The Autocratic Approach to Homelessness

 

President Trump issued another poorly thought out Executive Order yesterday entitled ENDING CRIME AND DISORDER ON AMERICA’S STREETS. It contains many myths about homelessness as well as an unrealistic approach.  As a psychiatrist who focused on this issue in the population I treated for decades, I consider myself qualified to comment on this executive order and why it will fail.  Many of the central points have already been covered on this blog and I will connect to them when relevant.  Here is a section by section look.

“The overwhelming majority of these individuals are addicted to drugs, have a mental health condition, or both.  Nearly two-thirds of homeless individuals report having regularly used hard drugs like methamphetamines, cocaine, or opioids in their lifetimes”

There is the common conflation with homelessness and drug addiction and mental illness.  While these conditions are overrepresented in homeless populations – the idea that the overwhelming majority of the homeless are drug addicted or mentally ill is a myth per the government agency that directly monitors the problem (3). According to that agency the majority of the homeless do not have mental health or substance use problems and the majority of people with those problems are not homeless.

Further violent crime rates are about ¼ of what they were in 1993.  It follows if homelessness is higher in the context of dropping violent crime rates it is not likely a causative factor.

The order conflates mental illness with violent crime and suggests that it puts the public at risk for violent crime.  It suggests that the solution is to get them off the street and into institutions to protect the public.  Based on the lack of connection to crime that is a doubtful solution.  Further there has been a decades long initiative by federal and state governments to shut down long term bed capacity.  The US currently ranks 30 of 35 OECD countries in terms of psychiatric bed capacity.  That current minimalist bed capacity does not meet suggested standards to keep emergency department waits at an acceptable range and there is no evidence that the trend is changing.

The United States already uses jails as the largest psychiatric institutions.  Roughly 70,000 of the 350,000 incarcerated have a significant mental illness and receive various levels of inadequate care.  So where exactly are the “long-term institutional settings for humane treatment” supposed to come from? 

“seek, in appropriate cases, the reversal of Federal or State judicial precedents and the termination of consent decrees that impede the United States’ policy of encouraging civil commitment of individuals with mental illness who pose risks to themselves or the public or are living on the streets and cannot care for themselves in appropriate facilities for appropriate periods of time.”

I have written about civil commitment may times on this blog.  I have personally initiated and testified in hundreds if not thousands of civil commitment, guardianship, and conservatorship proceedings over a period of 35 years in the states of Wisconsin and Minnesota.  As far as I know there is no US policy to encourage commitment.  All civil commitment comes down to a county decision by a judge in that county.  Further – that commitment decision is affected by real world circumstances on the ground at the time including the financial state of the county, the number of commitments done per year, the ideological biases of the attorneys and judges, and the known outcomes of the court proceedings.  As an example of the latter, if a judge releases a patient from a hospital without commitment and that person kills or injures someone or themselves – it is less likely that court will take a similar risk in the future.

Inability to care for self is the third standard for commitment after danger to self (aggression directed at self as self-injurious behavior or suicidal behavior) and danger to others (outward directed violence and aggression).  It is the least likely standard to result in civil commitment and the most likely to result in a patient being discharged back into a homeless situation.

On a social media forum, a link was posted to me about 18 U.S. Code § 4248 Civil commitment of a sexually dangerous person. Although it was not explained it seemed to be a rebuttal to my statement that all commitments are local.  Sexually dangerous person is not a psychiatric diagnosis and it is not likely to be a significant factor in homelessness.  Additionally, the federal government does not track this diagnosis in terms of the total number of people incarcerated because of it. 

“provide assistance to State and local governments, through technical guidance, grants, or other legally available means, for the identification, adoption, and implementation of maximally flexible civil commitment, institutional treatment, and “step-down” treatment standards that allow for the appropriate commitment and treatment of individuals with mental illness who pose a danger to others or are living on the streets and cannot care for themselves.”    

This is an ironic statement considering the massive cuts to Medicaid and long history of federal cuts to any programs that fund long term care of the mentally ill.  Medicaid is a major funder of both health care for homeless populations and people with serious and persistent mental illness.  The idea that there will be funds available to massively convert the current rationed, stripped down services to a cornucopia of outpatient, inpatient, and residential services is more than a little unrealistic. 

A realistic goal would be to fund Assertive Community Treatment (ACT) and Forensic Assertive Community Treatment (FACT) teams across every county in the US. This approach to supportive treatment has been known since 1975 – but rarely encountered due to rationing at various levels.  The goal of this treatment is to support people with severe mental illnesses living housed and independently in the community and assisting them every step of the way with access to medical and psychiatric care.  There is no more humane approach. 

“Fighting Vagrancy on America’s Streets.  (a)  The Attorney General, the Secretary of Health and Human Services, the Secretary of Housing and Urban Development, and the Secretary of Transportation shall take immediate steps to assess their discretionary grant programs and determine whether priority for those grants may be given to grantees in States and municipalities that actively meet the below criteria, to the maximum extent permitted by law: (i) enforce prohibitions on open illicit drug use; (ii)  enforce prohibitions on urban camping and loitering; (iii)  enforce prohibitions on urban squatting”

Are there grants for enforcing existing laws?  With the draconian cuts already made by this administration exactly how much is available to enforce existing laws and would it be used with more effect in other areas. Trump has already cut $27 billion in funding for affordable housing and that has been estimated to affect 23 million households.  Homelessness assisted grants have been cut by $532 million or 12%.  These proposals have been described as “devastating” by housing advocates.  That is hardly a serious effort to address homelessness.

Instead, this appears to be an attempt to villainize the homeless and blame them for their predicament.  The wording in this section about monitoring unregistered sex offenders and suggesting that all arrested homeless are screened as sex offenders seems like the approach taken with undocumented immigrants.  Suggest a group of people are guilty until proven innocent and further suggest that law enforcement can make any problem go away.

“..ensure that discretionary grants issued by the Substance Abuse and Mental Health Services Administration for substance use disorder prevention, treatment, and recovery fund evidence-based programs and do not fund programs that fail to achieve adequate outcomes, including so-called “harm reduction” or “safe consumption” efforts that only facilitate illegal drug use and its attendant harm”

This is an overtly dangerous section of the order.  What is the administration calling “harm reduction”, “safe consumption”, and “illegal drug use”.  Would medications for opioid use disorder treatment (MOUD) fall under this category?  Would clinics prescribing methadone maintenance and buprenorphine maintenance be under even tighter scrutiny that they currently are? The wording suggests a level of accountability to an administration that clearly has none itself.     

This executive order is a good if not perfect example of an authoritarian approach to the problem.  Experts in the areas of homelessness, civil commitment, mental illness, and substance use have not been consulted.  Rather than expertise we see and overriding theme that law enforcement will be used to crackdown on the homeless. It suggests that there are systems of care that do not exist and cannot exist due to previous rationing and the more draconian measures from this administration.  In all of the rhetoric about the homeless problem in the US, the average American is led to be believe that this is a crisis unique to this country.  Real data (1) suggests otherwise.  The US has had a roughly 0.2% of the population homeless over the past 13 years and this is comparable to many OECD countries in Europe. Further – this is higher than the social democracies in Scandinavian countries and homelessness does correlate with economic disparity – another factor poorly addressed by this administration.

For all the above reasons – I don’t see any reason why this order will have much of an effect on the homelessness problem.  It probably will present many photo-ops of law enforcement disrupting homeless camps and arresting people.  The unfortunate outcome here is that there is ample opportunity for doing good across many problems – but apparently little interest in that.      

George Dawson, MD, DFAPA

 

References:

1:  OECD - Social Policy Division - Directorate of Employment, Labour and Social Affairs OECD Affordable Housing Database, 2023. – http://oe.cd/ahd

2:  ASAM Statement on Executive Order to Increase the Use of Involuntary Civil Commitment of Unhoused People with SUD.  https://downloads.asam.org/sitefinity-production-blobs/docs/default-source/advocacy/press-releases/asam-statement-exec-order-final_7-25-25.pdf

3:  United States Interagency Council on Homelessness.  Data and Trends.  (accessed 07/25/2025):  https://usich.gov/guidance-reports-data/data-trends

Metaphorical Brain Talk

 

There is a current paper written by Kenneth Kendler on metaphorical brain talk in psychiatry (1).  It is open access and I encourage people to read it.  I automatically read anything written by Kendler because he is probably my last remaining hero.  That is ironic given that he is only slightly older than me.  If you are not familiar with his work there is a Wiki page that will partially bring you up to speed.  I have referenced him many times on this blog.  His writing is consistently next level when it comes to psychiatric research and theory.  If you find yourself reading collections of “greatest papers in psychiatry” and don’t find his work there.  Throw that collection away and read Kendler.

In this paper he reviews the history of metaphorical brain talk (MBT) in psychiatry and what he sees as four implications for the field. He defines this as describing the altered brain function is psychiatric disturbances in a way that seems explanatory but have no explanatory power.  Examples would include the infamous chemical imbalance trope.  He reviews MBT across discrete periods in psychiatric history and gives examples in each one of these time frames.  Since this is an open access paper – I encourage any interested readers to look at all the examples.   I will touch on a few points that I find interesting.

He first reviews Asylum Psychiatry from 1790-1900.  Several authors wrote about conditions they observed in their patients using descriptive phrases like brain excitement, disordered nervous system, morbid action of vesicular neurine, peculiar and special force in the cerebral masses, excitement and vividness always emanate from one portion or spot of the brain, etc.  On the one hand the metaphors are obvious and consistent with Kendler’s characterization that they are biologically meaningless.  On the other the images are vague and the significant part of the metaphor is descriptive language of mental activity. 

In other writing Kendler has referred to this era is psychiatry as the era of protopsychiatrists. I have reviewed that history on this blog and agree that psychiatry as the profession we know today probably did not start until the 1920s in the US even though it was well established in Europe for a longer period.  The European version included physicians who were also described as neurologists, neuropathologists, psychiatrists, psychologists, and alienists.  If you read references to these physicians today – the descriptions are often interchangeable and research is required to clarify their qualifications and training. 

There was more going on during this period than meaningless metaphors.  Alois Alzheimer was a psychiatrist and neuropathologist (11).  Between 1891 and 1907, Alzheimer described several neurodegenerative diseases including vascular dementias and the disorder that would eventually come to be known as Alzheimer’s disease along with the clinical correlations of memory loss, inadequate self-care, and paranoia. Otto Binswanger (1852-1929) was a Swiss psychiatrist, neurologist, and neuropathologist who was also active at the time. In 1894, he described “encephalitis subcorticalis chronica progressive” while attempting to differentiate types of dementia from dementia caused by tertiary syphilis that was called general paresis of the insane or GPI at the time.  GPI was a very common reason for institutionalization at the time accounting for 20% of admission and 34% of the death in asylums in the 19th and early 20th century before the advent of antibiotics.  Both Alzheimer’s Disease and Binswanger’s Disease remain controversial entities to this day in terms of the definitive neuropathology and likely etiopathogenesis.  An important historical lesson is that these early psychiatric researchers did practice psychiatry while doing neuropathology and often had students who went on to have significant contributions to the field outside of neuroanatomy.  In the case of Alzheimer, Franz Nissl (1869-1919) became his longtime collaborator and head of the Psychiatric Clinic at the University of Heidelberg where Karl Jaspers (1883-1969) was his student.  Jaspers wrote his text General Psychopathology while working for Nissl.         

His next historical period is The First Biological Revolution in Psychiatry 1870s – 1880s.  Griesinger was a key figure and his central thesis that mental illnesses were brain diseases.  He also published an influential textbook and journal.  His students promoted neuropathological research through autopsies as the primary method of scientific inquiry during that period. Kendler concludes that this method of research was a dead end for classical psychiatric disorders – but there seems to be more going on in the field than that.  Several of these physicians over the next 50 years identified themselves not just as psychiatrists but also neurologists and neuropathologists. Otto Binswanger ((1852–1929) and Wilhelm Griesinger (1817-1868) were designated as neurologists and psychiatrists.  Freud (1856-1939) did 6 years of basic research in comparative neuroanatomy, published a monograph on aphasia (6) wherein he coined the term agnosia, and was a Privadozent in neuropathology.  All of that before he invented psychoanalysis.

 The Reaction to the Revolution 1880-1910 is described next with a critique by Kraepelin of excessive and speculative biological theories of psychiatric disorders.  The critique largely is focused on Meynert’s (1833-1891) work.  The critiques focus primarily on highly speculative hypotheses based on neuroanatomy. Meynert’s neuroanatomy work and that of his colleagues and students is still recognized today (2-4).  His poetic license may have been excessive, but the neuroanatomy was solid.

Metaphorical Brian Talk of the 20^th Century focuses initially in Adolf Meyer. Like the other psychiatrists discussed so far, Meyer had additional skills and was employed as a neuropathologist following his emigration to the United States from Switzerland. He famously said: “My entrance into psychiatry was through the autopsy room”(8).  Meyer had an indirect link to Meynert because his supervisor August Forel was one of Meynert’s students.  A quote is included from a 1907 paper in which Meyer suggests that early American psychiatrists:

“…pass at once to a one-sided consideration of the extra-psychological components of the situation, abandon the ground of controllable observation, translate what they see into a jargon of wholly uncontrollable brain-mythology, and all that with the conviction that this is the only admissible and scientific way.”

Meyer is credited with psychobiology model of psychiatry.  He saw the brain and mind as an evolved unitary and dynamic structure reacting to the environment.  As such it would not necessarily show typical disease related changes at the gross or microscopic levels and could only be studied if environmental and social variables were considered. 

Meyer’s psychobiology approach championed a detailed clinical approach to psychiatric disorders and avoidance of biological reductionism.  That would put Meyer along with Kraepelin squarely in the camp against not only MBT but also any theory suggesting that there was a direct biological explanation for mental behavior or psychiatric disorders. Both were trained as neuropathologists and Kraepelin worked with Alzheimer. That would seem to lend a measure of credibility to their concerns.  

Kendler ends that section with a quote from Jaspers that the neuroanatomy discovered by the neuropsychiatrists is one thing but it cannot possible be correlated with mental phenomenon.  He refers to this as “brain mythologies”.  Meyer’s and Karl Jasper’s approached have been credited by McHugh and Slavney in their comprehensive 4 perspective approach to mental disorders (7).

Kendler concludes that the metaphorical brain talk in psychiatry arises from several sources.  First, our identity as physicians dictates that like other specialists, we need an organ to focus on and that has been the brain. That relationship was impacted by neurology seeming to take over conditions with overt and definable brain pathology.  He concedes that there is overwhelming evidence that psychiatric disorders arise in the brain (in fact he is a world expert in this) but there are still no specific mechanisms.  MBT is one way to address that fact.  He defers to a historian that this may be status anxiety relative to other specialties with more definable pathology and in some cases mechanisms and MBT is a way to address that.  His own take on MBT is much more reasonable when he describes it as a wish that at some point we will get to the deeper understanding of the brain that we all seek.

Despite the historical digressions, Kendler comes to the same conclusion that I did decades ago.  We do not have to make things up in discussions with patients and we do not need to use metaphors devoid of biological reality.  That does not mean there is no room for real brain talk – the kind that occurs when you are discussing the effects of brain trauma, strokes, dementia, epilepsy, and endocrinopathies.  It does mean that you can flatly say for any diagnosis there is no known etiology but the research supports this treatment plan and beyond you can provide a discussion or references to the latest research.

The explanatory gap in psychiatry between the biological substrate and mental life or associated disorder is obviously there but it is present in every other organ system to one degree or another.  It is quite easy to pretend that basic medical conditions like asthma or diabetes have all been worked out with biologically precise mechanisms of action – but nothing could be farther from the truth.  Endophenotypes exist for both conditions, most people are symptomatic despite treatment, and death still occurs even in mild cases. There is a definite dynamic of idealizing medical conditions as completely knowable and treatable – when they are not.  In those cases, the explanatory gap is very basic between biology and wheezing or blood glucose. In the case of psychiatric disorders – many more symptoms and ordinary functions are across that gap.  The explanation is much harder and any symptoms are less clearly rooted in biology.  

I am less concerned about the effects of MBT and how it potentially affects understanding the mental life of our individual patients.  That is what psychiatrists are trained to do.  We are face-to-face with a person who we are supposed to help and, in that situation, it is doubtful that MBT will add much. 

There are a few other reasons that may have facilitated MBT in the historical contexts discussed. Rhetoric is a powerful and rarely discussed aspect of the scientific and medical literature.   The metaphor users were all active neuroscientists in their day.  As such they were likely competing for positions, labs, associations, recognition, and funding.  This is commonly how rhetoric occurs in research communities and scientific literature. 

 A related issue is personality and notoriety. It is rare to see much commentary about these issues with 19th and 20th century scientists.  Once a certain level of fame is reached, are you more likely to speculate and theorize?  Can some of those speculations take on the form of MBT?  One of the most criticized neuropsychiatrists in this paper was Meynert for suggesting overly elaborate mechanisms that had no basis in science.  On the other hand, Meynert is still renowned for some of his neuroanatomical findings (4).  Is it possible that a scientist with that level of accomplishment did not care about the difference between speculation and scientific findings?  Is it possible that his students and post docs encouraged him to speculate beyond his findings – just brainstorming? Is he just taking a chance that he might be correct in order get credit for an innovative finding?  I suppose a translation of his book might offer a few addition clues, but the reason I have these suggestions is that I have seen this happen in current times.  We might reassure ourselves that our publications are not suffering from metaphorical overreach but problems with irreproducible findings suggest otherwise.          

The state of neuroscience for much of the timeline of this paper could be a factor.  Not a lot was known about neurons or neuronal transmission.  Neuron theory and the term neuron did not happen until 1891. I have a slightly different take on the history of psychiatry in the US and how psychiatry and neurology split.  Until 1934, most psychiatrists were also practicing neurology. Many were self-designated as neuropsychiatrists.  The ABPN decided to require board exams in both neurology and psychiatry to practice both and at that time psychiatry began to grow disproportionately relative to neurology.  It is still possible to be doubled boarded in both. It is also possible to practice neuropsychiatry or medical psychiatry based on residency training and practice.  I have long promoted the idea that modern day psychiatrists should practice intellectually interesting psychiatry and for me that uses the DSM as a scope of practice specifier and knowing all the medicine and neurology necessary to care of those patients.  

Revisiting the main point of Kendler’s paper.  In his summary he states his major concern has been an impoverished conceptual foundation in the field based on a brain centric focus and metaphorical talk about it.  I agree with anything metaphorical and on this blog have numerous posts addressing the chemical imbalance and biomedical metaphors being paced upon us by our critics.  In many ways – I don’t think the clinical brain focus has been enough. Psychiatrists need to be able to rapidly recognize neurological and medical emergencies in addition to the medical and neurological causes of psychiatric syndromes. Psychiatrists need to be able to diagnose aphasias as well as they can diagnose thought disorders.  Those skills can all be traced back to late 19^th century and early 20^th century psychiatry. I also see that era as precipitating controversy, dialogue, and pendulum swinging so far in the other direction that at one point the medical internship was temporarily removed from residency programs.   

The reality is that we will see people referred to us or walking in off the street who have brain lesions and/or medical problems or not. They will generally have a psychiatric problem that has been assessed and treated by several other people that did not work. Our job is to do a thorough assessment of their physical and mental problem and come up with a plan – even when there is no known treatment.  That plan includes relationship building, helping them be more competent, and helping them make sense of their world. 

All the irrelevant metaphors can easily be ignored.

 

George Dawson, MD, DFAPA

 

 

1:  Kendler KS. A history of metaphorical brain talk in psychiatry. Mol Psychiatry. 2025 Aug;30(8):3774-3780. doi: 10.1038/s41380-025-03053-6. Epub 2025 May 13. PMID: 40360726; PMCID: PMC12240831.

2:  Liu AK, Chang RC, Pearce RK, Gentleman SM. Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer's and Parkinson's disease. Acta Neuropathol. 2015 Apr;129(4):527-40. doi: 10.1007/s00401-015-1392-5. Epub 2015 Jan 30. PMID: 25633602; PMCID: PMC4366544.

3:  Meynert T, Putnam J (translated) (1872) The brain of mammals. In: Stricker S (ed) A Man. Histol. W. Wood & company, New York, pp 650–766

4:  Judaš M, Sedmak G, Pletikos M. Early history of subplate and interstitial neurons: from Theodor Meynert (1867) to the discovery of the subplate zone (1974). J Anat. 2010 Oct;217(4):344-67. doi: 10.1111/j.1469-7580.2010.01283.x. PMID: 20979585; PMCID: PMC2992413.

“The presence of neurons in the subcortical white matter of the human brain was first described and illustrated by Theodor Meynert in 1867, and additionally commented on in his subsequent publications (Meynert, 1867, 1872, 1884). Meynert illustrated these cells in both superior frontal (Fig. 1A) and primary visual (Fig. 1B) human cortex and pointed out that these are spindle-shaped (fusiform) neurons which are oriented vertically to the pial surface within the gyral crowns, but horizontally at the bottom of sulci. He also suggested that they have a special functional relationship to short corticocortical association fibres (fibrae arcuatae, or Meynert's U-fibres) and that these fusiform cells may therefore be regarded as intercalated cells of his Associations system of short corticocortical fibres (Meynert, 1872).”

5:  Cowan WM, Kandel ER.  A brief history of synapses and synaptic transmission. In:  Cowan WM, Sudhof TC, Stevens CF.  Synapses. The Johns Hopkins University Press, Baltimore, 2001. pp.  3-87.

6:  Freud S.  On aphasia: a critical study.  International Universities Press. New York, 1953.  Translation of 1891 German publication and introduction by E. Stengel.

7:  McHugh PR, Slavney PR: The Perspectives of Psychiatry, 2^nd ed. Baltimore, Johns Hopkins University Press, 1998

8:  Lamb S. Social Skills: Adolf Meyer's Revision of Clinical Skill for the New Psychiatry of the Twentieth Century. Med Hist. 2015 Jul;59(3):443-64. doi: 10.1017/mdh.2015.29. PMID: 26090738; PMCID: PMC4597240.

9:  Lamb S.  Pathologist of the Mind – Adolf Meyer and the Origins of American Psychiatry.  Johns Hopkins University Press,Baltimore, 2014. p. 255.

10:  Rutter M. Meyerian psychobiology, personality development, and the role of life experiences. Am J Psychiatry. 1986 Sep;143(9):1077-87. doi: 10.1176/ajp.143.9.1077. PMID: 3529992.

11:  Goedert M, Ghetti B. Alois Alzheimer: his life and times. Brain Pathol. 2007 Jan;17(1):57-62. doi: 10.1111/j.1750-3639.2007.00056.x. PMID: 17493039; PMCID: PMC8095522.

Photo Credit:  

I thank my colleague Eduardo Colon, MD for the surreal photo of the Foshay building in Minneapolis. 

The Latest Antidepressant Withdrawal Paper….

 

The big news this week was an antidepressant withdrawal paper that showed most people can stop an antidepressant without experiencing severe withdrawal symptoms.  This has been known for over 20 years.  It is only big news because of the rhetorical approach to paper writing in the psychiatric literature.  Everybody knows what confirmation bias is these days and that has a lot to do with the literature.  Quite remarkably, the camp that claims a high prevalence of severe withdrawal also writes from the perspective that most psychiatrists seem ignorant of withdrawal phenomena and need special instruction.  That despite decades of practice modification, teaching residents how to taper and discontinue medications, managing much more complex medication problems in acute care settings, diagnosing life threatening medication related problems, and having access to widely published guidelines on how to taper and cross taper and titrate medications.  

With that backdrop here are the highpoints and limitations of the paper.  The first remarkable finding is the title:  “Incidence and Nature of Antidepressant Discontinuation Symptoms.”  Discontinuation versus withdrawal is a decade old point of contention. The antidepressant detractors use the term withdrawal and at times have incorrectly suggested that antidepressants are addictive drugs. The antidepressant defenders have preferred the term discontinuation symptoms although some have just started using the term withdrawal as well. There is no consistent standard for medication that can lead to addiction and those that do not.  Part of the reason may be that physicians are trained to discontinue medications and with all classes that typically involves a gradual taper or a taper while titrating a medication that targets the same symptoms.

The overall study looked at 50 studies (N=17,858) in a meta-analysis and systematic review.  All studies were randomized clinical trials or open label trials with a randomized double blind discontinuation phase.  All the studies had to use a standardized measurement for discontinuation symptoms or adverse events. The antidepressant trials covered several diagnoses in addition to depression.  From the paper:

“The following diagnoses were studied: major depressive disorder (MDD) (k = 28), generalized anxiety disorder (k = 9), panic disorder (k = 4), fibromyalgia (k = 2), premenstrual dysphoric disorder(k = 2), posttraumatic stress disorder, generalized social anxiety disorder (k = 1),and compulsive-shopping disorder (k = 1). Two studies included women with (post)menopause.”

The main methodological points that need further elaboration are the withdrawal symptom scoring and the duration of treatment.  The original DESS (Discontinuation Emergent Signs and Symptoms) is from reference 2.  It was originally used on the sample in that paper of research 242 research subjects who had been on effective maintenance therapy for greater than 4 months or less than 24 months with either paroxetine, sertraline, or fluoxetine.  The maintenance therapy was interrupted for 5-8 days with placebo and their discontinuation symptoms were rated using the DESS.  The DESS items are listed below along with the original question format. 

As I read through the 43-item checklist – I noted that one of the commonest symptoms I have seen in antidepressant withdrawal – brain zaps was not present. Brain zaps are typically described as a sharp electrical sensation in the head or neck during SSRI/SNRI withdrawal.  They can be worsened by head, neck, or eye movements.  They are typically described as paresthesias and in the case of this checklist may be partially reflected in items 29, 39, and 40. 

The best starting point to gain an appreciation of the scope and complexity of this study is eTable 2a Study Characteristics in the Supplemental Content.  I have copied page 1 (of 5) below.  51 studies are listed including 44 for the individual symptoms meta-analysis, 16 for the continuous DESS meta-analysis, and 1 for the qualitative synthesis. The duration of treatment range for all groups was 13.5-17.8 weeks with significant outliers at each end.  Most tapering protocols were abrupt (35/51) with 14/51 1-week taper, 3/51 2-week taper, and 1/51 5–6-week tapers.  Just based on the characteristics in this table it would appear that most subjects were treated long enough to potentially develop acute discontinuation symptoms and that in most cases they would have been precipitated by the tapers used.

The medications studied in this table are also relevant since several are more likely to precipitate a withdrawal syndrome than others. In this case paroxetine (6), venlafaxine (1), and duloxetine (9) are less common in the table.  In this case I am not counting the extended-release versions (where noted) because they were designed to reduce the risk of discontinuation/withdrawal. This can be noted in eTable 2B. Summary DESS Scores of Studies Included Meta-Analysis where they produce the highest DESS score with paroxetine producing the highest.  Fewer significant withdrawal producing medications in the study is a strength because it reflects current psychiatric practice.  

The authors’ analysis shows that antidepressant discontinuation results in expected discontinuations symptoms at one week.  Dizziness and nausea were the commonest symptoms.  The incidence of withdrawal symptoms was less when active drug was compared to placebo.  Their key conclusion that all of the press has been based on:

“In conclusion, data from RCTs suggest that on average, those who discontinue antidepressants experience 1 more discontinuation symptom compared to placebo or continuation of antidepressants, which is below the threshold for clinically important discontinuation syndrome.”

They end by discussing the notoriety issue when limited data and analysis has suggested that severe, prolonged withdrawal/discontinuation syndromes are common and need elaborate tapering schedules.    

What are the overall lessons from this trial:

1:  The research design was well done to detect withdrawal symptoms measured with standardized methods.  The DESS scale is available and can be used as a reference to these research findings.  The main finding that there was an excess of one symptom in the withdrawal group but that was not enough to diagnose a withdrawal syndrome was remarkable and consistent with press reporting that the average withdrawal from antidepressants is mild and should not be a deterrent to their use.  The limitation of that conclusion is that the DESS is not a quantitative measure as indicated by the original authors (2).  Even though there is precedent in the literature for four symptoms or more being necessary for a significant withdrawal syndrome – clinically it can be much less.  As an example, dizziness (the commonest symptom) alone can lead to distress and disability.  Any person with vertigo can attest to that fact. I am not in agreement that it takes 4 symptoms for significant withdrawal. 

2:  The importance of placebo is clearly demonstrated in this study.  The authors provide a direct contrast between antidepressant and placebo discontinuation in aggregate and by specific DESS symptoms (see tables 1 and 2).  In several cases the DESS symptoms are greater in the placebo discontinuation category.  This is by definition a nocebo effect but it probably also reflects a high prevalence of the symptom being sampled in the general population (eg. palpitations, pain, upper respiratory symptoms).  Table 2 also highlights that vortioxetine was indistinguishable from placebo withdrawal.  The overall effect of placebo in these studies was that the incidence of withdrawal symptoms is lower in studies that incorporate a placebo.

3:  While the results of this trial are being celebrated at the political level it will not have much of an impact on clinical practice. Psychiatrists do not treat averages – they treat individual patients with highly individual responses to medications.  Despite these results there will be patients who get severe withdrawal symptoms from antidepressants.  There is more than enough information about the relevant medications and pharmacokinetics to minimize or prevent withdrawal symptoms from happening.

4:  In discussing the relevance of this widely publicized paper with patients - good clinical practice still necessitates that the following topics are covered in detail during informed consent discussions:

a)  The indications, risk, and benefits of antidepressant treatment for the specific patient and the options of other treatments (psychotherapy, lifestyle changes).

b)  The adverse effects of antidepressants including withdrawal as well as serious life-threatening adverse effects like serotonin syndrome.

c)  Detailed information on the suggested medication as an option at patient request – such as the FDA approved package inserts.

d)  Explicit call information for discussing both a lack of efficacy and any potential adverse effects including any change from baseline that was not explicitly discussed.

5:  In terms of settling any withdrawal or antidepressant controversy once and for all that is a doubtful outcome.  Research can be designed or interpreted to support extreme positions on either end. It is just a matter of time before the opposition comes out with a “new” analysis to support their contention that antidepressants are over prescribed dangerous drugs with very little therapeutic efficacy.  There used to be a research term called face validity or a subjective assessment of research hypotheses that applies in this situation. It should be apparent that antidepressants are useful medications and they can be safely prescribed to many people.  It should also be apparent that clinical care is self-optimized to improve outcomes rather than looking for possible positive and negative signals in an objective way.  These are all valuable lessons from another paper in this matter.

6:  There is also a thought experiment that can be considered in the case of known risk for antidepressant withdrawal. Suppose that a person has tried everything to treat their depression or anxiety disorder and found that the only thing that worked was an antidepressant.  Let us further suppose that missing even a single dose of that medication results in severe dizziness, brain zaps, and nausea. After a detailed conversation about tapering and discontinuing the medication or tapering the medication while starting a new one, or referral for ECT or TMS neurostimulation – the patient elects to continue the antidepressant with the risk of withdrawal.  I have had that conversation and similar conversations about side effects with many patients.  It is a common conversation and one that most people do not understand until they are in that position.  This is a position that tens of thousands of people are in – typically with medications that are far more toxic than antidepressants.        

7:  At the political and public health level - treating complicated disorders with complicated medications and other therapies do not lend themselves to easy polling solutions.  I notice that there are disclaimers on many commentaries these days that criticize one modality or another but in the end state "we do recommend that you seek treatment for this disorder."  It reminded me of the decades long practice in psychiatry of dismissing research based on conflicts of interest that were typically research support or compensation for working on drug trials.  I would give the same advice that I gave then to any psychiatrist who thinks that antidepressants are too dangerous or ineffective to use - don't use them. 

This was an excellent study that needed to be done. It reflects the reality of clinical psychiatry where practice has been modified over that past 20-30 years to use medications with better tolerability, safety, and efficacy.  This is done with every successive wave of newer medications in every medical specialty.  

Finally, not enough people see research papers as arguments for analysis.  When you do that – they can be analyzed from a scientific, rational, and moral dimension and just how rhetorical those arguments are.  In many cases in psychiatry – the papers are purely rhetorical.  I encourage more editors to do that analysis in what I expect will be rejoinders to this paper.  One of the best ways to do that is by comparing the paper to current clinical reality.    

Yes – real life counts for something.

 

George Dawson, MD, DFAPA

References:

1:  Kalfas M, Tsapekos D, Butler M, McCutcheon RA, Pillinger T, Strawbridge R, Bhat BB, Haddad PM, Cowen PJ, Howes OD, Joyce DW, Nutt DJ, Baldwin DS, Pariante CM, Lewis G, Young AH, Lewis G, Hayes JF, Jauhar S. Incidence and Nature of Antidepressant Discontinuation Symptoms: A Systematic Review and Meta-Analysis. JAMA Psychiatry. 2025 Jul 9:e251362. doi: 10.1001/jamapsychiatry.2025.1362. Epub ahead of print. PMID: 40632531; PMCID: PMC12242823.

2:  Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998 Jul 15;44(2):77-87. doi: 10.1016/s0006-3223(98)00126-7. PMID: 9646889.

 

Photo Credit:  Thanks to fellow Northland College Alumnus - Rick Ziegler.

Copyright Credit:  Both tables are unmodified from reference 1 and 2 and are used here for not-for-profit educational purposes only.  The copyrights are with the respective publishers noted in those references and are presented here unmodified.  

The Death-a-lo…. A Tale of Terror

 

This post is about a very unusual experience that occurs to a lot of kids.  I thought I would write about it from that perspective.  Consider the young boy in the photo at the top of this post from the mid-1950s. He would be the oldest of 5 children born to a working-class couple and this was their first home.  For 2 years around the time of this photo very unusual events would occur frequently at night. 

On a regular basis – he would wake his parents up - screaming.  What he could not articulate very well at the time was that he would see an old woman entering his room at night.  She walked through a narrow door from an adjacent room rather than a large door connecting the main rooms. She had either very long hair or headwear that accentuated her pale complexion.  She had a threatening facial expression.  She did not say anything or make any noise – but walked silently closer to the boy.  With each step he got more anxious and scared.  At some point he started screaming and did not stop until his mother or father came into the room to see what was the matter. Even then he was unconsolable.  He could only piece together that sequence of events after it had happened many (tens) of times.

His parents typically found him flushed, sweating, with his heart pounding.  It took him about 10 minutes to recover and no matter what they did – they could not speed the recovery process along.  They also could never figure out what was bothering him.  He could never make a clear description even after the recovery period.

Over repeated incidents, and being asked the same questions the apparition became known as the Death-a-lo. It was a name that came naturally to him, but his parents did not know what to make of it.  They did not understand what he was seeing.  They knew there was nothing in the room. They were also concerned that he was making so much noise at night that he may be waking the neighbors.  One day they were walking with him in a public area and 3 Catholic nuns walked by and he pointed to them and shouted: “Death-a-los”.  It was not clear if he was communicating a fear of nuns or a resemblance to the hallucination. When the boy was older – he noticed a chalk drawing of a woman at his grandmother’s house that also resembled the hallucination.  In the small town where the family lived – problems like this never really came to the attention of physicians.  There were no pediatricians or psychiatrists.  All medical care was done by primary care physicians.

Eventually those nocturnal hallucinations and hyperarousal resolved.  This boy went on to become a neurotic child preoccupied with somatic concerns and worries about premature death. For several years, he was concerned that he had a fatal illness – typically cancer or a lethal infection – usually rabies.  He was anxious about doing something wrong and making sure that he did things right.  Even though the hallucinations and night terrors were gone – he had lifelong insomnia and would lay awake late into the night. He constantly thought about things – thoughts of the past, things that had happened, what the future might be like, important things he learned in school, potential catastrophic events, and illnesses.  He was eventually able to put the insomnia to good use.  He could study all night long and was able to think creatively rather than just worry. 

This vignette is a description of sleep terrors or night terrors.  In the current psychiatric and sleep nomenclature (1,2), it is classified under the Non-Rapid Eye Movement (NREM) Sleep Arousal Disorders of the Parasomnias.  The characteristic feature of NREM Sleep Arousal Disorders is abnormal events occurring during incomplete arousals during the first third of the sleep cycle (slow wave sleep).  The main disorders are sleep walking and sleep terrors. About 1/3 of children have had at least 1 episode of sleep walking and roughly the same for sleep terror episodes at 18 months of age.  Sleep terror episodes diminish with age to only about 2.2% of adults. The prevalence of sleep terror disorder (recurrent episodes leading to distress and impairment) in adults and children (1-14%) varies widely depending on the methodology used for estimates (3).

There are potentially many etiologies of NREM sleep arousal disorders in prepubertal children, but it is probably best conceptualized as a developmental phase that will resolve with little to no intervention.  Some research papers will list algorithms to capture rare etiologies, but expert guidelines (4) suggest a detailed history to determine the features of the episode with a medical and full neurological examination.  More extensive testing is indicated only if there are abnormal findings or further differentiation is needed from sleep associated epilepsy or other parasomnias.  Differentiation from nightmares is not difficult based on timing, more clear recall of the nightmare event, and the lack of marked autonomic arousal.

Like most disorders of consciousness, there is no clear mechanism.  At the level of clinical neurophysiology – sleep EEGs will clearly show a transition from stage 3 and 4 slow wave sleep (N3) to a period of hyperarousal with increased muscle tone/movements, tachycardia, and hyperventilation.  I currently have permissions to display 2 EEGs of sleep terrors pending and will post them if I get those permissions.  

At the pathophysiological level, these arousals are like sleep inertia or incomplete arousals from slow wave sleep.  They can be induced by forced awakening of people in slow wave sleep.  Sleep disorders, sleep deprivation, circadian rhythm disturbances, physical illnesses, physical stimuli (excessive environmental noise, bladder distention, sleep disordered breathing), and prescription or non-prescription drugs that affect sleep states can all precipitate these episodes.  The developmental form is more likely to persist and no specific etiology is typically determined.

Sleep problems are very common in populations with psychiatric disorders.  That insomnia and some of the medications prescribed for primary psychiatric disorders can trigger NREM arousals and that should be part of the ongoing dialogue with any patients who are being treated.  Some studies indicate that these sleep problems are more likely in family members who have first degree relatives with psychiatric disorders, sleep disorders, and sleep disordered breathing.  In the case of the patient discussed above – his father probably died from sleep apnea and he was eventually diagnosed with severe sleep apnea at age 55 and has been using CPAP ever since.

There has not been a lot of work done looking at subsequent psychopathology and NREM arousal disorders. A study from 1980 (8) is still quoted suggesting that the sleep terror group is more likely to experience anxiety, depression, obsessive-compulsive tendencies and inhibit outward expressions of aggression. There has been very little work done on the phenomenology of sleep terror episodes – most likely since episodes are associated with amnesia. The Death-a-lo descriptions was possible only after many episodes over a period of at least one year.

Like most disorders, there is a wide range of severity with both sleep walking and sleep terrors.  Consultants will typically ask about the safety of the sleep environment and make suggestions where necessary.  All the previously mentioned factors that can lead to the arousal can be modified. There are environmental, behavioral, and pharmacological interventions (benzodiazepines, antidepressants, melatonergic agents).  The impression I get from reading the current literature is that the need for pharmacological intervention is rare.  That is probably expected when the disorder is time limited, environmentally sensitive, and can be treated with anticipatory or scheduled awakenings.  After the usual time of the disturbance has been determined – the parents wake the child up about 30 minutes before the event.  That is described as being as effective as medications – but whether a non-treatment comparison was done is unknown.

In the case of the boy in the vignette,  he is now in his 70s.  He has had no parasomnias since this pre-pubertal episode.  A few years later he did have an episode of severe visual hallucinations that occurred due to a febrile illness, but he has not been diagnosed or treated for psychiatric problems – apart from the lifelong insomnia and obstructive sleep apnea.

I basically did OK!

 

George Dawson, MD, DFAPA

 

References:

1:  Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed., American Psychiatric Association, 2013. DSM-V, doi-org.db29.linccweb.org/10.1176/ appi.

2:  American Academy of Sleep Medicine. International classification of sleep disorders, revised: Diagnostic and coding manual. Chicago, Illinois: American Academy of Sleep Medicine, 2001.

3:  Leung AKC, Leung AAM, Wong AHC, Hon KL. Sleep Terrors: An Updated Review. Curr Pediatr Rev. 2020;16(3):176-182. doi: 10.2174/1573396315666191014152136. PMID: 31612833; PMCID: PMC8193803.

“Sleep terrors typically occur in children between 4 and 12 years of age, with a peak between 5 and 7 years of age. It is estimated that sleep terrors occur in 1 to 6.5% of children 1 to 12 years of age, although a prevalence of 14% or higher has also been reported. The wide variation in prevalence can be attributed to differences in definitions of a sleep terror, methodology, and studied population. The lifetime prevalence of sleep terrors has been estimated to be approximately 10%. The condition is uncommon after puberty. In the pediatric aged group, the condition is more common in boys than in girls. In the adult population, both sexes are equally affected.”

4:  Avidan AY.  Disorders of arousal.  In:  Kryger M, Roth T, Goldstein CA, Dement WC.  Principles and Practice of Sleep Medicine. 7^th ed. Philadelphia, PA:  Elsevier, Inc, 2017:  1071-1086.

5:  Guilleminault C, Palombini L, Pelayo R, Chervin RD. Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics. 2003 Jan;111(1):e17-25. doi: 10.1542/peds.111.1.e17. PMID: 12509590.

6:  Loddo, G., Lopez, R., Cilea, R. et al. Disorders of Arousal in adults: new diagnostic tools for clinical practice. Sleep Science Practice 3, 5 (2019). https://doi.org/10.1186/s41606-019-0037-3

7:  DiMario FJ Jr, Emery ES 3rd. The natural history of night terrors. Clin Pediatr (Phila). 1987 Oct;26(10):505-11. doi: 10.1177/000992288702601002. PMID: 3652596.

8:  Kales JD, Kales A, Soldatos CR, Caldwell AB, Charney DS, Martin ED. Night terrors. Clinical characteristics and personality patterns. Arch Gen Psychiatry. 1980 Dec;37(12):1413-7. doi: 10.1001/archpsyc.1980.01780250099012. PMID: 7447622.

“Both groups had high levels of psychopathology, with higher values for the night terror group. These sleepwalkers showed active, outwardly directed behavioral patterns, whereas the night terror patients showed an inhibition of outward expressions of aggression and a predominance of anxiety, depression, tendencies obsessive-compulsive/, and phobicness. Although night terrors and sleepwalking in childhood seem to be related primarily to genetic and developmental factors, their persistence and especially their onset in adulthood are found to be related more to psychological factors.”

 

Killing Us Slowly…..

 

I became aware today of a Brown University study that estimates the current Trump tax cut bill will close about 580 nursing homes. Since the average nursing home has about 109 beds that means 63,220 people will be out on the street or worse.  Where do politicians (more specifically the Republican party and their constituents) think these people will go?  And why don’t they seem to care?

Over the course of my career – I have probably been in at least 50 different nursing homes in Wisconsin and Minnesota.  The care I have observed in most of those places is managed to be adequate to barely adequate.  By that I mean like all businesses they are managed to make money.  Unless they are privately financed by a foundation or high paying patients, that typically means there is minimal staffing and the most qualified people are typically RNs who spend most of their shift managing medications and medical problems.  That can mean long waits for medicines or care.  It can also mean that behavioral problems like agitation or overt aggression are allowed to escalate to a dangerous point.

When I first started doing assessments in nursing homes it was 1986.  In those days, there were very few diagnoses of Alzheimer’s Disease (AD) or vascular dementia (VaD) since the NINCDS-ADRDA criteria were not widely known.  Most of the people I was seeing had diagnoses of arteriosclerotic dementia, arteriosclerosis, or hardening of the arteries. At some point very early in this timeline, there was an initiative to make sure that old people with psychiatric diagnoses did not get admitted to nursing homes.  But like all political initiatives it was not always an either-or situation.  I would frequently see people with schizophrenia and bipolar disorder who had developed AD, VaD, Parkinson’s plus syndromes, or tardive syndromes in addition to the primary psychiatric disorder.  In many of those situations a subsequent rule about tapering antipsychotic medications to prevent oversedation and associated morbidities became a problem because of the need for maintenance medication.

Psychiatric services are needed in nursing homes for all of those reasons but they are rare.  The reason they are rare is funding – specifically rationing psychiatric services by both Medicare and Medicaid. I ran a Geriatric Psychiatry and Memory Disorders Clinic for a decade and we eventually closed because we could not maintain an adequate work quality and get adequate reimbursement. For a time, my clinic nurse and I decided to go out into nursing homes and see patients there to make it more convenient for patients, families and staff and see if it made a difference. We were reimbursed at an even lower rate for those efforts.  My speculation is that most of the psychiatric care and treatment in nursing homes is done by nonpsychiatrists and probably nonphysicians.  This in part is an additional reason for low quality care in most nursing homes.

Let’s consider the impact of all of these nursing home closures. First, it will greatly add to the current burden of emergency department (ED) congestion.  There is always a steady influx of nursing home patients to the ED with new diagnoses (pneumonia, urinary tract infections, cellulitis, etc). With further reductions in staffing, it may be more difficult to get them back.  I can recall one of my social work colleagues calling 22 different nursing homes one day to discharge one of our stable patients.  None of them would accept that patient. We were under intense pressure from the hospital at the time to discharge that patient because we needed to admit patients from the ED.  That whole chain of events will get worse – not the least due to the fact that far fewer nursing homes will accept people who have been admitted to an acute care psychiatric unit. There will be backups all around – on inpatient units and in the ED.  The same chain of events will occur on medical and surgical units who often put pressure on psychiatry to take their “stable” nursing home patients who may have a psychiatric disorder.

There will also be a steady-state of patients bouncing in and out of the ED-inpatient psychiatry or medicine-discharge sequence.  This is a familiar pattern in many hospital subpopulations that usually occurs because of a lack of adequate housing.  Expect to see more elderly nursing patients captured by this cycle.

Will there be excessive mortality and morbidity?  Of course there will be.  In the course of my career, I had to discharge patient to nursing homes where I knew they could not get the level of care they got on my inpatient unit.   I worked with highly skilled RNs – 4 on the day shift, 3 on the evening shift, and one on nights with 3, 2, and 2 nursing assistants respectively covering 20 beds. We cared for patients with complex medical problems that required frequent monitoring and intervention.  I knew there was no nursing home that I could discharge them to where they would get the same level of care and that would be a problem for them.

I have also walked in to a nursing home and seen the results with my own eyes. I recall visiting a 92 yr old woman with congestive heart failure and hypertension.  She was obtunded, cyanotic, and barely responsive.  When I asked the staff to check her oximetry and start oxygen they produced a nursing supervisor instead for a discussion.  When the oximetry was finally done it was 60% and she regained a normal conscious state with oxygen.  The assessment I made only required knowing this patient’s baseline state and asking what had happened given her chronic conditions.  Is that too much to ask in the case of nursing home staff?

In another more recent case – a 92 yr old man had C. difficile colitis following extended antibiotic therapies for post COVID-19 pneumonia.   During that time his body weight went from 130 to 87 lbs (he was 5’11” tall).  He was weak and barely able to ambulate. Despite the C. difficile diagnosis there were no infection control precautions and he shared a bathroom with 3 roommates.  Despite his clinical status (barely able to walk unassisted, not able to eat, BMI of 12.1) the insurance company paying for his care insisted that he be discharged home under the care of his family where he died the next day.  

Both of these cases are examples of low-quality care.  Rationing care is the most likely reason.  In one case the rationing is implicit (low staffing based on the need for profits from reimbursement) and explicit (inappropriate utilization review decision).   It all comes back to reimbursement.

A final consideration is that the funding cuts go far beyond nursing home care.  The most conservative estimate I have found is that the cuts would increase the number of uninsured by 7.8 million people and reduce Medicaid enrollment for 10.3 million.  Hospitals are legally obligated to treat all people with acute care conditions whether they have insurance or not. That means that many of these people will be in the ED-inpatient-discharge steady state cycle taking up beds.  They will also more likely be acutely ill and spend more time in the hospital.  All of that care is unreimbursed.  That means higher health care costs and premiums for everyone.  One projection is a doubling of premiums.  This is essentially another tax on the average American who is just trying to break even.  All of that is to provide tax cuts for billionaires and businesses while still incurring a 3-5 trillion dollar deficient.

It also means less access to hospital beds when you need it.  I have illustrated on this blog what can happen when you don’t have timely hospital bed access for what is considered a routine condition.

In the final analysis, nursing home care in the United States is seriously rationed care. Although there are some high-end nursing homes that require additional reimbursement and provide more supportive environments - most are not operating at that level.  They provide the basic function of providing care on a 24/7 basis to a severely disabled person that the family cannot care for.  Even that is a recent concept in American society.  As an example, one of my elderly ancestors had a closed head injury as a result of blast injury. He lived at a time when there were no nursing homes in his area only a poor farm, that cared for the indigent and poor elderly.  He had a problem with severe aggression and would routinely wreck all of the furniture in the house. I never learned how they were able to contain this behavior, but the modern question is whether this is an acceptable standard for families.  Can family members be expected to contain severe aggression from a family member with dementia and keep everyone safe?  I don’t see how.      

Severe rationing of health care in the bill being debated hurts us all…

 

George Dawson, MD, DFAPA

Photo Credit:  Thanks to Rick Ziegler for the thunderstorm photo. 

Clinical Trials Versus Clinical Treatment – Key Differences

This is always an ongoing source of debate in psychiatry – largely because of the forces that seek to delegitimize the field.  This post is not directed at them since they have a long track record of producing the same biased arguments.  This is my perspective as a person who has successfully treated people with severe psychiatric problems and been an investigator in clinical trials. I have first hand experience with the limitations of clinical trials and they can be considerable.  I am certainly not unique in that regard and it is important to know why those of us with that experience can dismiss headlines about psychiatric treatments not working as well as many of the associated reasons.

Let me preface these comments by saying that running a clinical trial at whatever level you are responsible for is hard work. I have been a co-principal investigator but most of my work was focused on research subject follow-ups and patient safety. I was the guy who got the call about unexpected side effects, lab reports, ECGs, and imaging studies. In those cases, it was my job to decide if the problem was due to the study drug (or placebo) or an intercurrent illness and decide if it was safe for the research subject to proceed.  If the decision was to stop the protocol, there is always at least one person who upset with that decision. There is a study coordinator who wants to maximize retention and study completers. There are the research subjects and their families who may consider the research drug the latest hope – even though they do not know if they are getting placebo. There are other investigators and research assistants who all want to maximize research participation.

Let me start by framing the main differences between research and clinical treatment starting at the top of the diagram.  Clinical trials are sampling the general population on a very specific feature.  In medicine that is typically a disease state. That selection process is modified to be even more stringent to eliminate other variables.  In the diagram this is indicated by the inclusion and exclusion selection criteria. That does not exist in clinical practice where any number of complicating factors need to be addressed in addition to the main indication for treatment. 

This recruitment phase in clinical trials is critical because there is limited funding, and adequate sample size must be recruited, and therefore there is an acceptable time frame. 70% of clinical trials do not recruit the number of subjects they need in the expected time frame.  Currently in the US, less than 3% of adult cancer patients participate in clinical trials (ref 1 p. 268).  In older research it was often stated that only 5% of eligible subjects participate in research. In my experience that number is accurate.  In some of my studies it approached 2% at times.  In other areas the numbers are higher but they typically max out at about 25% and there is a significant difference between experimental trials and retrospective or epidemiological trials that are less demanding.

The ratio of enrolled/screened is important because it suggests a skewed sample from the population that might be more evident if the reasons for declining research were explored.

Response to the recruitment problem is typically that it is taken care of by randomization – but is that accurate?  For example, if people do not want to take a chance on a new medication or randomization does that eliminate potentially good treatment responders from both arms of the trial?  If a trial is debated in the press – like many psychiatric trials are - will that increase the nocebo response in both arms? If a trial involves discontinuation or substitution of a current medication that had been somewhat effective does that lead to increased problems with nocebo effects and drop puts.  The impact on the physician-patient relationship can be affected by both offering and not offering trial participation.  Physicians are most likely not to suggest that stable well treated patients participate for altruistic purposes.  Recruiting pressure on the clinical trial team may lead them to accept suboptimal research subjects with a history of participation in multiple trials, subjects with milder illness or equal comorbidity (e.g. anxiety = depression), or subjects who are more likely to drop out.

These are just a few of the factors that can affect the recruitment and enrollment phase that are not very well investigated or recorded. Speaking from experience, I can say that what looks like an acceptable treatment protocol is often modified as investigators start to panic about low enrollment in the trial.

On the clinical side there are different problems. No matter how complex the patient’s situation there are typically waiting lists of patients to be seen by psychiatrists.  This is true even though only about 6% of the medical workforce that prescribes psychotropic medications are psychiatrists. There are no exclusion criteria and rather than the potential trial participant effect where trial participants are likely to do better even if the medication is ineffective (ref 1, p. 258) – patients referred to see psychiatrists are generally less healthy, more likely to have chronicity, less likely to adhere to treatment, more likely to have a substance use disorder, and more likely to have medical and psychiatric comorbidity.

In addition to the placebo and nocebo effects there are a number of lesser-known factors affecting the experience of people in clinical trials and clinical care.  Some of them will alter the entire trial sample.   For example, a recruitment bias due to failing enrollment can result in equivocal cases being enrolled (for example an adjustment disorder with depressed mood rather than major depression in a depression trial). These subjects are more likely to appear to respond to nonspecific factors.  Many people diagnosed with depression have a long history primary insomnia and may appear recovered if their insomnia is treated by the antidepressant or adjunct medications allowed in some protocols. I have participated in some protocols where all of the investigators were instructed to avoid any semblance of psychotherapy and not enroll anyone who might have a personality disorder.  These are some of the occurrences behind the scenes that can affect clinical trials.

The number of times a person volunteers for clinical research can be an issue. There is very little written about this, but there are some centers that specialize in research and often recruit healthy patients for early drug trials and compensate them. There are some online sites that say you can volunteer for as many studies as you qualify for in any given year.  There are obvious concerns about whether subjects need a break between trials as well as deception involved in gaining access to the trial, adhering to the protocol, and skewing the trial results (2-4).  I also have the concern that it is easy to fake some psychiatric disorders to get into a paid trial. The trials I have been in as an investigator were all through academic centers where reimbursement was primarily to cover travel expenses.  The professional patient role was probably less in those circumstances but it is an issue that is only covered in the research literature on a sporadic basis.

With the number of variables listed in the diagram – it takes a lot of thought to figure out the impact on the trial and clinical care.  It is useful to keep in mind a few overall points. First, there is a lot more going on in the trial than an effect based only on the biological effects of a medication (placebo, nocebo) (5).  Second, clinical care is not like a clinical trial.  If someone is very ill and they are not responding to a medication or having side effects – a change needs to occur very quickly.  That is typically the same day on an inpatient unit or a day or two later in the outpatient clinic.  In a clinical trial, the subject can drop out or discuss other options with the investigator but those options are very limited and slow.  Major side effects typically need to be reported to the Human Subjects Board monitoring the research protocol, the protocol sponsor, and in some cases the FDA. Third, clinical care by its very nature incorporates many of the nonspecific factors associated with a nondrug positive response usually termed a placebo response. These same nonspecific factors can occur in psychotherapy trials as well as complementary medicine trials. 

Another important aspect of clinical trials is the measurement issue.  Various rating scales are typically employed as representations of psychiatric diagnoses. There are standardized and valid scales to measure adverse drug effects and, in some cases, more specific symptoms like sleep.  Global ratings by the investigators are added as an additional measure of validity.  These are all crude measures and unless subjects are selected specifically for a phasic severe disorder – the ratings will fluctuate significantly over the course of the trial based on various factors. In addition to the psychological, environmental, and biological factors some authors in medicine and biology have started to use the Heisenberg effect to describe this uncertainty (6). Since these measurements are not of discrete entities and cannot be represented by wave functions – this term is used at the level of a crude analogy for uncertainty in biological measurement.

Clinical care is much different.  There has only been a pretense of measurement.  There has been some publication of measurement-based psychiatry as an offshoot of evidence-based medicine.  I don’t think it offers much of an improvement over clinical psychiatry.  In psychiatry like all of medicine we are taught to recognize and respond to patterns not rating scales. I was reminded just this week of a referral I got of a patient who was described as having a histrionic personality disorder based on DSM criteria and some additional psychometric testing. It was apparent to me with a few minutes that the patient was manic and the correct diagnosis was bipolar disorder.  Psychiatrists are taught by seeing real patients, recognizing their problems, and organizing a treatment plan around those patterns. Referring to rating lists based on DSM symptoms that are in turn based on patterns in real people leaves a lot of room for interpretation.

Nobody seems to think about the selection process involved in clinical trials versus clinical care.  On the clinical trials side, the severity of conditions that research subjects are recruited for has decreased substantially over the years.  One reason is that inpatient trials and inpatient research units are essentially gone compared with 40-50 years ago. That eliminates research subjects with significant suicide risk and inability to function due to mood disorders. The overall research population has less severe illness.  The clinical side is stratified with most medical treatment of mental illnesses being provided non-psychiatrists.  This mitigates the lack of severity in clinical trials but also leads to psychiatrists treating people with severe disorders and comorbidity who would not typically be eligible for clinical trials. My personal observation is that this leads to a much better clinical response than is typically seen in RCTs.  Observational and registry-based studies also provides valuable insights into the true clinical response that is often poorly characterized in RCTs.  

The treatment aspect is also a critical difference.  There are few people who would want to receive treatment the way it is set up in clinical trials. People with any degree of a problem would not get adequate treatment. Most clinical trials are set up to see if there is an adequate efficacy and safety signal for the FDA to allow the medication on the market.  Post marketing surveillance is used to detect rare but severe side effects that might result in a new medication being withdrawn from the market.   

Clinical treatment is timely and effective in psychiatry.  Like the rest of medicine, it is not perfect and a lot can go wrong.  Based on my  experience as a researcher, a quality assurance reviewer, a teacher, and a colleague in large departments most people can count on finding a good if not excellent psychiatrist to provide effective treatment.  

 

 

George Dawson, MD, DFAPA

 

References:

1:  Piantadosi S.  Clinical Trials: A Methodological Perspective. 3^rd ed.  Hoboken, NJ: John Wiley and Sons, Inc, 2017: 886 pp.

2:  Shiovitz TM, Zarrow ME, Shiovitz AM, Bystritsky AM. Failure rate and "professional subjects" in clinical trials of major depressive disorder. J Clin Psychiatry. 2011 Sep;72(9):1284; author reply 1284-5. doi: 10.4088/JCP.11lr07229. PMID: 21951988.

3:  Pavletic A, Pao M. Safety, Science, or Both? Deceptive Healthy Volunteers: Psychiatric Conditions Uncovered by Objective Methods of Screening. Psychosomatics. 2017 Nov-Dec;58(6):657-663. doi: 10.1016/j.psym.2017.05.001. Epub 2017 May 9. PMID: 28651795; PMCID: PMC5680154.

4:  Lee CP, Holmes T, Neri E, Kushida CA. Deception in clinical trials and its impact on recruitment and adherence of study participants. Contemp Clin Trials. 2018 Sep;72:146-157. doi: 10.1016/j.cct.2018.08.002. Epub 2018 Aug 21. PMID: 30138717; PMCID: PMC6203693.

5:  Quitkin FM, Rabkin JG, Gerald J, Davis JM, Klein DF. Validity of clinical trials of antidepressants. Am J Psychiatry. 2000 Mar;157(3):327-37. doi: 10.1176/appi.ajp.157.3.327. PMID: 10698806.

6:  Atkins PW.  Physical Chemistry. 5^th ed.  Oxford: Oxford University Press. 1994:  380-387.

 The issue of superposition is conflated with the uncertainty involved in biological measurement. It is the described as an analogy rather than the definition of superposition from quantum mechanics.  

Workforce Reference:  40,000 psychiatrists/290,000 nurse practitioners + 209,000 primary care physicians + 115,000 physician assistants – certified = 40,000/654,000 = 0.06 or 6%. 

Graphics:  I produced the above graphic with Visio.  Click to enlarge.