Tuesday, February 25, 2025

What happened to the Serotonin Hypothesis?

 


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 three slides that follow:

 


 


 


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). 



While there has been no overt rejection of the serotonin hypothesis – people remain interested in it and it is useful to consider why.

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 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:  Bloom, F.E. and Kupfer, DJ. Neuropsychopharmacology: The Fourth Generation of Progress. New York: Raven Press, 1995.

4:  Davis KL, Charney D, Coyle JT, Nemeroff C. (2002) Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia: Lippincott Williams & Wilkins, 2002.

5:  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.


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.

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