The Times They Are A-Changin’ – or Are they?

I was walking around last week at dusk on a couple of nights. For the first time I decided to listen to some music as I walked. I would never do this if I was cycling because you need to hear the tire noise of approaching vehicles and I was using noise cancellation headphones tied into my music library. I also decided to use shuffle mode and that is also unusual – I typically repeat tracks until I get tired of them and that often takes a long time. For some reason, my phone kept playing Dylan songs. It reminded me of how I really did not like Dylan when I was young and listening to Hendrix and the Who. My interest peaked when he got the Noble Prize for Literature. It peaked again when I heard him interviewed and he talked about how easy it was to write music when he was younger. The music just seemed to flow and all he had to do was write it down. It was how mathematicians were described in Nasar’s biography of John Nash. Young mathematicians typically produced most of the ideas that advanced the field.

A lot of the songs were melancholy tunes about relationships gone bad.  Some were lessons in how not to be codependent. I was acutely aware of being an old man dressed in black listening to this music and free associating to similar events in my life from long ago. Before it got too maudlin - The Times They Are A-Changin’ came on:

Come gather 'round people

Wherever you roam
And admit that the waters
Around you have grown
And accept it that soon
You'll be drenched to the bone
If your time to you is worth savin'
And you better start swimmin'
Or you'll sink like a stone
For the times they are a-changin'

I could have sworn that what I heard walking around in the dark was a direct reference to the United States in that song. But looking it up later - it was not there. The song snapped me out of interpersonal reflection and into the current threat to American democracy.  For the past several days I had been responding to social media posts about the disconnect between what appears to be going on in national presidential politics and the reality of the situation. Just that day I responded to a poster questioning why Christians appear to be in lock step with a candidate who does not appear to have similar values and how Biden has done very well in the White House but seems to be struggling in the polls against a candidate with a known poor record who orchestrated an insurrection against the US government? A candidate who has been charged with 91 felonies. Even more mysteriously, the entire Republican party with rare exceptions is supporting Trump and most want his endorsement in local and state elections. How can a candidate with that many flaws still be in contention at this point and dominating a party that was originally abolitionist and got Lincoln elected as their first President before the start of the Civil War?  It does not make any sense and I will look at the hypotheticals below.  I tried to put as many as possible into the graphic at the head of this post – but only the coarsest details are possible:

1:  A general lack of critical thinking:

It has been a long time since I took a high school English class, but from what I recall even back in those days there was very little emphasis on rhetoric. Critical thinking generally involved the decoding the author’s intent, detection of symbolism and defending an opinion on a theme: “Do you find Lord of the Flies to be optimistic or pessimistic and why?”  Rhetoric was largely confined to debate teams that a small percentage of students participated in.

It has never been more important for the average citizen to be informed and aware of what might be rhetorical distortions. There used to be some level of assistance from professionally edited news, but that is no longer reliably available. Today it is possible to get all your news from a site that you agree with on ideological grounds – no matter how far from reality that site gets. Apart from these echo chambers on the Internet, the main street news offers minimal assistance.  You might find stories about the polarized electorate with no discussion of what that means or if one side is more polarized than the other.  Threats and overt violence were introduced into the political scene with no comment that this is almost an entirely right-wing phenomenon that is often tied in with gun rights and bragging about who owns the most guns. The right wing owns both moral and gun extremism in the US and yet there no criticism of this in mainstream media. Most importantly, political violence against specific groups should be unacceptable in the US and it is increasingly apparent.

2:  President Biden is too old: 

This seems to be a popular trope in both campaign propaganda and as material for comedians.  Bill Maher for example, will often detail the accomplishments of the Biden administration as being some of the most significant in decades only to incorporate polling questions about his age and conclude he should step down and let someone else run. No suggestions about who that should be and judging from the declared candidates there is no one of suitable name recognition or accomplishment who could run and expect to get support equal to Trump’s locked in MAGA constituency. If you look at my graphic – any candidate the Democrats advance will not have the amount of leverage with the voters based on the factors listed.

But backing up – is 80 years old – too old?  I saw President Biden on the bike and I saw him fall. It was clearly a mistake that people make when they are not used to toe clip pedals. The part that most people seem to ignore is that he got up with no problems. That is not the mark of a feeble old man and neither is the current schedule he has been keeping. More to the point – he has an awareness of how things need to run in the Executive Branch, how information needs to be managed, how consultation with staff is a critical function, and how to manage alliances.  There is minimal evidence that his predecessor has that level of awareness.  

There is certainly no current evidence that Biden cannot do the job given his list of accomplishments and some high-profile incidents – most notably his performance at the last State of the Union address. Ageism is certainly a prominent cultural bias in the US.  If I were a foreign actor wanting to manipulate the American electorate – I would use it, especially if I knew the opposition party could easily be convinced to use it.  The current group of Republicans could be expected to jump on it even though some of their members of Congress are older than Biden.

3:  The Republican base has been manipulated and brain washed by culture war tropes: 

This is undoubtedly a factor at some level.  I have written on this blog about how the GOP has become a party of gun and moral extremists – not out of some strict Constitutional interpretation or religious belief, but out of political expediency. It is easy to manufacture some ideological position to elicit emotional responses from some voters and get them to believe they are in a morally or Constitutionally superior position. Fortunately, that is not how democracy works but it is how the current crop of Republicans want it to work. In the meantime, public safety, education, and women’s health have all been compromised. On the day I am typing this a Constitutional Amendment for reproductive rights was passed in Ohio blocking attempts to pass restrictive abortion laws. Whether this can be a rallying point against moral extremism is an open question at this point.

4:  Fragmentation among Democrats: 

There is some concern that progressives within the party have gone too far in areas of social consciousness particularly social justice issues involving race and the LGBT community. The concern is amplified by the Republican’s rhetorical use of the term woke as a pejorative. That has allowed them to indiscriminately use the term to criticize health care, educational, social, and economic policies as being too woke (translation politically correct) and simultaneously suggest that most Americans would not find it to be acceptable. That can range from books in a high school library that were read by several older generations to college admission policies to protests about excessive use of force by the police.

The current war between Israel and Hamas is a similar flashpoint. One analysis suggests that progressives see the world though a simple lens of colonizers and victims. That has been spun into Israel starting a genocidal war in Gaza or even the US starting or backing such a war. In the most extreme case, social media was abuzz with young people supporting a letter allegedly written by a famous terrorist, blaming the United States for terrorist attacks. That has also led to protests and threats to Jewish college students in the United States. All of that misses the point that violence is being incited against US citizens who happen to be Jewish and that Hamas clearly started the war and clearly stated their ongoing goal is to destroy Israel and kill their citizens.

5:  Activation of far right white supremacist and antisemitic groups:  

There is no doubt that fringe groups that were essentially silenced for many years were activated during the Trump administration and actively support him. In my own neighborhood there was widespread dissemination of white supremacist literature for tens of miles in all directions.  That has never happened in the Midwest during my lifetime. Further investigation linked the same group spreading that literature to antisemitism.  Investigation by local officials and law enforcement did not identify the specific perpetrators and no charges were ever filed.

6:  Activation of antisemitism in younger generations: 

The facts are not disputed and various theories have been proposed. The history is forgotten explanation seems to have a lot of traction.  At least it seems to have garnered the most speculation. In other words, with less exposure to Holocaust survivors and the history of World War II, younger generations are unlikely to believe the actual historical events – a clearly documented genocide against the Jewish people. That seems to minimize any role of activated antisemitic hate groups and social media. Many of these groups are now at the point that they show up in public demonstrations and are attempting to recruit new members from suburban neighborhoods. The wave of antisemitism in the younger generation has had far reaching effects on college campuses, in some cases to the point that departments and administrations failed to condemn the recent terrorist attack against Israel or an obvious problem of antisemitism on their campuses. This generation uses TikTok as a preferred social media site. In a recent press release they described removing tens of thousands of antisemitic posts.  Just how long that posting has occurred is unknown.

I think it is also useful to recall that political violence directed at minority groups is a well-known tactic of fascist and totalitarian states.  In the early days of the Internet online discussions often became heated to the point that accusations of Naziism were often made.  This led to Godwin’s Rule or as an online discussion grows longer (regardless of topic or scope), the probability of a comparison to Nazis or Adolf Hitler approaches 1.  That is basically nerd speak to say that analogies to Nazis based on Internet discussions is probably absurd. What I have seen lately suggests to me that we are beyond the absurd stage when people are injured and living in fear.  If it walks and talks  like a Nazi….

 7:  The social media propaganda machine:  

Social media seems to always be in the news. The common topic is how it is a malignant force in the lives of teenagers and children. There is concern that you can get “addicted” to rapidly scrolling and clicking on too many sites. People talk about the dopaminergic effects of this activity – like the neuroscience is known. Even though we had a foreign government actively interfering in the last Presidential election through social media and email hacks – nobody seems focused on that happening again. US Intelligence agencies predicted that it would happen again and it would probably be more vigorous than the last time. It is also more difficult to detect because the foreign actors are all using servers within the United States. Several agencies are responsible for detecting and monitoring this activity – but 1 year out none of them are reporting on what they see or what kind of misinformation is being posted. You don’t have to be a secret agent to think about who these foreign actors are. Russia was clearly involved in the last Presidential election and given the situation in Ukraine – they would clearly prefer Trump over Biden.  Putin has actively encouraged Russian hackers at all levels including those who steal money from average Americans.  Trump has made it clear that he would not support Ukraine and he clearly had a negative impact on NATO.  Biden has been able to reverse most of that damage and unify NATO.  Iran, China, and North Korea also have an interest in a Trump presidency.  These countries either have a direct interest in supporting Trump based on his probable policies or just weakening the US by more divisiveness in the electorate.

 8:  Uncritical voters:  

I heard Iowa voters asked about why they are voting for Trump and why he is so popular in their state.  I heard the following responses:

 “He is a businessman.”

 “He says what is on his mind.”

 “I don’t care what he has said or done – I am voting for him.”

These responses and his previous performance – all indicate that many Trump voters are not focused on any policy.  It would probably be difficult because most of the policies that Trump seems focused on at this point have to do with revenge against his perceived enemies.  That is typically a low bar – they are people who either disagree with him or want accountability.  That leads me to a previously stated conclusion I made that a lot of Trump’s base are nihilists who just want to burn the system down. It is difficult to find more nihilistic behavior than orchestrating an insurrection against the US government and refusing the peaceful transfer of power.

Given the above analysis – I think the negative sentiment about President Biden is primarily the product of foreign actors manipulating the American electorate. That also explains the disconnect between many of the demographic features of Trump voters and their candidate.

I do not want to put all of this on young voters.  There are clearly older voters who demonstrate similar levels of cluelessness, probably borne out of long-standing biases.  It is up to voters of all ages to not believe what you see in social media echo chambers, clear propaganda from hate groups, and similar attitudes that may have existed in your culture for generations. We cannot turn the United States over to a man and a party of extremists who have proven time again that they have no vision for the country or where it is headed. In Congress the Republican majority has clearly demonstrated that they cannot govern. We cannot be influenced by groups seeking to divide Americans and destroy the values that this country was founded on.

We all must start swimmin’ to save American democracy.

 

George Dawson, MD, DFAPA

References:

1:  Hotez, Peter. "On Antiscience and Antisemitism." Perspectives in Biology and Medicine, vol. 66 no. 3, 2023, p. 420-436. Project MUSE, https://doi.org/10.1353/pbm.2023.a902035.

2:  Scherer, Nancy & Miller, Banks. (2009). The Federalist Society's Influence on the Federal Judiciary. Political Research Quarterly - Polit Res Quart 62. 366-378. https://doi.org//10.1177/1065912908317030. 

Graphic Credit: I made this graphic 

Supplementary 1:  Why I wrote this post - this post is not an analysis of the psychiatric status of either candidate.  I am on record on this blog that the role of assessing the President's fitness to work in that office is supposed to be assumed by lay people working with him or her.  Many people working with Trump have provided scathing critiques of what they observed. I have not seen any from the Biden administration. 

This post was written basically as an exploration of how a candidate who seems so intellectually, emotionally, and temperamentally unfit for the office (as determined by multiple independent assessments by non-mental health professionals) has such a draw with the electorate. It seems mystifying until you look at the diagram and realize that more of the factors that leverage the electorate are stacked against Biden rather than Trump. In fact - replacing Biden in the graphic results in minimal gains. If I had to speculate on the biggest effect I would see it as all of the factors impinging on the social media on Trump's side.  

For the record, I am not a life long Democrat and in fact ran as an Independent in 2000 for the US Senate from Minnesota. As a life long skeptic of both major parties, that was an eye opening experience. I am currently highly motivated to write about political extremism that I see from Republicans and the fact that it is only getting worse.  Giving Trump the job again when we already know what happened the last time is a clear mistake.  Allowing the Republican Party to maintain a nongoverning, culture wars, nihilistic response is also a massive mistake for the Republic.   

 

Supplementary 2:

Will add some examples to highlight the graphic as the I see them on a day to day basis:

Taylor Lorenz - excellent example that I saw today on TMZ is this interview.  Before this the TMZ crew showed Biden's attempt at humor with a birthday cake and they continue this into the interview like he is trying to win young voters with jokes.  Ms. Lorenz of course jumps on the opportunity to point out that Biden has not been focused on what Millennials or Gen Z want.  She cites an example of student loan forgiveness was not a focus apparently forgetting that his $430B student loan forgiveness plan was shot down by the right wing Supreme Court.  All three justices appointed by Trump (Gorsuch, Kavanaugh, Barrett) voted against the plan in a 6-3 vote (Biden v. Nebraska).  Instead she praises Trump for being "authentic."  With brilliant analyses like that Biden does not stand a chance. 

Adam Kinzinger - seems like a rare positive force in American politics today.  I saw him on Real Time with Bill Maher last week where he clearly stated that there was only one pro-democracy political party in the US and it was the Democrats. The former Republican Congressman clearly described why fanaticism is a negative coercive force in politics and that is why it needs to be eliminated. He also founded the Country First PAC as a way to distance himself from right wing extremists and conspiracy theories. 

Gen. Mark Milley - questioned about President Biden's performance by 60 minutes.

Hierarchical Diagnoses

 

The notion of hierarchical diagnoses comes up from time to time, so it is about time that I made some comments about it. Like most criticism of psychiatry, I think the concept is overblown and will illustrate why that is. The idea of hierarchies in diagnosis is basic.  It means prioritizing the most clearly defined illness.  Clearly defined in this case may mean a clearcut phenotype or disease mechanism.  In the psychiatric examples provided that generally means a feature high in the hierarchy that is not replicated at lower levels, but many features at lower levels that overlap.  

The overall goal is to not end up with a long list of conditions or diseases that could fit the presenting problems and end up treating everything on the list rather than the most likely cause of the problem.  I think of it as second year med student differential diagnosis.  When you are learning physical diagnosis you take an exhaustive history, review of systems, and physical exam and try to come up with a differential diagnosis list.  Even with that beginning level of knowledge in medicine you start to realize that diagnosis number 3 to 8 are improbable and start to focus just on the top 2. By the time you are an intern those lengthy differential diagnoses lists are a remote memory.

It also involves the application of the parsimony principle.  Is there a single diagnosis that incorporates all the features of the observed disorder rather than a list of conditions?  I can illustrate this with an example right out of my physical diagnosis text from medical school (1):

“In selecting the diagnosis from a list of hypotheses, the physician is to choose a single disease to explain all of the patient’s manifestations rather than explain them by the coincidence of several diseases.  This is called the law of parsimony. For example, when a patient is found to have a dilated heart, hepatomegaly, ascites, and pedal edema, the single diagnosis of cardiac failure explains all of the findings. It is more likely to be the true diagnosis than to suppose a coincidence of heart disease producing cardiac enlargement, cirrhosis of the liver producing hepatic enlargement, and nephrosis leading to edema from hypoproteinemia.  Nevertheless. The “law” must be applied cautiously.  The experienced clinician realizes that in the process of aging the patient accumulates the more debilitating conditions the longer he lives, and his demise is often accompanied by a combination of several diseases.” (p. 3-4)

And from a comparable section of DSM-II (2):

“The diagnostician, however, should not lose sight of the rule of parsimony and diagnose more conditions than are necessary to account for the clinical picture. The opportunity to make multiple diagnoses does not lessen the physician's responsibility to make a careful differential diagnosis.”

This excerpt on strictly physical diagnoses of non-psychiatric conditions illustrates a couple of points.  First is that disease states in general do accumulate over time.  Some are more likely to occur during different time frames during a life time.  The age at onset is a relevant concept but even then, there are exceptions. Secondly, transdiagnostic symptoms (covering many diagnoses) are common in the physical world. In the example edema and ascites are the obvious example but even the gross organ findings can be considered transdiagnostic signs.  For example, there are hundreds of possible causes of cardiomegaly and hepatomegaly, even though from a clinical standpoint the majority are not all fully investigated.  Once heart failure develops it is treated as a syndrome without a specific pathophysiological cause.  That illustrates a third point in the diagnostic process and that is the triage aspect.  Whatever is acute and life threatening gets priority and is diagnosed and treated first. I will illustrate how all these concepts apply directly to psychiatric disorders.

Hierarchies are thought to be more important in psychiatry because of symptom overlaps as well as certain diagnoses being more important not to miss. A common problem is the overlap of anxiety and depression. Some people have long history of both disorders concurrently or one morphing into another. Ghaemi (3) has suggested that mood disorders should be prioritized over anxiety disorders in the hierarchy.  He stresses the importance of diagnosis in this process and suggests that treatment of depression in this case would be the priority. He also briefly reviews some evidence in diagnostic hierarchies that basically show that they can be arranged so that diagnoses at the top of the hierarchy would contain the symptoms of every lower level in the hierarchy. For example, if bipolar disorder with psychosis is at the top of the hierarchy those patients would also have the symptoms seen at defined lower levels in the hierarchy like unipolar depression, schizoaffective disorder, schizophrenia, anxiety disorders, and personality disorders.  He claims that there is a current emphasis to make every possible diagnosis rather than a hierarchical approach, but does acknowledge that some psychiatrists “intuitively practice this way.” (p. 223).  Treatment setting is an obvious factor – with acute care psychiatrists seeing clear presentations of the more severe forms of schizophrenia, unipolar depression, and bipolar disorder.  They would be most likely to treat these acute forms and the pharmacotherapies are very similar.

It is always good to remember the task of the psychiatrist in all these academic exercises particularly when they are coupled with criticism of the psychiatrist in the field. What is the task of that psychiatrist?  That task varies with setting but after 22 years in acute care, the job is to recognize the acute illness and treat it while keeping the patient and the staff safe.  How well does a bipolar disorder->unipolar disorder->schizophrenia-> obsessive compulsive disorder-> anxiety disorder-> personality disorder->attention deficit~hyperactivity disorder (BUSOAPA) hierarchy hold up in that setting?

Probably not very well. That psychiatrist is confronted with an entirely different hierarchy. The first syndromic level encountered: “Is this patient medically stable? Are these symptoms I am seeing manifestations of an intoxication, withdrawal, or secondary medical condition?”  I routinely encountered these cases and often had to send them directly to the intensive care unit for both acute conditions threatening the life of the patient and acute conditions creating the psychiatric symptoms. The second syndromic level: “Is this patient responsive to me during the interview?  If not, are they delirious, catatonic, or is there another psychiatric reason?  Did I miss an acute medical condition like a stroke and aphasia at the first syndromic level?  The third syndromic level: “Is this person able to produce an accurate history that I need to make a diagnosis and formulate a treatment plan? Does the history that they are giving me sound plausible?”  If not why not why - and what needs to be done?  Do I need to gather a lot of collateral history to get the full picture?

These considerations place the BUSOAPA hierarchy at the minimum as a hierarchy within a hierarchy that contains about 40 or 50 psychiatric diagnoses and many more if all possible medical diagnoses masquerading as psychiatric diagnoses are considered. The diagnoses also have clear implications for Ghaemi’s concern that a hierarchical model would reduce misdiagnosis and polypharmacy.  Patients with alcohol use disorder (AUD) can experience psychotic symptoms and mood symptoms.  I have seen them misdiagnosed as having schizophrenia and bipolar disorder. Does that mean AUD should be at the top of the hierarchy?  Placing it there would skew the data because most people with AUD do not have those severe symptoms, but on the other hand if they were misdiagnosed with schizophrenia or bipolar disorder – appropriate treatment with benzodiazepines for alcohol withdrawal may be held to the detriment of the patient.

A recent exercise was sent to me to see if it suggested a need to modify DSM criteria for major and mild neurocognitive disorder.  The patient was described as having Alzheimer’s disease, cerebrovascular disease, an HIV infection, and heavy chronic alcohol use.  They had symptoms of psychosis.  They were coded as having major neurocognitive disorder due to all the listed etiologies.  The problem is that the current diagnostic criteria use a hierarchical approach and state that for probable Alzheimer’s Disease in both the major and mild neurocognitive disorder categories the mixed etiologies need to be ruled out or eliminated. That is currently difficult to do on a clinical basis and will lead to more uncertainty in the Alzheimer’s Disease diagnosis using these criteria. In terms of the BUSOAPA hierarchy – it is an argument to put the neurodegenerative disorders diagnoses at the top since they frequently contain most of the symptoms of psychosis, mood disorders, and anxiety while having unique cognitive profiles that would not be seen at lower levels.

Getting back to Ghaemi’s original argument for empirically studied hierarchies in psychiatry to reduce misdiagnosis and improve treatment by reducing polypharmacy – is that likely? They might work at the level of nomenclature only.  Hierarchies might work in highly selected environments with low acuity patients.  I am thinking about an outpatient psychiatric teaching clinic. It might be easy to illustrate how the patient population matches what is happening hierarchically.  In other settings looking at higher levels of acuity – the acuity becomes the hierarchy. Residents in acute care should learn almost immediately that pharmacotherapy in the inpatient setting needs to be directed at the likely acute diagnosis.  Even then that clearcut diagnosis can be obscured in the outpatient setting. The best example I can think of is women with postpartum bipolar disorder +/- psychosis who are stabilized and eventually readmitted with diagnoses of schizophrenia or schizoaffective disorder. In that case, the diagnosis was in the top spot of the BUSOAPA hierarchy based on the direct observations of the inpatient psychiatrist, but it was modified on an outpatient basis by staff who did not directly observe the acute manic episode. A violation of the hierarchical model to be sure, but also poor continuity of care and ignoring what happens in acute care.         

That brings me to the issue of hierarchies in previous versions of the DSM. I will focus on DSM-II because it is the most clearcut.  The explicit hierarchies in DSM-II included both acuity and severity.  Specifically:

“1. The condition which most urgently requires treatment should be listed first.”

And:

“2. When there is no issue of disposition or treatment priority, the more serious condition should be listed first.”

And:

“It is recommended that, in addition to recording multiple disorders in conformity with these principles, the diagnostician underscore the disorder on the patient's record that he considers the underlying one.”

These three sentences from DSM-II capture what appears to be the concern about diagnostic hierarchies in subsequent versions of the DSM.  They easily map on to what happens clinically as depicted in my diagram at the top of this post. It is also consistent with the general approach to all medical diagnoses and the training of psychiatrists.

A long list of diagnoses is a rookie mistake. Experienced psychiatrists are generally trying to address the main problem and the urgent problem. There is some evidence for that in the numbers of diagnoses that are used in clinical practice and those numbers are considerably lower than the usual DSM-5 count. That does not mean that polypharmacy will not be involved, but it does mean that any polypharmacy used is there to address the main problem and not multiple separate diagnoses all at once.  The concepts of comorbidity and transdiagnostic symptoms are discussed these days like they represent new ideas. Any physician trained in a medical school and residency program knows about both starting with medical and surgical diagnoses and progressing to psychiatric diagnoses. The general concepts are the same. The necessary evaluation in psychiatry should adequately reflect the complexity of the situation and that means a detailed longitudinal history and that can include disorders that are commonly viewed as symptoms – like primary insomnia. 

A detailed longitudinal history may not lead to a correct current diagnosis until the symptom patterns change. The best example in the case of a pure psychiatric disorder is bipolar disorder.  Goodwin and Jamison (4) make this point in their discussion of false unipolar disorder – people with recurrent unipolar depressive episodes until the first episode of mania occurs. In their table they show that according to three different longitudinal studies, patients experience 1 to 5 episodes of unipolar depression without a manic episode and they constituted a significant portion of the unipolar sample.  A hierarchical rule in this case results in misclassification until a manic episode occurs. 

A strictly hierarchical diagnosis will also not capture clinic reality.  It can potentially lead to catastrophic results.  The best example I can think of is schizophrenia and depression. If you consider schizophrenia in a hierarchy independent of depression, you will miss the opportunity to treat serious depression in patients with a schizophrenia diagnosis.  It is also a case of seeing a new patient treated for both diagnoses and considering what medication to stop.  The features of schizophrenia are such that the presentation of depression is very subtle and medication changes of antidepressants and antipsychotics should only be changed with extreme caution and after adequate collateral history has been obtained.

Criticizing DSMs is a popular American sport. That has resulted in elevating the DSM to levels that are really not consistent with the way these documents are viewed by psychiatrists. The documents are generally limited by the fact that they are not treatment manuals and do not incorporate considerable amounts of research that could provide guidance in these areas. With a document that is limited to nomenclature – any changes including hierarchies will result in a loss of information at another level.  To me this seems like an endless exercise in trying to reduce uncertainty to an unachievable level.  

That is why psychiatrists need to be trained and don’t result from reading a manual.  

 

George Dawson, MD, DFAPA

 

References:

1:  DeGowin RL.  Bedside Diagnostic Exam.  3^rd ed.  Macmillan Publishing Company, New York, 1976: 3-4.

2:  Diagnostic and Statistical Manual of Mental Disorders. 2^nd ed. Washington, DC.  American Psychiatric Association. 1968: 2-3.

3:  Ghaemi SN.  The concept of a diagnostic hierarchy. In: Ghaemi SN.  Clinical Psychopharmacology: Principles and Practice.  New York.  Oxford University Press. 2019: 222-230.

4:  Goodwin FK, Jamison KR.  Manic-Depressive Illness. New York.  Oxford University Press. 2009: 66.

Buspirone and Gepirone

 

Buspirone and gepirone are interesting compounds.  As shown in the above 2D structures they are structurally similar -  with the main difference being a cyclopentane ring in the azapirone structure in buspirone and two methyl groups at the same atom in gepirone. That results in the molecular formulas of both compounds to be slightly different.   

Buspirone was initially proposed as an antipsychotic medication (2) but it showed no efficacy in clinical trials.  Buspirone was FDA approved for the treatment of anxiety on September 29, 1986.  Gepirone was approved for treatment of depression on September 28, 2023. The 37-year lag time for approving gepirone has always been a mystery to me, especially given the amount of buspirone I have prescribed over the years.  Buspirone came out during an era of benzodiazepine prescribing that at times was excessive.  Alprazolam or Xanax was heavily marketing just prior to the release of buspirone and it did not take long for some experts to recommend using higher doses than the package insert to treat anxiety and panic attacks. That led to complications including excessive use and in some cases withdrawal seizures.  When buspirone was marketed, there was emphasis placed on the fact that it did not lead to excessive use, it did not affect the GABA receptor like benzodiazepines, it did not have synergism with beverage alcohol, and it did not have any withdrawal liability.  As a result, many primary care physicians tried to use it as a substitute for patients taking benzodiazepines. It was ineffective when used in that manner because of the behavioral pharmacology.  A person taking buspirone did not notice any immediate effects, unlike benzodiazepines and it did not reinforce its own use.  It also did not start to work immediately and had an onset of action more like an antidepressant. These properties had the effect of creating the perception that it was an ineffective medication and that was reinforced by some experts – who claimed that only benzodiazepines were useful for anxiety. 

Historically the enthusiasm for benzodiazepines decreased over time with antidepressants (SSRIs, SNRIs, and TCAs) being recommended for anxiety and panic rather than benzodiazepines. Some psychiatrists (like myself) used buspirone for both primary anxiety without panic and antidepressant augmentation. I found that it was an effective medication for those indications but it required a detailed discussion with the patient, especially if they had previous benzodiazepine exposure. The very favorable side effect profile – including no intoxication or withdrawal effects were an important consideration.  Generally, people exposed to that discussion did well on buspirone and were able to avoid benzodiazepines.

The activity of both compounds is thought to be mediated by 5-HT1A agonism as noted in the table below.  Using the PDSP Ki database as the source, more detailed receptor information is available for buspirone than gepirone, probably because the latter approval date.  Partial data is also given for 2 metabolites of gepirone one of which is active at the 5-HT1A receptor.

 

 

Receptor	Buspirone	Gepirone	3’-OH-gepirone	1-PP-gepirone
5-HT1A	5 - 77	38	58
5-HT1B	>10,000	>10,000
5-HT1D	>10,000
5-HT2A	138	3,630
5-HT2B	213.8
5-HT2C	489	>10,000
5-HT3	>10,000
5-HT4	>10,000
5-HT6	398
5-HT7	375
DA D4.2	78-136	58
DA D2 like	1,210
α-2	>1,042	>1,042		42

 All receptor affinities are Ki as nM from PDSP Ki database. Affinities for human receptors included where available.

 

What is the evidence these medications are effective?  The real mystery for these medications is their efficacy and favorable side effect profile compared with clinical use. In terms of side effects – I don’t think it is an overstatement to say that they have the most favorable side effect profile of any psychiatric medications. In my experience, it was rare for anyone to get a side effect.  If it happened it was most likely dizziness.  In prescribing to hundreds of people – I can recall exactly one person who got sedated. When used for antidepressant augmentation I have observed two people become hypomanic and that resolved with discontinuation of the buspirone.

I have no real information to explain the partial and delayed approvals. Most of the clinical trials for both medications occurred in the late 1980s and early 1990s. At that time there was clear evidence that both were effective for anxiety and depression and yet only buspirone was approved at the time for an anxiety indication. Psychiatrists are more typically aware of the off-label use of buspirone as an antidepressant augmenting agent from the Star*D study protocols (3).  At the time buspirone was described as one of the three best studied augmentation strategies for treatment resistant depression with lithium and thyroid hormone being the other two.

Interestingly – I am not aware of any head-to-head comparisons of azapirones to typical antidepressants for the treatment of depression. There are currently 67 studies on ClinicalTrials.gov with buspirone listed as an intervention. Most of these studies investigate the use in novel clinical situations or mechanism of action.  There is one study about anxiety and quality of life when it is used to treat depression and that currently has no publications.  Another references the Star*D study from 20 years ago.

The best single source for the efficacy of azapirones in depression, anxiety, and some novel situations is a chapter by Ninan and Muntasser(4). Their general conclusions are that buspirone is effective in treating generalized anxiety disorder (GAD), GAD with depression, and is more effective in treating the depression associated with anxiety than benzodiazepines. In studies with a crossover design and initial benzodiazepine exposure – response to buspirone was reduced but not eliminated. In a head-to-head comparison of buspirone 30 mg and venlafaxine ER (75 or 150 mg) for GAD both were superior to placebo but venlafaxine was superior to buspirone.  Buspirone has demonstrated efficacy in studies of both non-melancholic and melancholic depression.

Gepirone ER was studies in 3 RCTs for major depression and was effective in all three. One of those studies was a dose ranging study and only the higher dose was noted to be effective.  Gepirone was also studied in GAD with diazepam as a comparator.  Both medications were efficacious, but diazepam had a more rapid onset and consistent effects.  The anxiolytic effects of gepirone occurred at 6 weeks. When both medications were discontinued rebound anxiety occurred with diazepam but not gepirone.  There is some evidence from the buspirone trials that the anxiolytic effect of these medications improves over time.

The current azapirones are interesting and neglected compounds in clinical psychiatry.  They have not been vigorously studied for their primary indications of GAD and major depression.  Most of the interest in this class of medications was generated in studies that look at antidepressant augmentation. Although there is always a lack of pharmacosurveillance data in the US, my speculation is that second and third generation antipsychotics (aripiprazole, brexpiprazole) are much more likely to be prescribed as augmenting agents – despite the risk of tardive dyskinesia and metabolic effects (the azapirones have neither). In my experience with buspirone, I found it to be effective for GAD and antidepressant augmentations.  Despite the theoretical risk of serotonin syndrome – I never saw any symptoms of serotonin toxicity.  If gradually titrated - side effects were rare.  In any detailed informed consent discussion, the azapirones come across as having distinct advantages over other medication classes - primarily from the side effect perspective. With all medication there is a question of efficacy – but in relatively non-urgent situations most people prefer to try the medication with the lowest risk of adverse events – first.

 

George Dawson, MD, DFAPA

 

References:

(1) Piercey MF, Smith MW, Lum-Ragan JT. Excitation of noradrenergic cell firing by 5-hydroxytryptamine1A agonists correlates with dopamine antagonist properties. Journal of Pharmacology and Experimental Therapeutics. 1994 Mar 1;268(3):1297-303.

(2) Le Foll B, Payer D, Di Ciano P, Guranda M, Nakajima S, Tong J, Mansouri E, Wilson AA, Houle S, Meyer JH, Graff-Guerrero A. Occupancy of dopamine D3 and D2 receptors by buspirone: A [11C]-(+)-PHNO PET study in humans. Neuropsychopharmacology. 2016 Jan;41(2):529-37.

Modest occupancy of D2/D3 receptors cannot R/O MOA of this plus 5-HT1A as MOA.

(3)  Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, Quitkin FM, Wisniewski S, Lavori PW, Rosenbaum JF, Kupfer DJ. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR∗ D) study. Psychiatric Clinics. 2003 Jun 1;26(2):457-94.

(4)  Ninan PT, Muntasser S.  Buspirone and gepirone. In: Schatzberg AF, Nemeroff CB.  The American Psychiatric Publishing Textbook of Psychopharmacology.  3^rd ed. Washington DC, American Psychiatric Publishing, 2004: 391-404.

(5)  Robinson DS, Rickels K. Buspirone.  In:  Schatzberg AF, Nemeroff CB.  The American Psychiatric Publishing Textbook of Psychopharmacology.  5th ed. Washington DC, American Psychiatric Publishing, 2017: 585-600.

“We speculate that had buspirone’s sponsor persuaded a depression rather than a GAD indication, buspirone might have well become the first 5-HT1A partial agonist developed as an antidepressant. At present, however, buspirone exists in the shadow of numerous approved antidepressant drugs with high clinical exposure and promotion”. (p. 591-592)