Thursday, June 30, 2022

Chemical Imbalance Theory – Again and Again


I had this letter published today with my co-author Ron Pies, MD. It is basically a rebuttal to a more elaborate article (linked at the top of the letter) on chemical imbalance theory. I encourage any interested reader to look at that argument and then read our brief essay on why none of it supports a chemical imbalance theory.  Both Dr. Pies and I have written about this in the past – me on this blog and Dr. Pies in other literature (5-8). Several other authors have also discussed related issues (1-4, 9).  I think the refutation is fairly straightforward so this blog will be about the process. Why does this along with many other inaccurate portrayals of psychiatry continue to come up in the literature?  What follows is a few very clear answers but I fully realize that theses and explanations are rarely adequate to counter rhetoric.

1:  Repeating inaccurate claims is a standard strategy these days – it actually has been for decades.  The clearest modern example if the Big Lie of the last Presidential election.  Even a comprehensive presentation of the real evidence by the January 6th Congressional Panel is not enough to shake the belief of election deniers.  In fact – election denial has become the latest cottage industry delivering hundreds of local lectures across the country.  Chemical imbalance theory has a similar life of its own and a group of proselytizers.  If the political comparison is too harsh – consider the advertising approaches. Any number of products that make health claims are sold every day based on repeating the same messages.  For years alcohol carried the message that it was a heart healthy product that increased HDL cholesterol and reduced the risk of heart attacks. Now we know that those studies were biased because they included alcohol users in recovery in the control group.  Dietary supplements are a $62 billion dollar industry despite questionable value and some concerns about toxicity in healthy populations with no clear nutritional deficiencies. All of these examples illustrate the power of repetitive messaging.

2:  It appeals to anecdotal experience – a common response is “well I heard somebody say it”, “I saw it posted on a web site”, or “my psychiatrist said it to me.”  Anecdotal experiences exist and obviously we cannot examine the intent of every statement. The reality for psychiatrists is that in psychopharmacology and biological psychiatry lectures, in textbooks, and in the published literature there is no reference to “chemical imbalance theory”.   In fact after reviewing the literature I concluded that comprehensive theories really don’t exist in psychiatry. On the other hand, over the past 40 years there have been over a hundred hypotheses about the causes of depression.

3:  There are clear biases against psychiatry as a field – when reading authors whether in professional journals, periodical, or books it is always useful to consider what else they have written. Is the book or paper a one-sided harsh criticism?  Does their previous work seem to make similar statements about the field?  It is already known that psychiatry gets much more than the expected levels of criticism in the press.  Is that criticism warranted? In many areas of this blog, I have pointed out that it is not warranted and, in many cases - it is grossly inaccurate.

4:  There have been no accurate histories of the intellectual development of the field.  To be sure there are specialized biographies of prominent historical figures and some of their influences but no clear timeline of how developments build on previous thought. I recently read that now that one of these historical figures has “scholars” rather than clinicians describing his work – we could expect much more, but I am not seeing it. To me – people who train and teach in the field are still the primary keepers of the working intellectual development of the field and everything that is relevant.

 Given all of these factors what can readers of our published letter do with that information?  If you are a psychiatrist or a physician – think carefully about your use of terms.  If you have used the term “chemical imbalance theory” or just “chemical imbalance” as a metaphor or something else – please reconsider. I think it is more useful to patients to let them know that depression or other clinical entities cannot be reduced to a single chemical event and I would invite you to use a statement from Nicholas Giarman – a noted neuropharmacologist:

“…nosologically it might be fair to compare the depressive syndrome with the anemias. Certainly, no self-respecting hematologist would subscribe to a unitary biochemical explanation for all of the anemias.”

 Nicholas J Giarman (1920-1968)  – The Biochemical Basis of Neuropharmacology – Fourth Edition 1982. p. 212


An explanation of heterogeneity and brain function would be ideal, but given time constraints and variable expectations of patients – an illustration of biological complexity is superior to a hopelessly inadequate metaphor. The same is true for literature that is handed out to patients. In that case, quoting the typical disclaimers in FDA approved package inserts as well as a brief summary of the research evidence for specific patients is a more optimal approach.

That is the real take home message.  


George Dawson, MD, DFAPA   


Supplementary 1:  What about advice to patients?  If you are considering taking an antidepressant or any other medication as a patient that usually means you are having a significant problem that you expect help with. The literature critical of psychiatry often suggests that this decision is casually made but that is not my experience either as a patient or a prescribing physician. Consider what is written about the mechanism of action of antidepressants. Chemical Imbalance Theory often implies that there has been dishonesty in presenting how a medication works and by extrapolation that psychiatrists don’t know much about anything. In fact, there are probably very few medications that you take where the mechanism of action is known with any high degree of certainty.  Aspirin was used for 70 years before its mechanism of action was determined (10).   Acetaminophen was first used clinically in 1887 and a preliminary report suggesting several potential mechanisms of action became available in 2009 (11).   Most decisions to take medications are not made based on knowing a mechanism of action. The overemphasis on mechanism of action of antidepressants is most likely based on pharmaceutical company advertising in the 1980s and 1990s.  At that time, the manufacturers of newer antidepressants emphasized that they were novel agents that probably worked through different mechanisms than the older medications and had a more favorable side effect profile.

As a patient you are entitled to as much detail on mechanism of action as you want and I hope that you will be able to get it directly from your physician or from other sources. I have treated basic scientists for depression and bipolar disorder and was able to give them adequate information – so it is definitely out there. But at a practical level – every person with a significant problem wants relief from that problem and no additional problems. The clinical discussion needs to be focused on whether the medication is working and the side effects are either non-existent or tolerable.  Further – informed consent means that you should have adequate information to make a decision about taking a medication.  That includes the likelihood of severe adverse drug events as well as more common side effects. Another common discussion in the media these days is withdrawal from antidepressant medications. A prescribing physician should be able to discuss that side effects in detail as well as rare events and a plan to address them.


1:  My co-author Ron Pies, MD read this post and made valuable suggestions for modifications.  It is difficult to indicate but he is a co-author of this post.

2:  Eduardo A. Colon, MD took the photograph used at the top of this post.


1:  Morehead D. It’s Time for Us To Stop Waffling About Psychiatry. Psychiatric Times.  Dec 2, 2021

2:  Morehead D.  It’s Time for Us to Realize We Are All on the Same Side.  Psychiatric Times. Jan 18, 2022

3:  Morehead D.  The History of Psychiatry—A History of Failure? Psychiatric Times. April 19, 2022

4:  Morehead D.  Is There a Cure for Ignorance? The Shocking Truth About Psychiatric Treatment.  Psychiatric Times. June 27, 2022

5:  Pies RW.  Debunking the Two Chemical Imbalance Myths, Again.  Psychiatric Times. August 1, 2019

6:  Pies RW. Nuances, narratives, and the “chemical imbalance” debate. Psychiatric Times. April 1, 2014.

7:  Pies RW.   Psychiatry’s New Brain-Mind and the Legend of the “Chemical Imbalance”.  Psychiatric Times.  July 11, 2011

8:  Pies RW.  Doctor, Is My Mood Disorder Due to a Chemical Imbalance? Psychiatric Times.  August 12, 2011

9:  Ruffalo, M. L., & Pies, R. W. (2018, August 19). The reality of mental illness: Responding to the criticisms of antipsychiatry. Psychology Today.…

10:  Montinari MR, Minelli S, De Caterina R. The first 3500 years of aspirin history from its roots - A concise summary. Vascul Pharmacol. 2019 Feb;113:1-8. doi: 10.1016/j.vph.2018.10.008. Epub 2018 Nov 2. PMID: 30391545.

11:  Smith HS. Potential analgesic mechanisms of acetaminophen. Pain Physician. 2009 Jan-Feb;12(1):269-80. PMID: 19165309.