
definition, a theory is a group of related principles that can explain
and predict phenomenon in a restricted domain. The domain will vary according
to the discipline. Medicine and psychiatry depend on empirical theories that in
turn are proven or disproven based on observation and evidence. That
demarcation extends to biology in general.
Examples of theories include Evolution, Thermodynamics, The Periodic
Table in chemistry, and Germ Theory. Any
casual look at the biogenic amine hypotheses with respect to serotonin, norepinephrine,
or dopamine will clearly show an elaboration of the neurochemistry and molecular
biology of these systems. It will also show that the research is ongoing and
that levels of prediction are not generalized enough for any marker to be used
for prediction. At that level, biogenic amine theories do not exist and never
have. There is additional confusion added by the common term conspiracy theories
because in science they are really pseudo-theories and do not satisfy
the general definition of a theory. They provide false explanations and predictions.
Scientific laws explain how any branch of science
organizes observations and explains them.
A good example would be the First, Second and Third laws of
thermodynamics. They are taught in physical
science and engineering courses and do predict observations in physical systems
at the macro level. There are some specific
laws in biology like mitochondrial DNA being inherited only from the mother and
both parents contributing equal amounts of genes to offspring in sexual
reproduction.
And finally, a hypothesis is a first step in
developing laws and theories. It
consists of speculation about experimental observations at a more fundamental
level. The Serotonin Hypothesis for
example was proposed since multiple observations about serotonin in depression
were converging to suggest it played a central role in the disorder. It also
occurred at a time when there was much active research on neurotransmitters and
synaptic function. If it had been more widely accepted and there was a more
comprehensive formulation that would have happened. It did not and in at least one authoritative
source – the American College of Neuropsychopharmacology – the Serotonin
Hypothesis disappeared after the Fourth Generation of Progress in 1995.
I have included that transition in the four slides that
follow. I decided to include material from Goodwin and Jamison's Manic-Depressive Illness because it includes a commentary from the pathophysiology section of their book on bipolar disorder:
A comparison of dedicated chapters on serotonin between the 4th and 5th generations is also useful. In the 4th generation there were 12 serotonin focused chapters and in the 5th there was one general chapter.
As noted in the final summary of serotonin (last slide) , the research emphasis transitioned from strictly neurochemistry to the associated neurobiology and macro observations of brain networks. At the same time current literature continues to emphasize the importance of serotonin systems in psychiatric disorders. Although the ACNP Generation of Progress texts stopped with 5th edition I searched for evidence of the serotonin or any biogenic amine hypothesis in a recent comparable text (5). There were no neurotransmitter centric mechanisms with a more primary focus on imaging receptors and transporter proteins and how neural circuitry was impacted. Suggested mechanisms for depression converged on neurotrophic, immune, and neuroendocrine pathways (see table of contents below).
1: The search for the
underlying pathophysiology of psychiatric disorders has continued
emphasis. The speculative mechanisms are
broad and there are numerous hypotheses carried forward – much like the
serotonin hypothesis. It seems unlikely that there will be a single basic mechanism
leading to disorders based on the heterogeneity and polygenic nature of studied
populations (see number
of variants for major depression in the Polygenic Score (PGS) Catalogue.
2: Studying
biological systems requires an appreciation of complexity – particularly when
prediction is a dimension of theories. It is well known for example that
biologically identical or nearly identical organisms can produce different
physical and behavioral outcomes and until all of those mechanisms are appreciated
and incorporated into hypotheses and theories – widely accepted overall theories are unlikely.
3: There are imperfect classifications in biology, medicine, and psychiatry. One of the basic
tenets in medicine is that no two people with the same diagnosis are alike. There are
obvious differences in biology, psychological and sociocultural factors.
4: Physical theories are not perfect. There is active debate about theories that seem to be settled science and whether or not they are complete. Many of those theories are predictive up to a point and useful for many applications - but deficient in some ways. This is all part of the active process of science.
Despite these considerations – obvious questions about the serotonin hypothesis persist. Why are medications with a high affinity for serotonin receptors and serotonin transporter (SERT) effective medications for several disorders? Why in a recent preclinical study (6) was elevated extracellular serotonin a common signal for several treatments – some of which did not target serotonin systems? And – is it possible that serotonin signals are just the initial sequence of a larger series of events that leads to an antidepressant or anxiolytic response?
I would be remiss to not remind readers of the importance of
analyzing the rhetoric in any scientific paper you are reading on psychiatric
topics. On the issue of theories for example, my original source makes the following
observation:
“What is a theory” is not as hard to answer as jesting
Pilate’s “What is truth?”. Indeed, one
difficulty with our question is that there are so many accepted answers, not
that there is none. That is, the term
theory is used in several distinct and legitimate ways in science and medicine,
and an explanatory catalogue of those uses would fill many pages.
“We will limit ourselves to the concept of a theory that
suggests understanding, reliability, and grounded belief.” (p. 113)
If you find yourself suddenly reading about theories,
hypotheses, or laws in psychiatry or any other branch of medicine look for the author's definitions of those terms. Most textbooks
in medicine and biology may mention brief definitions and references to thermodynamics
and evolution but beyond that the terms are missing. These terms are much more common in physical sciences
where the studied objects are more easily classified and experimental
observations are clearer.
So what is the answer to "When did the serotonin hypothesis of depression disappear?" One short answer is "between 1995 and 2002." But the reality is that it is still with us despite active campaigns against it and several proclamations in the press that it is "dead". At this rate it may outlive its detractors.
George Dawson, MD, DFAPA
References:
1: Albert DA, Munson
R, Resnick MD. Reasoning in medicine: an
introduction to clinical inference.
Baltimore, USA: The Johns Hopkins
University Press, 1988: 112-149.
2: Pies R, Dawson G. The Serotonin Fixation: Much Ado About Nothing New. Psychiatric Times. 2022 Aug 22
3: Goodwin FK, Jamison KR. Manic-Depressive Illness. New York: Oxford University Press, 1990.
4: Bloom, F.E. and Kupfer, DJ. Neuropsychopharmacology: The Fourth Generation of Progress. New York: Raven Press, 1995.
5: Davis KL, Charney
D, Coyle JT, Nemeroff C. (2002) Neuropsychopharmacology: The Fifth Generation
of Progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
6: Charney DS, Gordon JA, Buxbaum JD, Picciotto MR, Binder EB, Nestler EJ. Charney and Nestler's Neurobiology of Mental Illness. New York: Oxford University Press, 2025.
7: Witt CE, Mena S, Holmes J, Hersey M, Buchanan AM, Parke B, Saylor R, Honan LE, Berger SN, Lumbreras S, Nijhout FH, Reed MC, Best J, Fadel J, Schloss P, Lau T, Hashemi P. Serotonin is a common thread linking different classes of antidepressants. Cell Chem Biol. 2023 Dec 21;30(12):1557-1570.e6. doi: 10.1016/j.chembiol.2023.10.009. Epub 2023 Nov 21. PMID: 37992715.
Supplementary 1: I contacted several experts involved in this research over the years. So far none of the researchers I have contacted have responded to my questions that were specific to the serotonin hypothesis.
Supplementary 2: The book cover images and quotes are all property of their copyright owners and do not imply any connection to this blog. They are used here for illustrative and educational purposes. I encourage any readers of this blog to do their own research by reading the reference materials. The ACNP 4th and 5th Generation of Progress are both available to read free online at the ACNP web site.
