Sore feet, Biomechanics, and Orthotics...

 

 I am a big believer in biomechanics. That belief is rooted in my personal experience with physical therapists and sports podiatrists.  That experience all started about 25 years ago.  At that time I had been cycling 150-200 miles per week for over a decade, speedskating, and doing resistance training. That all sounds like a high level of activity and it is.  But what is hidden in all that activity is the effect of biomechanics.

Cycling involves a flexed position at the hips and mainlining that position for hours at a time. The result is significant strengthening of lower leg flexors, hip extensors, and some hip flexor strengthening if you actively pull up on the pedals.  These patterns are recognizable in the hypertrophy pattern in the legs of cyclists.  At the same time, not a lot of energy is expended in muscles needed to maintain antigravity posture.  As a result cycling is one of the few exercises where energy expenditure can nearly match cardiac output – since not much additional energy is used for postural muscles.

Skating is a more strenuous combination of energy required for maintaining a flexed posture while translating lateral falling movements to forward propulsion and maintaining an unnatural posture. That also involves external to internal hip rotation under pressure as you move from the outside edge of a flat ground skate blade to the inside edge and then pushing off that inside edge.  Another critical point during skating is the hip hinge – a maneuver that I was never taught - to maintain the lumbosacral spine in a flat rather than flexed position when the spine is in a flexed skating position.  All of these movements combined with tight fitting skates, gravity, and centripetal forces while cornering puts tremendous pressure on the feet.

It only took a few years of this level of exercise to create a significant amount of foot pain. I remember deciding to try to walk off the pain one day at work. At the time I was employed by a large medical center.  Walking around the complex was probably about ½ mile.  On my first few attempts I could barely make it due to severe foot pain and back pain.  I could skate 10 miles or bike 150 miles but I could not walk around the block.

My first attempt at addressing this problem was to see a sports podiatrist right at the medical center where I worked.  I also had Haglund’s deformity of the calcaneus bones on both feet and was concerned about possible hallux valgus or bunion formation on the right. The podiatrist examined my feet, took the history and determined he needed to make a pair of orthotics.  After wearing them for 1 day – my foot pain was nearly gone and it resolved completely over the next week.  The orthotics were expensive so I had to transfer them from shoe to shoe.  That could not be done with my custom molded skates but they did fit in my cycling shoes.  I wore them successfully for at least 10 years before they started to fall apart.  I did not develop a bunion and the Haglund’s deformity did not get any worse and improved with just the orthotics. When I called the sports podiatrist's office again, I was advised they no longer did custom orthotics because of inadequate reimbursement. They had no ideas about where I could get another pair.

The theory of orthotics is that they restore the normal arch anatomy of the foot.  I was presented today with the additional theory that they also condition the intrinsic muscles of the foot to maintain those arches.  Both of those theories are somewhat controversial probably because of the diverse methodologies used to study the biomechanics of the foot. The main arches of the foot are shown in the diagram below as the medial longitudinal arch (MLA), lateral longitudinal arch (LLA), anterior transverse arch, and posterior transverse arch.  The bones that make up the MLA are colored pink and the bones that make up the LLA are colored green.

Over the past 10 years my exercise routine has changed to focus more on treadmill workouts. I use typical Bruce protocol parameters to vary the workouts from 3 -12 METS and typically do 90-120 minutes per day with additional weight training. The feet have become a serious problem again with soreness at the insertion of the right Achilles tendon around the entire perimeter, sharp shooting pains through the right arch, and excessive pressure and callus formation of the second toe on both feet.  I have Morton’s toe – a condition that occurs due to a short first metatarsal so the second toe is longer than the first.  At first I thought that this could be remedied by buying longer shoes. Even though I had worn 10.5 for 50 years – I went up to a size 11.  The problem was unchanged.  I tried running shoes that felt spongier than my typically runners.  Things were worse and I got some additional knee pain. I tried several weeks of not elevating the angle on my treadmill and that was also not helpful.

I finally went into an orthotics store today to get new orthotics. There was no medical staff around. The person who assisted me identified himself as a mechanical engineer who decided to change professions after he experienced significant relief from the orthotics he was currently selling. He had a measurement system used to estimate force distribution around the feet that produced the image at the top of this post.  He explained the orthotic system consisting of three different shoe inserts and demonstrated how this system resulted in a different weight distribution than standard shoes.  He had a checklist of other points such as pain in the back or at various joints that he said would be useful for follow up. He educated me in how long I could expose my feet to the three different orthotics and how it needed to be titrated over time. He said that none of what I purchased could be refunded – but I could get a different fitting in the next 60 days and he would call me from time to time to see how things were going. I walked out wearing the orthotics that I could use 24/7 and was reassured that I could use them starting today.

I will post how this goes over the next few months.  I am hopeful that I will get the same amount of relief that I got from my original orthotics 25 years ago.  I am also hopeful that it will correct additional biomechanical problems like my right foot inverting (rolling out) as I walk and an associated clunking sensation in the right knee as well as hip soreness and clicking during exercise.  I will be very pleased if the right Achilles pain resolves because it has become a chronic problem that I experience 20% of the time.  I decided some time ago to exercise through that pain and it does work.

So far, the cost is high.  Each of the orthotics costs three times what I paid for the originals 25 years ago.  That seems like a lot but considering inflation that is about right.  The only difference is the recommended three different sets.  There is no guarantee and all sales are final.  If they do work, this business keeps all of your specifications on record and service is possible at any of their stores.  I can’t help thinking about the economics of this situation and what it implies for health care in the United States. Orthotics have become a commercial product that you can purchase at a strip mall. I don’t know the range of sizes available or how that is determined, but I know they were not custom fit like the first pair I got from a sports podiatrist.  The retail procedure is much more expensive. At the same time, the podiatrist I was seeing could no longer afford to make them because of inadequate reimbursement.  I guess this is one way we contain health care costs in the US.  Making it retail for much higher reimbursement as opposed to rationing it at the expense of licensed health care providers.  It took me a long time to figure out that American capitalism is not about superior products.  Most of the time it is just about making money and how you can get advantages to do that.  The true test will be in the results that I will revisit over the next several months.

 

George Dawson, MD, DFAPA

Supplementary 1:  A biomechanics approach is also useful because pain can be addressed without any additional measures like medications or injections. At least that is the best case scenario.  It makes little sense to take over-the-counter pain medications when orthotics or physical therapy work for the pain. The previous orthotics I used corrected my foot and ankle pain and low back pain.  It also resulted in improved posture.  All of that from subtle (1-2 mm) changes in the position of my feet.  If these orthotics also work for strengthening the intrinsic muscles of the foot that is also an advantage over having to do specific exercises for those muscles along with wearing the orthotics.  I never found the exercises for the intrinsic muscles of the foot to be very effective.  

Supplementary 2:  Practically all of the running and athletic shoes these days have an insert in the bottom of the shoe.  This appears to provide some arch support - but it does not.  The staff person I was assisted by referred to it as a sock liner.  By definition it is typically a foam layer that your foot rests on and it is not designed to provide much support. There can be a very uncomfortable coarsely finished inner shoe surface below the sock liner.  An insole by definition is designed to provide support and an orthotic is a specifically designed insole to provide more support.  Numerous examples are available on any Internet search.    

References:

1:  Venkadesan M, Yawar A, Eng CM, Dias MA, Singh DK, Tommasini SM, Haims AH, Bandi MM, Mandre S. Stiffness of the human foot and evolution of the transverse arch. Nature. 2020 Mar;579(7797):97-100. doi: 10.1038/s41586-020-2053-y.

2:  Asghar A, Naaz S. The transverse arch in the human feet: A narrative review of its evolution, anatomy, biomechanics and clinical implications. Morphologie. 2022 Dec;106(355):225-234. doi: 10.1016/j.morpho.2021.07.005.

3:  Wang H, Wu Y, Liu J, Zhu X. Investigation of the Mechanical Response of the Foot Structure Considering Push-Off Angles in Speed Skating. Bioengineering (Basel). 2023 Oct 18;10(10):1218. doi: 10.3390/bioengineering10101218.

4:  Chauhan HM, Taqi M. Anatomy, Bony Pelvis and Lower Limb: Arches of the Foot. [Updated 2022 Nov 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK587361/

5:  Collier R. Orthotics work in mysterious ways. CMAJ. 2011 Mar 8;183(4):416-7. doi: 10.1503/cmaj.109-3802. Epub 2011 Feb 14. 

 

Image credit:

1:  Foot impressions at the top are from the retail store and are from my feet done today 3/29/2025.

2:  Anatomical images of arches are from reference 4 – reproduced here without alteration per the CC license as follows:  This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Trump Derangement Syndrome - Will It Become a Mental Illness in Minnesota?

 

It came to my attention yesterday that a bill has been proposed in the Minnesota Legislature to declare Trump Derangement Syndrome a mental illness.  Anyone unfamiliar with the mental illness statutes in Minnesota might ask why there are definitions like that in the law in the first place. The purpose of these definitions is threefold as far as I can tell. First, they define the behavioral evidence in terms of severity necessary to meet the standard of severe mental illness.  In common parlance that is typically described as risk to self, risk to others, or inability to care for oneself because of mental illness.  No diagnostic criteria or reference to diagnostic manuals is made. The definitions are there as lay standards so that potentially any interested person can act on them. Second, they are necessary criteria for civil commitments, guardianship, and conservatorships in the state. In other words, a psychiatric diagnosis by itself is not sufficient criteria for any of those proceedings.  The statutory requirements must also be met.  Finally, the criteria also determine eligibility for additional treatment resources like case management and outreach services.     

To confirm the validity of this proposal I sent emails to both of my state representatives Rep. Elliot Engen (R) and Sen. Heather Gustafson (D). I expressed my concern that the mental health statutes in the state are for the serious business of civil commitment, guardianship, and conservatorship proceedings and therefore I needed to know if Trump Derangement Syndrome was a serious proposal and if it was – what they were going to do about it.

I have not heard back at this point but the press coverage is increasing so I will talk about it as if it is legitimate.  Where does this come from and what does it really mean?  During the previous Trump election there was a lot of controversy about whether he had a psychiatric diagnosis – primarily a personality disorder.  There was a lot of discussion about narcissistic and antisocial personality disorders. There were several high-profile psychiatrists and some academics who maintained these positions.  These criticisms still surface today.  At the time, I critiqued those positions based on the APA’s Goldwater Rule.  Psychiatric profiling was invented by Jerrold Post, MD for intelligence gathering and it was not meant to be applied to politics.  The Goldwater Rule states that a direct assessment must be done and any information released with informed consent.  Those controversies basically faded because the public criticism had no impact and it was obvious that a lay standard in the 25^th Amendment rather than public speculation is the overriding consideration:

“Section 4:

Whenever the Vice President and a majority of either the principal officers of the executive departments or of such other body as Congress may by law provide, transmit to the President pro tempore of the Senate and the Speaker of the House of Representatives their written declaration that the President is unable to discharge the powers and duties of his office, the Vice President shall immediately assume the powers and duties of the office as Acting President.”    

Even though a substantial number of Trump’s first staff disapproved of his performance or thought he was incompetent – there was no effort to invoke the 25^th Amendment.  He was subsequently rated as the worst President to date by polled historians.  We also learned that if the President or his party control the Supreme Court – it is possible that an entirely different standard applies than it does to the average citizen. It is clearly possible that the President can commit crimes and escape prosecution. 

The idea that Trump is an unlikeable person is easily explored with the following thought experiment.  How many people like liars? Trump is described as lying an unprecedented amount in the history of American politics – tens of thousands of lies.  At times the lies are characterized as bullshitting using Frankfurt’s philosophical definition.  According to Frankfurt - bullshitters have more disregard for the truth than liars.  So, pardon me if you think bullshitting is more acceptable.  How many people object to a person who routinely calls other people names and ridicules the disabled?  How many object to threats?  How many object to racism, misogyny, and white supremacy? How many object to withdrawing foreign aid amounting to less than 1% of the budget if it results in the deaths of hundreds of thousands of people (3.3 million according to a New York Times estimate from AIDs, malaria, TB, lack of vaccinations, and a lack of food).  How many people like the administrative, justice, public health, and research infrastructure of the United States being decimated on an arbitrary basis by Trump appointed designees?  How many people like loyal government employees working in non-political positions in the US Postal Service, the Veteran’s administration, and the National Park System terminated either for a completely fictional cause or without cause?  I think the point is made even though this is only a partial list of what Trump has done to cause people to legitimately dislike him.  I could probably come up with a much longer list.  For completeness sake – let me add – how many people like a President who attempted to overthrow the US government and who has continued to lie about the election for the next 4 years?

That brings me to the statute:

Subd. 28.Trump Derangement Syndrome.

"Trump Derangement Syndrome" means

2.24 the acute onset of paranoia in otherwise normal persons that is in reaction to the policies

2.25 and presidencies of President Donald J. Trump. Symptoms may include Trump-induced

2.26 general hysteria, which produces an inability to distinguish between legitimate policy

2.27 differences and signs of psychic pathology in President Donald J. Trump's behavior. This

2.28 may be expressed by:

2.29

(1) verbal expressions of intense hostility toward President Donald J. Trump; and

2.30

(2) overt acts of aggression and violence against anyone supporting President Donald

2.31 J. Trump or anything that symbolizes President Donald J. Trump.

        

On the face of it – this definition is poorly written by people who are obviously not mental health professionals. The wording can be taken as colloquial rather than technical.  That means the terms “paranoia” and “hysteria” are whatever the politicians decide to use them for and that could include name-calling. Concern about the Trump on-again off-again tariffs?  You are just paranoid. 

The idea that these meaningless expressions would cause “an inability to distinguish between legitimate policy differences and signs of psychic pathology in President Trump’s behavior” is laughable.  First, as previously noted nobody is making any psychiatric diagnoses on Trump.  That time has passed.  His party is more than willing to let him do whatever he wants.  Second, it does not take a mental health professional to decide if someone is unlikeable, or doing things that you do not like, or using rhetoric that you do not like, or is conducting themselves in an immoral or unethical way that you do not like.  We all do it every day.  We are all judged on our behavior every day and accountable in many ways.  The vague wording in the preamble in this statutory language is intentional and it gives the proponents plenty of freedom to determine what they think is “intense hostility” toward Trump.  They could at least include a scale using examples of Trump’s intense hostility to others. As hostile as Trump was to Zelensky in the tragic White House meeting or possibility some of his milder name calling incidents directed at Clinton, Harris, or Obama?  The essence of this language is that it sends the strong message that if you criticize Trump – you are at risk.  He is basically beyond criticism even though he is the most objectionable President on record.  The “overt acts of aggression and violence…” language is already illegal without this nonsensical modification.

Like most things in the Trump administration there is no scientific backing to any of this language.  The rhetoric is slightly more interesting. Anyone paying causal attention to the news has seen the pattern of outrage followed verbal aggression (mainly name calling and lying) that is a standard part of MAGA theatrics over the past several years. If you really have not - just turn on one of their news channels, podcasts, or radio broadcasts. Better yet – attend a school board meeting and witness the screams about book banning and other things that are often not even happening. More recently that has spilled over into MAGA town halls meetings to the point that the GOP has had to shut them down.  Other than the obvious appeals to excessive and inappropriate emotion in these meetings there are two additional patterns that cannot be missed.

The first is what I like to call the gangster approach to pseudo negotiation. This was evident in the meeting between Zelensky, Trump, and Vance. Before any actual content was discussed both Trump and Vance were accusing Zelensky of “not respecting them” or saying “thank you’.  This is what you will find in any rapper beef but it obviously has no place in high level diplomacy.  What were Trump and Vance trying to do here?  To anyone familiar with rhetoric, this is a standard attack on the person rather than their argument. Zelensky never got his argument out and then to add insult to injury he was told to leave the White House as if he had really done something wrong.

The second is a variation on that theme. Whenever Trump is even mildly confronted, he acts like he has been wounded.  One of his comments is “You are not very nice; you are not being very nice to me.”  He will rationalize the rest of his behavior such as refusing to talk or attacking the journalist or their organization based on that sensitivity.  He will often attack the journalist typically by calling them names or questioning their ability.  In some cases, he will suggest that the interviewer has some nefarious purpose or that they are part of a “fake news” conspiracy against him.  In more recent developments he is suggesting that the people in the media who he does not like will be prosecuted.

Both patterns are obvious in the news and in life. We typically encounter this kind of behavior as adolescents from bullies in schools. Recall that bully on the playground who likes to make up nicknames for classmates just to humiliate and embarrass them. He persists in using the nickname even though you and your friends don’t like it.   You all acquiesce because he is bigger and will beat you up if you protest too much. Occasionally some smaller kid stands up to the bully and punches him in the nose.  At the meeting with the principal – the bully and his father claim the other kid started the fight.  They are typically outraged and tearful.

That is the real reason for a Trump Derangement Syndrome statute.  It allows even more leverage against the people who protest the bully.  Now some politician can gaslight them in addition to Trump bullying them and calling them names.  

This is not a mental illness.  It is a political tactic.  It is an affront to anyone with a real mental illness, their caregivers and treatment providers. If this language is allowed to stand in Minnesota it adds to the embarrassments that this administration has placed on the American people and will result in a gaslighting defense for America’s number one bully.

 

George Dawson, MD, DFAPA          

To editors: I have a more concise 500 word version of this essay that could be published if there is an interest and the publication seems right.  Contact me if you are interested.  

Supplementary 1:  There still is a possibility that this proposal is a hoax. If that is true there will be a predictable response from Republicans suggesting that this response is just another example of Trump Derangement Syndrome.  Their rhetoric can be cancelled by pointing out that their technique of flooding the zone is really just another application of Brandolini's Law and it is unfortunate that they do not devote as much energy to serious governing.

Supplementary 2:  The parallels between patterns of authoritarian suppression in Russia/USSR and the current administration are unmistakable.  Non-medical and political "diagnoses" are widely used to suppress and detain dissidents and other targets of political oppression. In the US, the current administration is making strong initiatives to suggest any criticism of the President is illegal as well as many forms of legal protest.  

Supplementary 3:  Added on 3/28/2025 nearly 2 weeks after the original post. At this point I have not heard back from either of my elected officials. The proposed statute remains on the site at the following link - but it has been modified to show that one of the co-authors has been removed.  That co-author has been arrested for allegedly for coercion and enticement of a minor in connection to a prostitution sting.  As a result I have to conclude that it is still going forward.  

Graphic:

The graphic in this case is taken directly off the Minnesota Revisor web site – an official site of the state government.  The link I used is available below – but it disappears and gets updated to a new link frequently:

 https://www.revisor.mn.gov/bills/text.php?number=SF2589&version=0&session=ls94&session_year=2025&session_number=0 

 

More Than You Wanted to Know about Bird Flu and Chickens...

 

Are chicken flocks only culled in the US?

I ran into typical MAGA disinformation on the Internet the other day.  The post stated "not a single chicken" had been killed in Canada or Mexico due to the bird flu compared to millions in the US.  Since all the social media sites have been captured by MAGA I decided to debunk the claim that only flocks of chickens with avian influenza in the US are culled and not chickens in Canada or Mexico.  After reading pandemic misinformation for the past 5 years – it seemed like this was going to be an easy task and I was not wrong.

The latest North American bird population estimates were about 7 billion birds in 529 species in 2019 (1,2).  That represented a decline of about 3 billion birds since 1970.  Habitat loss, ecosystem destruction, and climate change were considered significant factors according to these authors. Anthropogenic threats like collisions with vehicles and other manmade structures, poisoning, and predation by domestic animals was also estimated to be a significant factor. Domestic cats kill roughly 1.3 to 4 billion birds annually (3). By comparison the estimate of bird deaths from contact with windmills is about 140,000 – 328,000 annually (4).      

Considering the chicken population in all 3 countries – the US has a total of 1.53 billion chickens annually that includes 1.2 billion broiler chickens alive at any one time and about 350,000 egg laying chickens. The total chicken population in Canada is 173.94 million.  In Mexico the total chicken population is 611.2 million.

Meat, poultry, and egg production in the US is regulated by the USDA and the Poultry Products Inspection Act (PPIA).  That includes other poultry like geese, ducks, guinea hens, and other more exotic domesticated birds.  In Canada it is the Canadian Food Inspection Agency (CFIA).  In Mexico it is the Ministry of Agriculture and Rural Development.  The culling of domestic chickens because of avian influenza has become a contentious political issue and a source of right wing misinformation. Additional misinformation has included blaming the Biden administration for culling chickens and driving up egg prices. The question of how these decisions get made, especially when large numbers of infected chickens are euthanized has been answered by experts in the past.  Here is one quote from CBS News when asked about the loss of 148M poultry since 2022:

"It's a staggering number, there is no doubt," said Jodie Guest, a professor of epidemiology with Emory University's Rollins School of Public Health in Atlanta. "But it is, and always has been a policy across administrations, with the USDA, that this is how they handle infections like this among poultry. And as we've seen bird flu move [across] species, it becomes even more important to try to contain that infection in the flocks that it's in, so that we don't continue to see spread."

The USDA has an infographic on measures to contain avian influenza outbreaks.  From that page “Birds are destroyed usually within 24–48 hours of detecting the disease. USDA pays for birds that must be destroyed.”  The cost of a live chicken can range from $5 to $20.  There seems to be a question about whether infected birds need to be euthanized.  This is the rationale provided by the American Veterinary Medical Association (AMVA):

“Recovery of poultry from HPAI is extremely rare. Infected poultry typically are euthanized and poultry products destroyed when HPAI infection is confirmed. The outcome also may be influenced by the producer’s participation in secure food supply plans. If regulatory officials authorize you to treat, keep in mind that the FDA prohibits extralabel use of adamantine and neuraminidase inhibitor classes of antiviral drugs in chickens, turkeys, and ducks.”

HPAI in this case is Highly Pathogenicity Avian Influenza defined as causing high mortality in poultry and are H5 and H7 influenza viruses.  Not all viruses belonging to those classes are highly pathogenic.  There are also Low Pathogenicity Avian Influenza (LPAI) viruses that may not cause any symptoms in affected birds.  There is the possibility that LPAI viruses can mutate into HPAI viruses and they are monitored for that reason. In the US – ill or deceased domestic birds are typically reported at the state level to animal health officials. They decide what level of analysis needs to be done and recommend protective measures.  Any casual historical search of previous outbreaks in avian populations will also reference significant culling of domestic fowl in all three countries. 

In the US, 148M domestic birds have been euthanized due to the latest outbreak of avian influenza including 20M egg laying chickens.  Exact numbers of euthanized poultry in Mexico since 2022 are harder to come by but are in the millions.  In Canada the number is about 14.5M.  I have not found a site that examines the differences in euthanized poultry between countries.  Variability will depend on wild bird exposure, total populations of domestic birds exposed, size of the domestic flock, biosecurity measures, and farm density. 

In summary, there is a consensus about approaches to HPAI in domestic birds. There is really no evidence that either Canada or Mexico does not recommend euthanizing infected birds.  There is no evidence that significant numbers of domestic fowl have not been euthanized in both countries currently and during past HPAI pandemics. From a veterinary medicine standpoint, it does not make sense – because most of the HPAI infected population dies and they act as a source for further mutations and facility contamination. The discrepancies in the total populations euthanized in all 3 countries occur because of policies (reimbursement for dead birds in the US), levels of oversight (state and federal in the US), and varying levels of reporting.  There is no evidence that the culling of birds is due to a political initiative or an initiative to adversely impact the economy.  And why would any rational President want to do that? 

 

George Dawson, MD, DFAPA

 

References:

1:  Pennisi E. Billions of North American birds have vanished. Science. 2019 Sep 20;365(6459):1228-1229. doi: 10.1126/science.365.6459.1228. PMID: 31604214.

2:  Rosenberg KV, Dokter AM, Blancher PJ, Sauer JR, Smith AC, Smith PA, Stanton JC, Panjabi A, Helft L, Parr M, Marra PP. Decline of the North American avifauna. Science. 2019 Oct 4;366(6461):120-124. doi: 10.1126/science.aaw1313. Epub 2019 Sep 19. PMID: 31604313.

3:  Loss SR, Will T, Marra PP. The impact of free-ranging domestic cats on wildlife of the United States. Nat Commun. 2013;4:1396. doi: 10.1038/ncomms2380. PMID: 23360987.

4:  Loss SR, Will T, Marra PP. Estimates of bird collision mortality at wind facilities in the contiguous United States. Biological Conservation. 2013 Dec 1;168:201-9.

5:  Ornelas-Eusebio E, García-Espinosa G, Laroucau K, Zanella G. Characterization of commercial poultry farms in Mexico: Towards a better understanding of biosecurity practices and antibiotic usage patterns. PLoS One. 2020 Dec 1;15(12):e0242354. doi: 10.1371/journal.pone.0242354. PMID: 33259478; PMCID: PMC7707464.

6:  CDC site on Avian Influenza (map of counties affected):  https://www.cdc.gov/bird-flu/situation-summary/data-map-commercial.html

7:  CDC site:  2020-2024 Highlights in the History of Avian Influenza (Bird Flu) Timeline. https://www.cdc.gov/bird-flu/avian-timeline/2020s.html

8: Barman S, Turner JCM, Hasan MK, Akhtar S, Jeevan T, Franks J, Walker D, Mukherjee N, Seiler P, Kercher L, McKenzie P, Webster RG, Feeroz MM, Webby RJ. Reassortment of newly emergent clade 2.3.4.4b A(H5N1) highly pathogenic avian influenza A viruses in Bangladesh. Emerg Microbes Infect. 2025 Dec;14(1):2432351. doi: 10.1080/22221751.2024.2432351. Epub 2024 Dec 9. PMID: 39584394; PMCID: PMC11632930.   

Details of the specific viral analysis for HPAI are included in this paper

 

Addendum:  I currently have an email in to Mexico's Secretariat of Agriculture and Rural Development (Secretaría de Agricultura y Desarrollo Rural) requesting more official numbers on the total numbers of domestic fowl euthanized due to HPAI since 2022. 

Graphic Credit:  From Wikimedia Commons.  Rollover photo or click to see full credit and CC license. This is the original unaltered photo.

Mouse-to-Mouse Resuscitation

 

A paper came out in Science 2 weeks ago (1) on the behavior of mice toward their unconscious or dead peers.  They have resuscitation-like behavior that consists of biting the face and tongue, clearing the airway, elevating the tongue of the unconscious mouse to revive them. Mice who were the recipients of this behavior recovered sooner than mice who did not receive these efforts.  The authors went on to see if they could localize the behavior in the brain and using modern neuroscience techniques, they able to show that they had localized the behavior to a brain substrate.  These papers have implications for psychiatry both at a theoretical and practical level.

In this experiment researchers used genetically identical mice (cross bred for 20 generations).  They followed their reactions closely across time epochs as they encountered a familiar partner anesthetized and unresponsive or euthanized (dead) mice. When compared with the active partner, mice spend 47.4% of the time interacting with the unresponsive partner compared to 5.8% of the time with the active partner.  They also displayed a specific pattern of behaviors directed facial area, trunk, limbs and head of the unresponsive partner. 31.8% of the time was directed at the orofacial area.  The overall duration of contact was extended with the unresponsive partner and it was more focused on the orofacial area.

To confirm the sequence of events, short acting (isoflurane) anesthesia was used to observe the partner response as the anesthetized mouse became less and then more responsive.  Time spent interacting with the anesthetized partner and the topology of interactions (more targeted orofacial activity correlated with the time anesthetized.  Deceased cagemates caused the same pattern of interaction but not sleeping cagemates because during sleep the directed behaviors led to movements of the sleeping mouse. This suggests that mice can differentiate responsive and unresponsive states in their partners.

The orofacial focused behaviors were studied under a high-speed camera.  It was discovered that in nonresponsive mice the tongue was bitten and pulled out of the mouth by casemates.  A similar tongue protrusion did not occur in unresponsive mice.  Pulling the tongue out resulted in a larger airway and the removal of foreign objects in the mouth. Placing the foreign object in a non-oral orifice did not result in removal. Stimulating the oral mucosa was also a strong stimulus for the righting response and arousal. 

Familiarity was a stronger stimulus for eliciting the grooming and resuscitation like behaviors than sex differences or similarities.  When given a choice between familiar partners – one anesthetized and one not – there was a preference for the anesthetized partner.  That did not persist when both target mice were unfamiliar.  The authors also demonstrated that the time spent with the unresponsive mouse did not decrease over a period of days – it did not show habituation.

After characterizing the unique behavioral aspects of the resuscitation like behavior the authors looked at the neural substrate. One hour after exposure to the unresponsive mice the cagemates were given 4-hydroxytamoxifen to label activated neurons.  Following 2 weeks of exposure several brain structures previously implicated in the observed behaviors including the medial amygdalar nucleus (MEA), paraventricular nucleus of the hypothalamus (PVH), basolateral amygdalar nucleus (BLA), hippocampus, and ventromedial hypothalamic nucleus (VMH) were examined. The number of tdTomato+ cells were noted in mice that had responded to unresponsive mice compared with controls (active partners).  This marker is a sign of the transcription factor c-fos and that neurons were recently active. Using a second set of probes roughly twice as many PVH oxytocin neurons were c-fos + and oxytocin + in the mice exposed to an unresponsive partner. 

An additional optogenetics experiment was done to look at the oxytocin PVH neurons.  Optogenetically silenced PVH neuron had the expected effect of reducing interaction time with the unresponsive partner. Optogenetically activating PVH neurons had the effect of increasing interaction time with an unresponsive stranger mouse.  An oxytocin receptor antagonist has the expected effect of reducing interaction time with the unresponsive mouse.

The authors conclude that they have demonstrated the necessity of both an oxytocin neuronal substrate and oxytocin signaling for very specific interactions and behaviors toward unresponsive mice.  Further, encountering a dead or anesthetized partner is required to elicit this response but it does not occur with a sleeping partner. They point out that rapid responses to an unresponsive partner can reduce the time it takes for recovery and decreases the risk of predation.  They suggest further work needs to be done on defining the neural network and sensory cues necessary for these behaviors.

As I read this paper I had a few thoughts:

1:  The hypothalamus is underemphasized in psychiatry.  We spent a couple of decades studying neuroendocrinology that was primarily focused on the pituitary gland. In clinical work, this is also an important system to be able to assess. But in much of the work about the theoretical basis of behavior – not much is said about the hypothalamus.  One example is the proximity of neurons underlying aggressive and sexual behavior in the lateral hypothalamus. 

2:  Social behavior versus the neurobiological substrate – psychosocial reductionists frequently treat the brain like a tabula rasa - not much is there until some kind of social learning or adverse event occurs.  In this case, adaptive complicated behavior is observed without any training.  The experiment illustrates both an anatomical and neurochemical basis for the behavior. Why would we expect anything to be different in humans?  And further - given the general case of biological diversity why wouldn't we expect this behavior to be absent in some and overdeveloped in others?  Even though the authors did not demonstrate this - why would we not expect that it could also be a learned behavior in individuals where it was not present or very robust?

3:  The measurements of activity in both the resuscitation-like and non-resuscitation behaviors were interesting.  Even though the overt behaviors were easily observed as occurring or not occurring – the neurons involved always had some level of activity. In other words – no target behavior did not equate to no neuronal activity.  It is not simply a case of networks being on or off. This has implications for how we attempt to correlate networks with behavior and the meaning of networks having a certain level of baseline activity.

All things considered; I thought this was a great paper. It reminded me of my biochemistry and pharmacology seminars in medical school where we would have spent a lot more time on the experimental methodology in this paper.  I did check my latest copy of The Molecular Biology of the Cell (7^th edition) and found that the discussion of optogenetics relative to this paper was very brief, but I suppose that makes sense.  From the standpoint of animal behavior this also recalls so-called altruistic behavior of some animals.  I have a file of that behavior observed in Humpback whales (Megaptera novaeangliae) interfering with killer whales (Orcinus orca) and hope to post something about that as well.

 

George Dawson, MD, DFAPA

 

References:

1:  Sun W, Zhang GW, Huang JJ, Tao C, Seo MB, Tao HW, Zhang LI. Reviving-like prosocial behavior in response to unconscious or dead conspecifics in rodents. Science. 2025 Feb 21;387(6736):eadq2677. doi: 10.1126/science.adq2677. Epub 2025 Feb 21. PMID: 39977514.

2:  DeNardo L, Luo L. Genetic strategies to access activated neurons. Curr Opin Neurobiol. 2017 Aug;45:121-129. doi: 10.1016/j.conb.2017.05.014. Epub 2017 May 31. PMID: 28577429; PMCID: PMC5810937.

Image Credit:

Generated by ChatGPT based on my parameters.  The original paper has a great image of the specific behaviors mentioned in this post. 

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 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). 

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 (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.

Should GLP-1 agonists be added to the drinking water?

For starters GLP-1 agonists are drugs like Ozempic and Weygovy.  See this post for a current list.  It is hard not to hear about them since they are heavily hyped in just about every form of media. They are being touted as a cure for just about everything.  Various celebrities are either promoting them or denying that a dramatic weight loss was associated with their use.  Some in the weight loss and exercise industry are pushing back with statements about side effects and rapid weight gain if you ever stop taking them.  The sales of these drugs is a windfall for the pharmaceutical industry and current pricing means that other businesses that make money from rationing access to medical care and medications will be trying to prevent their use.  I thought I would post a contrast today between the latest review of conditions these medications have been researched for and a new paper that suggests they may increase the frequency of psychiatric disorders.

The rest of the title comes from my experience in many medical settings over the decades.  Any time a medication is commonly prescribed you can count on someone saying “We should just put it in the drinking water.”  Examples over the years have been amoxicillin, H-2 blockers like ranitidine, statins, beta blockers, lorazepam, and even haloperidol.  It all depends on the prescription frequency in a particular setting. At the rate GLP-1 agonists have been hyped - somebody is saying it somewhere.  The irony in that statement is that many medications are now in the water supply and not doing anything for anybody.

When I describe this group of drugs as hyped that is exactly what I mean.  The only comparable hype has been for cannabis and psychedelics/hallucinogens.  Typical newspaper headlines about GLP-1s say they are wonder drugs and go on to describe them as indicated for several conditions ranging from addiction to Alzheimer’s disease.  Currently 5.4% of all medication prescriptions in the United States are for GLP-1 agonists.  These drugs have been around for 20 years and during that time transitioned from use primarily for Diabetes Mellitus Type 2 to weight loss. Despite all the clinical trials and experience with them I do not think the final verdict is in and the main papers relevant to this post will illustrate why.    

The first paper (1) is a large observational study using databases from the Veterans Administration (VA) health care system (1).  The authors describe the rationale of their study as looking at the real-world outcomes of the use of GLP-1 agonists – both the positive effects and adverse outcomes. They had an N of 1,955,135 followed for a median of 3.68 years looking at 175 health outcomes.  The authors use an interesting methodology.  Patients were recruited based on incident use of a medications for Type 2 diabetes mellitus (T2DM) between October 1, 2017 and December 31, 2023.  That created 4 groups based on the medical treatment of T2DM)  including GLP-1 agonists (N= 232,210), sulfonylureas (N= 247,146), Dipeptidyl peptidase-4 (DPP-4i) inhibitors (N= 225,116), and SGLT2i inhibitors (sodium-glucose cotransporter 2 inhibitors) (N= 429,172).  There was also a treatment as usual (TAU) group (N= 1,513,896) with Type 2 DM who took non-GLP-1 antihyperglycemics between the study dates of October 1, 2017 and December 31, 2023.  As a point of reference, I have included a table of the medications in each class used for T2DM. 

Glucagon-like peptide 1 (GLP-1) agonists	exenatide (Bydureon) exenatide (Byetta) liraglutide (Victoza) liraglutide (Saxenda) dulaglutide (Trulicity) semaglutide (Wegovey) semaglutide (Ozempic) semaglutide (Rybelsus) tirzepatide (Mounjaro) tirzepatide (Zepbound)
Sulfonylureas	Glipizide Glimepiride Glyburide
dipeptidyl peptidase 4 (DPP4) inhibitors	alogliptin (Nesina, Vipidia) sitagliptin (Januvia) saxagliptin (Onglyza) linagliptin (Tradjenta)
sodium−glucose cotransporter-2 (SGLT2) inhibitors)	bexagliflozin (Brenzavvy) canagliflozin (Invokana) dapagliflozin (Farxiga) empagliflozin (Jardiance) ertugliflozin (Steglatro)

 

This study was designed to assess groups on 175 health outcomes from these treatment cohorts compared with two control groups.  One control group was a composite of equal numbers of diabetic subjects using oral hypoglycemics and the other control groups was diabetics who continued GLP-1 agonists that they had already been started on.  Results varied but generally the health outcomes measured were significantly improved on the GLP-1 agonists compared with the controls and across categories.  For example, when GLP-1 agonists were compared with the sulfonylurea, DPP4, and SGLT2 classes outcomes were improved in 13.14%, 17.14%, and 11.43% of the outcomes respectively. 

Risk of adverse outcomes were 8%, 7.43%, and 16.57% in the same order.  Those adverse events in aggregate included: nausea and vomiting, gastroesophageal reflux disease (GERD), sleep disturbances, bone pain, abdominal pain, hypotension, headaches, nephrolithiasis, and anemia. 

When comparing the addition of GLP-1s to treatment as usual (the composite control) better outcomes were observed in 24% and increased risk of adverse outcomes in 10.86% of outcomes.

The reduced risk of several CNS disorders were estimated by hazard ratios and they were modestly decreased for alcohol use disorder, cannabis use disorder, stimulant use disorder, opioid use disorder, suicidal ideation of self-injury, bulimia, schizophrenia, seizures and neurocognitive disorders.  Risk reductions were in the 10-16% range. 

The authors of this paper use several graphing techniques to present their data.  They graphed hazard ratios for both improved and adverse outcomes and made negative log transformed Manhattan plots as a measure of statistical robustness as alternate graphing technique.  The paper is open access and I encourage reading the paper to see these data presentations.  I included a partial Forest plot at the top of this post to illustrate some of these graphs and the outcomes they measured. The blue dots indicate reduced risk relative to controls and the orange dots indicate increased risk (calculated as hazard ratios (3).

The strength of this study is that it summarizes a large amount of data across a VA database.  Since it is administrative data it is collected in nonstandard way and the diagnoses are not necessarily made by experts - this data may not be as robust as a prospective randomized clinical trial.  The population was older white veterans and that may be a factor when considering pleotropic effects.  The authors conclude that the GLP-1 agonists had broad pleotropic effects based on the spectrum of positive results and preclinical work.  They emphasize the positive results for neuropsychiatric diseases and disorders.  They discuss the issue of suicidal behavior and point out that earlier studies raised concerns to the point that the European Medicines Agency investigated and found no evidence for causality.  This study showed decreased suicidality and possible antidepressant effects.  The results generally showed significant positive effects on outcomes across major disease categories with a clear group of adverse effects.   

For comparison there is a recent large retrospective cohort study (2) that uses deidentified data on patients from 66 different health care organizations.  This appears to be a database with a commercial purpose, but I cannot identify what that purpose might be based on their web site.  In their rollover map, most of the deidentified patients in this database are Americans.  The study was approved by an IRB in China and I assume that is where the analysis takes place.  The study was focused on examining the effects of GLP-1 agonists on patients being treated for obesity.  Subjects were selected for a diagnosis of obesity and incident use of a GLP-1 agonist. It was a retrospective cohort analysis similar to the first study but propensity score matching was done to pair treatment subjects more closely with controls. Exclusion criteria included use of any other weight loss drug and any psychiatric diagnosis or significant symptom like suicidality.

The main results of this study are summarized in 3 tables in the body of the paper (Tables 2, 3, and 4).  Psychiatric outcomes were measured over a period of 5 years and the percentage of patients with major depression, any anxiety, any psychiatric disorder and suicidality (ideation or behaviors) we measured at 6 months, 1 year, 3 years, and 5 years.  The cumulative incidences of disorders and suicidality increased over these intervals.  Hazard ratios were calculated compared with the control population and they were generally doubled.  

Results stratified on demographic factors and GLP-1 agonist potency showed that both sexes had higher than expected psychiatric morbidity associated with GLP-1 agonist use but that women had significantly higher hazard ratios across all categories. Age was inversely correlated with older populations having lower risk of psychiatric comorbidity. Finally, the potency of the GLP-1 agonist directly correlated with potency of the GLP-1 agonist and time of exposure.  The authors discuss the limitations of their study and implications for future use and study.

Both studies generally illustrate some of the advantages and problems of conducting large clinical trials. The numbers in the hundreds of thousands or million plus range would be very difficult if not impossible to conduct randomized clinical trials on.  It is manageable using the naturalistic retrospective designs employed here commonly referred to as real world designs.  The obvious limiting factor is expense and the methodological problem of drop outs over time.  In these specific cases the first study is selecting a subject cohort based on a diagnosis of diabetes mellitus type 2 (DMT2) and the second obesity.  Both are heterogeneous populations with some overlap.  If I was influenced at all by some of the current psychiatric literature, I might suggest transdiagnostic features common to both but the importance of that term seems inflated relative to common medical diagnostic formulations.  Instead - I will use the parlance of medical trials and point out that there are signals in both papers.  Those signals are both good and not so good.  In the first paper there were clearly improvements in many medical outcomes when T2DM was treated with GLP-1 agonists in about 25% of the conditions studied and adverse outcomes in about 10%.  Improvement occurred in conditions outside of the endocrine/metabolic sphere including some psychiatric conditions. In the second study, significant increases in psychiatric conditions were noted to occur associated with GLP-1 agonist potency and total exposure in a population selected for obesity treatment.  The authors are careful to point out that obesity and metabolic syndrome may be a risk factor for mood disorders and they provide an excellent discussion of how trial design and patient selection may have affected these results.  

When these trials are reported in the news, they are generally not reported as showing modest results.  Side effects are typically ignored.  I have not heard anything about the study that showed that increased rather than decreased psychiatric morbidity may be a possible outcome.  The media generally reports them as miracle drugs and patients with the best possible results are given as examples.

GLP-1 agonists are clearly serious medications with potentially serious adverse effects.  The prescription of these medications requires close monitoring and thorough patient education.  If I was prescribing these medications today - in the informed consent discussion I would include the potential for modest outcomes, potentially increased psychiatric side effects, the general potential for side effects, and why outcomes may be variable.  I would also make sure to let people know that long term outcomes at this point are not known with any degree of certainty.    

   

George Dawson, MD, DFAPA

 

References:

1:  Xie Y, Choi T, Al-Aly Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat Med. 2025 Jan 20. doi: 10.1038/s41591-024-03412-w. Epub ahead of print. PMID: 39833406.

2:  Kornelius E, Huang JY, Lo SC, Huang CN, Yang YS. The risk of depression, anxiety, and suicidal behavior in patients with obesity on glucagon like peptide-1 receptor agonist therapy. Sci Rep. 2024 Oct 18;14(1):24433. doi: 10.1038/s41598-024-75965-2. PMID: 39424950; PMCID: PMC11489776

3:  Spruance SL, Reid JE, Grace M, Samore M. Hazard ratio in clinical trials. Antimicrob Agents Chemother. 2004 Aug;48(8):2787-92. doi: 10.1128/AAC.48.8.2787-2792.2004. PMID: 15273082; PMCID: PMC478551.

4:  Sam AH, Salem V, Ghatei MA. Rimonabant: From RIO to Ban. J Obes. 2011;2011:432607. doi: 10.1155/2011/432607. Epub 2011 Jul 6. PMID: 21773005; PMCID: PMC3136184

Graphic credit:

Table at the top of the post of form Reference 1 and it is not copyrighted. The comparison Table was made by me.