Happy Labor Day 2024

 

More labor like I am used to seeing it in the upper Midwest. 

In keeping with the tradition of previous labor days - this is my annual greeting. I started writing these Labor Day greetings as an update on the work environment for physicians.  My rationale is that over my nearly 40 years in medicine that environment has continuously deteriorated.  Like any field there have been obvious improvements and innovation in clinical care along the way.  Even though that has happened the work environment has worsened every year leading to widespread physician dissatisfaction, burnout, and moral injury along the way. 

I was fortunate enough to hang on until about three years ago when I retired.  Compared to working my entire career as an employee - retirement is quite literally a walk in the park. I  stay active in the field by reading, writing this blog, and working on various publications. I get plenty of rest and exercise. I have time for activities that were on hold for decades during my working years. I have not seen or treated any patients in about 3 years. A friend of mine who went back to work told me that he had to work on an inpatient unit for 2 months because the organization he worked for had that requirement for anyone who had not seen enough patients in the past two years.  If you were an acute care psychiatrist like myself that requirement makes little sense. Reading all of the notes and plans from the first week of outpatient practice should suffice.  After all we have a Presidential candidate who brags about passing a rudimentary cognitive screening exam - and he has a briefcase with all of the nuclear missile launch codes. 

I do miss the detailed conversations with people and discussions about how to approach their problems.  In some of the discussion formats there is still controversy about psychotherapy in psychiatry.  The only way I can see this as a real controversy is if we are arguing that all psychiatrists should be psychoanalysts.  I don't think that anyone believes that any more. But it has always been clear to me that psychiatric practice needs to be informed by psychotherapy and that includes psychoanalytical/psychodynamic psychotherapy both on the expressive and supportive sides. Psychiatrists need to be able to talk with people in a therapeutic way across a number of diagnoses and settings.  Psychiatrists need to be able to maintain relationships with people who have a very difficult time maintaining relationships with anyone. Psychiatrists need to maintain relationships with people who are actively avoided by their own families and acquaintances.  The only way that will happen is if a psychiatrist is trained in these techniques.  Without them - a person is just talking with another doctor about medical treatments. 

As I have stated many times on this blog in the past - that type of quality psychiatric treatment takes time.  Taking time away from psychiatrists and their patients is one of the functions of modern healthcare administration.  It leads to the previously mentioned problems in the work environment.  I did an update just before typing this post by searching developments in the physician work environment in the past year.  The same concerns about dissatisfaction, burnout, and moral injury were still there.   There was something slightly more specific on the AMA web site pointing out how Medicare reimbursement is not indexed to inflation and does not cover the expenses.  That leads to higher volume work (something that managed care rationing was supposed to prevent) and in many cases lower quality.  It can also lead to a lack of available care as physicians drop out of Medicare or just have too much low reimbursement work to see new patients.  But that message from the AMA is far from optimal.  It seems to imply that if patients were aware of these problems they would lobby politicians to improve working conditions for doctors.  Patients already know the problems - at least some of them.  I had several patients comment on the low reimbursement I was getting from Medicare for seeing them.  It might be useful if physician organizations like the AMA provided information on how to set up a practice that would maintain financial viability.    

I did try to volunteer as a research analyst.  I was involved in a great research project at the time I left my last employment.  I offered to analyze data for a local large healthcare organization (one of the three largest in Minnesota).  I emphasize again that I offered to work for free on this data analysis and any subsequent publications.  The research project I suggested had never been done in a large healthcare organization - but had been done in registry studies in Sweden and Denmark.  There are no national registries in the United States and all of the data is proprietary.  That company was not interested in me working for free even though I did plenty of free work for them when I was an employee working on research committees.  The only difference was that I still had to generate revenue by seeing enough patients while doing the additional work for free.  That offer still stands for any serious research being done in psychiatry.

That is my brief Labor Day message this year.  It is repetitive because physicians have very little leverage against businesses and governments and that had led to the current work environment problems.  I continue to go to conferences and see a lot of people who I know are still actively working.  From their descriptions they are working too much.  Like me they enjoy talking and working with people.  That is probably how a person ends up in psychiatry.  I wish them well in the coming year and hope for developments that will make their work easier.  And as always - I hope all of my colleagues make it to retirement.

George Dawson, MD, DFAPA

Supplementary 1: I decided to include this graphic from about 4 years ago that I made to indicate how much physician/psychiatrist time is diverted away from clinical care basically to satisfy some administrative requirement.  It should be obvious that has increased greatly over time and although other health care providers are also affected the burden is somewhat disproportionate on the physicians.  As I pointed out - during this time frame I replaced 4 full time employees when I was expected to also do their work.  It is also apparent that a lot of this worked is free for other organizations (managed care organizations, pharmacy benefit managers, etc).  

 

Graphics Credit:  click directly on the photo and it will take you to detailed information on the origins, credits, and CC license on Wikimedia Commons. 

Review of Ketamine: The Story of Modern Psychiatry's Most Fascinating Molecule

 

Keith Rasmussen is Professor of Psychiatry at the Mayo Clinic and the author of an authoritative text on electroconvulsive therapy - Principles and Practice of Electroconvulsive Therapy.  I noticed the pre-release literature on his book on ketamine and waited for months to get a copy.  After reading it I can say it was one of the best books I have read in psychiatry.

The book is organized into 9 chapters.  The first 4 are on the history and pharmacology of ketamine.  That is followed by 4 chapters on clinical applications including depression, as a model for schizophrenia, chronic pain, other psychiatric disorders, substance use disorders, and ketamine assisted psychotherapy.  There is a final chapter on whether ketamine is a neurotoxin or a neuroprotectant and several experimental applications are discussed.  Many of these chapters could be freestanding reviews of the literature. In writing these reviews, authors will often use table summaries either as an outline or in the body of the review. Rasmussen uses one or two paragraph long summaries of research papers and is aware that can be a tedious approach. For that reason, he omits a long discussion of preclinical research in one chapter.

The initial chapter is an introduction to the molecule.  We learn that it belongs to a class of arylcycloaminohexanes and that phencyclidine (PCP) was the initial drug synthesized from that class. PCP was invented for use as a general anesthetic, but it failed because of severe behavioral reactions.  Additional structures were synthesized from that class and ketamine was eventually developed on a preclinical basis. The molecular structures of both compounds are provided in the book but the structure of ketamine on page 12 is in error (it shows a chlorine atom in position 2 on a cyclohexane rather than a phenyl ring but the IUAPC naming in the caption is correct).  I have posted both structures below.  The purported mechanism of action is discussed in several places – at the level of the NMDA receptor and how pathological processes like excitotoxicity and apoptosis occur and may be interrupted.

 

When I took my first medical school pharmacology course in 1984 – the adverse reactions were noted in the anesthesiology section for both PCP and ketamine.  Rasmussen writes like a chemistry major who experienced organic chemistry as an important course. He discusses detailed chemical structures, reactions, stereochemistry, and the Grignard reaction. These explanations have the purpose of explaining of how compounds are named and why the synthesis of ketamine is outside of the expertise of local meth cookers.  At the same time, he does not get too technical when it comes to receptor binding affinities (I did not notice a single K_i).  Beyond that he details where ketamine is currently produced (China, India, Mexico) and provides two cases of clandestine operations in China that were using 8.5 million tons of ketamine precursor before they were shut down by authorities (see Supplementary 1 footnote).

The book is a thorough documentation of the time course of PCP and ketamine use.  He discusses landmark papers and points out research papers that were probably the original observations and papers that are highly cited.  As I read the book, I went to the references and underscored many of these papers.  The reference section alone is 44 pages long.

Each chapter about the potential clinical applications of ketamine is a through discussion of the existing literature and the limitations of that literature. He discusses the research design of many of these studies and what research is needed in the future.  He discusses the unanswered questions about ketamine. 

Does the book have any shortcomings.  A lot of reviewers seem to describe needing to be entertained by the books they are reading. Almost everything I read is a scientific paper or book.  Some of that content is exciting, but generally I would not see it as entertaining.  The closest this book comes to being more difficult to read were long sections that summarize scientific papers. 

Should you read this book?  Like all books – a lot depends on your level of expertise.  I consider myself to be an expert in both ketamine and PCP based on both my pharmacology knowledge and what I have seen clinically. I learned a lot reading this book and I think practically all psychiatrists and psychiatric residents will find this book useful.  Neurologists are an additional audience for the sections on neuroprotection in cases of traumatic brain injury, stroke, subarachnoid hemorrhage, and status epilepticus.

You will see information in this book that you will not read anywhere else.  It is footnoted to scientific articles and the discussion is even handed – the possible good and the bad.  A thread runs through this book from the very first page that all human drug responses are complicated based on biological heterogeneity and some of that can be age based. That means there are no “miracle drugs” for everyone.  There is an extensive discussion of the substance use aspects of the drug and it is presented as a clear danger.  I think that all acute care psychiatrists and residents could benefit from reading this book and it could form the basis of a journal club or a resident seminar in pharmacology. The style of writing reminded me of a text that I consider to be the most well written – Fundamentals of Biochemistry by Voet, Voet, and Pratt.   

What about people on the other end of the spectrum of ketamine knowledge?  There is plenty of information in this book that may be useful to you.  The book is well organized and researched.  It has an excellent index that will contain references that you do not have.  The information density in the book is much higher than I expected from reading the initial chapter and introduction.  There are interesting historical points including a section of three very well-known ketamine users, their experiences, and publications related to their use.  If you are involved in a research project involving ketamine or PCP – this book is a good source of background information.  This book can also potentially benefit journalists tasked with writing about ketamine and other psychiatric treatments.  

I really like all the details about the medicinal chemistry of ketamine.  It reminded me of some online discussions I have had with physicians who thought that organic chemistry was an unnecessary prerequisite to medical school.  If you share that opinion – chemistry at a more detailed level than you typically see in a pharmacology text might not interest you.  It is still there in an accessible form. 

This is a very good book – well researched and written. Dr. Rasmussen presents a very even approach to ketamine.  He presents the research and clinical findings of what really occurs with the use of ketamine.  No speculation is involved. It took a lot of hard work and accumulated knowledge to write this book and any physician reading it will realize that. With a few modifications the next edition of this book could become a classic text in psychiatry.

 

 

George Dawson, MD, DFAPA

Reference:

Rasmussen KG.  Ketamine: The Story of Modern Psychiatry's Most Fascinating Molecule.  Washington DC.  American Psychiatric Publishing.  2024; 295 pp.

Supplementary 1:  The more I thought about the figure quoted for precursor amounts used in the illicit manufacture of ketamine in China - the more skeptical I became.  The specific quote from the book is:  "In 2009, Chinese authorities seized two secret laboratories with a total of 8.5 million tons of precursor material, which is simply gigantic!" (p. 44).  Since illicit production estimates based on precursors are generally in the hundreds of metric tons - millions of tons certainly are gigantic.  From the first reference (1) listed below:  

"China produces massive amounts of ketamine, reliable estimates for the prevalence of ketamine abuse are not available. As of today, five Chinese factories are officially licensed to produce ketamine, but there are reports of illicit production on an industrial scale. In 2009, Chinese authorities reported the seizure of two illicit laboratories producing 8.5 million tons of the immediate precursor of ketamine."

In this case, the total precursor was 8.5 million tons and the UN Drug Report (2) was referenced at the head of the paragraph.  From that report (page 117):

"In 2009, China reported seizing two illicit laboratories processing hydroxylamine hydrochloride, the immediate precursor chemical for ketamine, and seizing 8.5 mt of this substance."

Note that the "mt" designation in this report is metric tons rather than million tons.  A metric ton is usually defined as 1,000 kg reducing the size of this estimate by about 2 million fold (8,500 kg compared with 7.7 million kg), but that is obviously still a significant amount of precursor.

Supplementary 2:  This interview of the author became available in the Psychiatric News on this date (11/5/2024)  

Ketamine: Miracle Drug or Double-Edged Sword?

https://psychiatryonline.org/doi/full/10.1176/appi.pn.2024.11.11.13

References:

1:  De Luca MT, Meringolo M, Spagnolo PA, Badiani A. The role of setting for ketamine abuse: clinical and preclinical evidence. Rev Neurosci. 2012;23(5-6):769-80. doi: 10.1515/revneuro-2012-0078. PMID: 23159868.

2:  UNODC, World Drug Report 2010 (United Nations Publication, Sales No. E.10.XI.13).

Protesting...

I am more than a little fed up with unnecessary wars and deaths. My college days were defined largely by an unnecessary war in Vietnam. I was in the first reactivation of the military draft largely because nobody wanted to go off to Vietnam for no clear reason and fight a war. That first draft was a lottery system by birthday and my lottery number was 215. I was in college at the time and could have received a deferment but I decided to waive it and gamble that my number was high enough to keep me from being drafted. Taking the deferment meant being put in a “second priority group” and continued draft eligibility. I was lucky and 215 was never called. 

On the campuses those days, almost everyone was a war protestor and, in my state, there were some very large protests at the University of Wisconsin. Those protests permanently changed the face of State Street in Madison – where the local drug store was redesigned to look more like a pill box after the windows were repeatedly broken out. The 1960s and 1970s in the US was an era of repeated demonstrations and protests, many of them violent and many resulting in loss of life. On August 24, 1970 - radicals parked a Ford Econoline van packed with explosives next to Sterling Hall at the University of Wisconsin in Madison.  The explosion destroyed the six story building and killed a researcher who was in the building at the time.  The target was the Army Mathematics Research Center.

One unnecessary war in Vietnam, was apparently not enough and the United States went on to prosecute 2 more in Iraq and Afghanistan.  Both of those wars took a tremendous toll in terms of mortality and morbidity to American military personnel and the civilian population and infrastructure of both countries.  Both wars are often rationalized after the fact that Saddam Hussein and the Taliban were not good for the populations of either country, but that is not the reason that either war was initiated. Iraq was invaded on the false premise that it had "weapons of mass destruction".  Afghanistan was invaded because the US military failed to catch Bin Laden as he fled across the country.     

 That brings me to the current era of protests and the expected protests tomorrow at the Democratic National Convention in Chicago. There is a lot of speculation in the press that it may resemble the protests that occurred at the Democratic National Convention in August 1968 – also in Chicago. The 1968 convention followed the assassinations of both Martin Luther King, Jr and Robert F. Kennedy earlier that same year. There were 10,000 demonstrators in Chicago confronted by 23,000 law enforcement and National Guard. The focus of the protests was the war in Vietnam with a secondary issue of lowering the voting age from 21 to 18. Despite violent confrontations between protestors and the police – no deaths or serious injuries were reported. There was subsequent legal action that involved charging 7 of the organizers with conspiracy to riot – and those charges were eventually dropped. In that original protest, many of the organizers had celebrity status and some of the concepts they presented during the protests gained notoriety.  The more radical and violent groups of the 1970s like the Weather Underground did not participate in the protest.

The overall dynamic of the protest was focused on a lengthy and questionable war in Vietnam. The protest made sense because friends and family members were being drafted, killed, and injured in a war that was unnecessary. There was an immediate impact on the American people and political leaders in the United States were accountable. 

Reviewing the dynamics of the protestors who may be present at the DNC tomorrow. The current armed conflict in Palestine is an active war prosecuted against Hamas by Israel. The war was initiated by an attack by Hamas on Israeli citizens on October 6, 2023. That attack consisted of killing, maiming, and raping civilians as well as hostage taking. The specific details can be found here. Hamas is embedded in Gaza and Palestinian noncombatants are essentially hostages to the Hamas war effort.  Since that time, Israel has counterattacked and waged war against Hamas with the resulting destruction of much of the infrastructure in Gaza as well as over 40,000 civilian deaths. The leaders of Hamas and Israel have explicitly stated that their goal is to eliminate the other side completely. In other words – kill everyone on the other side and eliminate any state that they might occupy. These are explicitly stated goals and not my speculation. 

 Along the way, there has been a protest movement in this country that started on campuses. It has characterized the war in Gaza as genocide perpetrated by Israel. The precipitating event by Hamas is either rationalized or ignored. There have been many cases of Jewish students who are US citizens being harassed and threatened. The situation on campuses led to the resignations of University Presidents who had a difficult time determining the boundaries of free speech and antisemitic hate speech. At the same time, the situation in Gaza is a horrific human tragedy in terms of lives lost, war time injuries, families disrupted, starvation, lack of medical care and disease. The Israeli army routinely kills noncombatants – not just civilians but aid workers, and journalists. There have been many cases of deaths where they were no obvious military targets and there is a statement about an investigation of what happened. Spokesmen say that Israel is trying to minimize damage to the civilian population, but there is minimal evidence that is happening. 

 At some point, the protestors in this case decided to put blame on President Biden and Vice President Kamala Harris. I anticipate seeing varying degrees of this at the DNC tomorrow. As a war protestor from the 1970s, these protestors seem to have it all wrong. The current White House staff has been trying to broker an immediate cease fire and peace agreement for several months now. The US government is behind stopping the bloodshed and advocating for peace in an area where there have been decades of senseless wars. There is no more senseless war than one where each side is actively working to completely obliterate the other. That is a mode of thinking from before civilization existed and it may end up threatening to end civilization. 

 If you really want to protest something – protest the primitive thinking of total war promoters in both Israel and Hamas. Hold the leaders with that line of thinking accountable. Their goal of annihilating the other side as a solution is unrealistic and serves only to fuel future terrorism and state sanctioned revenge. It makes no sense at all to protest the peacemakers and call them names.  Protest the real warmakers here - the leaders of Israel and Hamas.

And don't fool yourself into thinking that the leaders of both Israel and Hamas are not looking at the American presidential election and trying to figure out how they can use it to their advantage.  That may include what happens at the DNC protests.

  

George Dawson, MD, DFAPA

Addendum 1:  I heard a protestor interviewed today (August 19) on BBC World News.  Unfortunately I cannot locate a transcript or audio clip so this is my recollection of what he said. He said that both parties in the US were responsible for supplying arms to Israel for a long time and that meant that Biden and Harris were currently responsible.  He had not heard anything new from Harris and therefore he remains hopeful but suggested that people will not vote for her unless she changes positions on Israel.  When the interviewer asked him if he wanted Trump to win he said: "Oh no - I don't want Trump to win but if he does it is because of the policies of Biden and Harris."

Well no it is not. Trump wins if there are insufficient votes for Harris and the situation is more complex than trying to resolve and Arab-Israeli dispute that has been going on for decades in a few months before the election. The protestor is also overestimating the leverage that the US has in this situation as well as the fact the combatants here are sworn to obliterate the other side and at no time have given a hint of becoming more reasonable. 

I am in the process of reading a book on how the US has become a grievance culture. Pick a cause, feel aggrieved, and go on the attack. It has become a cultural norm probably best exhibited by the stolen election meme used by the MAGA Republicans. This protest appears to have humanitarian motives, but it really minimizes the work that the Biden-Harris administration in concert with other countries are doing to secure a cease fire and take steps to end the hostilities.  Either way the additional point is missed that unless the needle is threaded with this agreement - it can easily become an election issue.  The protestor in this case does not want Trump, but he also does not want to do anything to help Harris. That is a conveniently unrealistic viewpoint. Deciding to not vote probably hurts Harris more than Trump because the GOP has the leverage of the electoral college - they have won the presidency with fewer popular votes.

George Dawson, MD, DFAPA

Update (9/2/2024):  The citizens of Israel seem to have no problem placing the accountability for the ongoing war directly on Netanyahu and his refusal to negotiate.  I hope this was noticed by American protestors placing blame on the Biden-Harris administration who are advancing the peace plan. Palestinians and Hamas have no luxury of influencing the leader of Hamas because there is no democratic process.  

https://www.yahoo.com/news/hostage-deaths-pushed-israel-breaking-155646402.html

Graphic Credit:  From WikiMedia Commons per their user agreement and CC license. Click for details.

Combinatorics Revisited…

I critiqued a paper that purported to show that Diagnostic and Statistical Manual criteria produce an impossibly large number of possible combinations and that this somehow invalidates their use.  As a refresher, combinations are basically any pool of n elements combined k at a time.  For example, in the case of major depression, the diagnosis requires at least 5 (k ≥ 5) of 9 (n=9) elements.  That would lead to a calculation of C(n,k)  = C(9,5) + C(9,6) + C(9,7) + C(9,8) + C(9,9) or  126 + 84 +36 + 8 + 1 = 255     I have illustrated the total combinations for the first expression at the top of this post.  In each case the elements 1 – 9 are the DSM diagnostic criteria for depression.  Note that adhering to the diagnostic criteria eliminates the last column of combinations to the far right since elements 1, 2, or 1 and 2 are required for the diagnosis. 

Reading the actual diagnostic criteria illustrates that this is a crude measure because there are implicit unknowns – most significantly the total number of medical unknowns suggested by the criteria “The episode is not attributable to the physiological effects of a substance or to another medical disorder.” Historically reviews of those disorders suggest that they are in the 200 to 300 range with some being far more common than others. If all those conditions were included in the combinatoric expression it would be very large – but not necessarily that much more inclusive because of the low frequency of many conditions.  Additional exclusion criteria include psychiatric disorders with depressed mood as a feature and any previous episodes of mania.  Since they are exclusion criteria – it is reasonable to say that there may be only 255 combinations of rule in symptoms, but being able to make the calculation is no assurance that they exist in practice.  

Following the authors assumption about the combinatoric possibilities we can substitute short had for criteria 1-9.  In the following manner (as noted in their Table 1):

1. Depressed Mood

2. Loss of Interest or Pleasure

3. Appetite/Weight Disturbance

4. Sleep Disturbance

5. Psychomotor Change

6. Loss of Energy

7. Worthlessness/Excessive Guilt

8. Concentration/Indecision

9. Death/Suicidal Thoughts

A further restriction is included in criteria A: “…at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.”  That eliminates any combination that does not include 1, 2, or 1 and 2.  That changes the above expression to 105 + 77 + 35 + 9 + 1 = 227 possible combinations just based on the numbers.  The authors were interested in seeing how many of these possible combinations exist in the clinic and that was the goal of this paper.   

The sample for the paper was 1,566 subjects with a diagnosis of major depression out of a total sample of 3,800 evaluations.  All subjects were being seen on a clinical basis and the Structured Clinical Interview for DSM-IV (SCID) was administered by trained examiners and the interrater reliability was sampled and posted for all of the depressive symptoms.  The number of subjects in each group of combinations was determined and the results were interesting.

For starters – 57 of the 227 combinations or about 1/4 did not occur in a single patient. In the case of 5, 6, and 7 criteria the combinations that did not occur are listed in tables 3, 4, and 5.  The most common combination was all nine criteria and that occurred in 10% of the sample (N=157).  The authors were able to observe that 9 combinations from the 9,8,7, and 6 criteria categories accounted for 40% of all diagnoses. They suggest that these might be prototypical combinations in a field of diagnostic heterogeneity. Apart from diagnostic prototypes the authors suggest that it may facilitate the search for biological markers but they conceded that those would need to be very large and expensive studies. 

As I thought about that proposition, a few things came to mind.  First, Mayo Clinic multi-omics studies. Some of these studies have already identified biomarkers and possible genetic markers on heterogenous groups of subjects with major depression.  The subjects were all administered standardized DSM based interviews and the combinatorics could be determined.  This would be an efficient way to see if symptom combinatorics match the biomarkers.  Second, why would we expect there to be any correlation between symptoms and biomarkers?  Most medical illnesses would not have a  correlation and in fact the more complex illness can be expected to produce significant non-specific symptoms like fatigue and malaise.  Some authors have suggested that very specific subtypes of depression are more likely to produce reliable biomarkers.  Taylor and Fink (2) have written extensively about melancholia and biomarkers associated with that illness.  I also recall work done by Linkowski and Mendlewicz (3) that they published in the endocrine literature.  Their work was almost exclusively on subjects with very severe forms of depression (HAMD ratings > 30) and their neuroendocrine biomarkers were more robust.  Third, is there a time domain consideration with the combinatoric groups?  For example, do the people meeting 8 or 9 criteria have depression that has persisted for a longer period and does attempted treatment or not treatment affect that group?  Fourth are some of these symptoms complexes generated by others - are they secondary to sleep and appetite disruption?

Either way, the application of combinatorics to some of these situations is very interesting in the field.  As noted in my previous post, combinatorics reflects biological scaling at some point. That occurs at the molecular as well as the evolutionary level.  Large numbers of combinations should be expected when combining either molecular components of organisms, metabolic networks, or the organism wide effect.

Thinking about these combinations clinically is also an interesting exercise.  During my tenure as an acute care psychiatrist it was rare to see anyone without most of the symptoms in an inpatient setting.  Doing consults on medical and surgery wards there were often more novel symptom combinations.  Looking at the author’s tables and the combinations they did not see in their study is an interesting exercise.  One example would be the combination 1,2,3,4,5,7,9 from Table 3.  That would be a person with depressive symptoms except for loss of energy and concentration problems. According to this study that person does not exist.  And of course all of the combinations that lack depressed mood, anhedonia, or that combination have been eliminated by definition.

I hope to expand my look at combinatorics to the genetic, evolutionary, and molecular levels in subsequent posts as well as trying to see if there are mappings from one level to the other.  I am also interested in any books or papers that use similar analyses so please send those references my way,      

 

George Dawson, MD, DFAPA

 

References:

1:  Zimmerman M, Ellison W, Young D, Chelminski I, Dalrymple K. How many different ways do patients meet the diagnostic criteria for major depressive disorder? Compr Psychiatry. 2015 Jan;56:29-34. doi: 10.1016/j.comppsych.2014.09.007. Epub 2014 Sep 6. PMID: 25266848.

2:  Taylor MA, Fink M.  Melancholia: The Diagnosis, Pathophysiology, and Treatment of Depressive Illness. 544 pp. New York, Cambridge University Press, 2006.

3:  Linkowski P, Mendlewicz J, Kerkhofs M, Leclercq R, Golstein J, Brasseur M, Copinschi G, Cuater EV. 24-hour profiles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness: effect of antidepressant treatment. The Journal of Clinical Endocrinology & Metabolism. 1987 Jul 1;65(1):141-52.

 

Apps:

Very good apps are available for calculating combinations, permutations, and the varieties.  For example – if you think back to your probability and statistics course in college at one point the professor was talking about combinations occurring where elements could be used more than once (with repetition). That is typically demonstrated by taking numbered balls out of a container and replacing them in one situation and in the other cases leaving them out. Those are different calculations.  For the above calculations the assumption is that each k element can only be used once (no repetition).  There are apps that give you both calculations.