Inappropriate Sinus Tachycardia (IST) In The Psychiatric Clinic

I don’t recall what I was researching the other day but I happened across a brief review paper on a subject I have been following for a while (2). That subject is inappropriate sinus tachycardia (IST). I posted recently about closely following the cardiac status of patients being seen by psychiatry both on the inpatient side and in the outpatient clinic. When that is done a significant portion of those patients will have tachycardia defined as heart rate of greater than 100 bpm. In some cases the heart rate ranges as high as 120 to 130 bpm.  Many of these patients are surprised to learn how high their heart rate is and what constitutes a normal heart rate. Others are very focused on the cardiac status and experience palpitations in periods of rapid accentuated heart rate. I commonly hear “it feels like my heart is coming out of my chest”.

That type of cardiac symptom can certainly occur during panic attacks. The majority of people I see with sinus tachycardia do not have panic attacks or panic disorder. They are generally anxious but the phenomenon I have not seen addressed is how much anxiety is due to the cardiac symptoms? Many have what I describe as cardiac awareness. By that I mean they can sense their heart beating by various mechanisms. Many can feel the pulsation of blood through the body especially in the head and neck area. Others can hear their heartbeat. Many can sense their heart beating against their chest wall. The person has that kind of focus any irregularity like occasional pauses or extra beats leads to heightened anxiety. As that anxiety builds some people will feel chest pain, chest pressure, and shortness of breath or near panic symptoms.

 A significant number of those patients will have anxiety associated with symptomatic IST. There are also groups of patients with frequent panic attacks, nocturnal panic attacks, night terrors, and medical problems associated with tachycardia and other cardiac symptoms.  It has been surprising to me to find that significant sustained sinus tachycardia is often ignored in primary care settings. The reason for that may be the latest review in UpToDate (1). In that review the authors define the syndrome and the evaluation and conclude that the condition generally has a benign course in that tachycardia induced cardiomyopathy is rare. They suggest that diurnal variation of the tachycardia may protect against that.

Since IST is by definition tachycardia with no known medical cause intrinsic heart disease and associated causes of tachycardia need to be ruled out. In psychiatric patients panic attacks and anxiety are typically considered psychiatric causes of tachycardia but they are rare causes of sustained tachycardia. The hyperadrenergic state of panic attacks generally resolves when the panic attack resolves and that is frequently in 20 minutes or less.  It is common to see very anxious people in clinics and when their vital signs are checked they are typically normal. Sustained tachycardia is more common with other comorbidities such as medication side effects, excessive caffeine use, stimulant use, alcohol or sedative hypnotic withdrawal, and in some cases insomnia. Deconditioning can also be a factor one person has been isolated and sedentary for any reason and they suddenly need to walk a distance to get to the clinic. There is a gray zone of overlapping conditions that need to be considered. For example, an acute pulmonary embolism, congestive heart failure, and emphysema or COPD can lead to cardiopulmonary symptoms including tachycardia. They can generally be ruled out by a medical history, review of systems, and brief examination.

Tachycardia secondary to medication side effects often requires tracking several variables.  In the ideal case, an indicated medication can be selected that does not have the side effect - in this case tachycardia. But there re some medications that are unique enough that they may be used in situations where the tachycardia persists because there are no other good alternatives. With clozapine (3) the tachycardia can be secondary to anticholinergic side effects, alpha blockade and hypotension, or intrinsic cardiac side effects like myocarditis. Patient often get tachyphylaxis to the anticholinergic effects but all of these variables need close monitoring. It takes a lot of ruling out to conclude that a patient on clozapine has IST and this is a good example of the importance of the baseline evaluation and reviewing avaiable records and vital signs in the electronic medical record.

A more common scenario is the anxious patient with no clear cardiac or pulmonary disease who has persistent tachycardia and in many cases palpitations. They are often treated with beta-blockers with some success. I have seen people have been unable to tolerate beta-blockers, people who did not respond beta-blockers, and some people with beta-blocker withdrawal who had severe anxiety panic and tachycardia because the beta-blocker was stopped too quickly. In both the review and the up-to-date summary, IST patients are commonly resistant to beta-blockers and need another intervention. The suggested intervention is ivabradine a novel medication described as a blocker of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker I_f current. That directly affects heart rate at the SA node. It also affects retinal currents leading to phosphenes or transient bright spots in the visual fields. 

The main indication for ivabradine is congestive heart failure. There are cardiac complications including atrial fibrillation. That suggests to me that most psychiatrists should probably not consider prescribing this medication unless there is ample clinical experience and the required monitoring is not intensive - similar to beta-blockers today.

The main message in this post is that close attention does need to be paid to vital signs on every inpatient unit and outpatient psychiatric clinic. It is not enough to say that tachycardia can be dismissed as anxiety. It is also not enough to use a quasi-medical intervention like telling the patient to drink more fluids if they have not been assessed for hypovolemia. A close look for intrinsic cardiac conditions and the list of conditions and the differential diagnosis from the review article below and the UpToDate review should be a minimal requirement for medical psychiatrists. If that cannot be done, the patient should definitely see their primary care physician preferably prior to initiating any treatment with a medication that would obscure the clinical picture. The evaluation and recommendations of the primary care physician should be available in the patients psychiatric chart. For completion, I also get copies of other cardiac testing that has been done including echocardiograms and exercise stress tests.

The advantage of a diagnosis of IST is that it recognizes there is a specific diagnosis to account for inappropriate tachycardia rather than a default psychiatric diagnosis. That is important because it protects the patient and potentially offers more effective care. The treating psychiatrist should still be in the loop for the necessary lifestyle modifications, education about the condition and monitoring and treating any associated anxiety.

George Dawson, MD, DFAPA

References:

1.  Munther K Homoud. Sinus tachycardia: Evaluation and management.  Section Editor: Jonathan Piccini, MD, Deputy Editor:Brian C Downey, MD in UpToDate.  Accessed on October 6, 2019.

2.  Ruzieh M, Moustafa A, Sabbagh E, Karim MM, Karim S. Challenges in Treatment of Inappropriate Sinus Tachycardia. Curr Cardiol Rev. 2018 Mar 14;14(1):42-44. doi: 10.2174/1573403X13666171129183826. Review. PubMed PMID: 29189171; PubMed Central PMCID: PMC5872261

3. Miller DD. Review and management of clozapine side effects. J Clin Psychiatry.2000;61 Suppl 8:14-7; discussion 18-9. Review. PubMed PMID: 10811238.

Physicians Preservation Act?

I got this idea today while reading the usual Twitter complaints about the electronic health record. A post by physician I knew was particularly poignant. She pointed out that she was getting burnout from the excessive time it takes to do EHR documentation compounded by the fact that nobody ever reads it. This is a complaint I have had for a long time.  I was lucky enough to be on the ground as the EHRs rolled out. There was quite a prelude to the rollout with about a solid 10-year buildup of documentation and billing requirements. Those requirements originated with the federal government specifically HCFA – the precursor to CMS. All of the initial EHRs were designed around these documentation and coding templates. It was strictly a business focus sold as something necessary for medical practice.

I can recall the first people on the medical staff who were designated to sell the system. They came to see me and I pointed out that I have never been a touch typist and the fastest I can type is 12 words a minute with two mistakes. When they realized I wasn’t kidding they tried to soften the blow by saying that we would be slowly transitioned to creating the entire document. During that transition time we would still be able to dictate admission notes and discharge summaries. When I complained that this would still be quite a burden on physicians producing all these documents I was told by an internist (who I had a very high opinion of) “You need to thank our CEO for getting us this state-of-the-art system.” That was one of the more depressing remarks that I’ve heard in my career.

I did try to make the most of it. I got an early version of Dragon and started dictating all my notes and into Word and pasting them into the EHR.  It was not pretty. There were many mistakes and if I missed some of those mistakes it could prove to be an embarrassing document. The nursing staff I worked with helped to edit those documents and point out the mistakes but some mistakes invariably went through. I learned that the nursing staff in my immediate proximity were the only people who ever read those notes. I was generating multiple 500 to 1000 word documents a day and suddenly realized that I had to complete that work between 10 PM and midnight every day. Within a few years the new car smell was off the EHR and things were getting ugly.  I started to see 18 to 20 page progress notes based on import and cut-and-paste features. My speculation is at one point the vendor was desperate to prove they could introduce some physician friendly features. The ability to start a new daily progress note based on yesterday’s note soon became history. Administrators decided that the new note looked too much like the old note even though they were based on same template.

EHR politics is always interesting to observe. There are a cadre of administrators and “super users” who are tasked with selling the product to the frontline physicians. There are also various helpdesks that are run by the vendor. Staff at those helpdesks are supposed to be available for troubleshooting and problem solving. The troubleshooting and problem solving eventually fades away. EHRs are typically implemented in modules. I walked into work one morning and realized that the module that allowed electronic prescribing was completely changed. The change was not announced and since it was an enterprise wide implementation there were hundreds of physicians trying to figure it out for themselves. It added hours to everyone’s day.

With the shift of billing, coding, and documentation to physicians many other jobs were lost due to the EHR. For 15 years I would go to the basement of the hospital every Sunday and make sure all of my records were dictated and signed. I ran into the same staff there every weekend who greeted me and assisted me with completing those records. Suddenly they were gone because now I was doing all of their work in the EHR. When I first started working at my job, I would dictate daily progress notes and they would be pasted into the chart by the secretarial staff the next day. Billing and coding specialists would come to the unit, read those notes, and attach a billing fee. I had no idea about the billing system and didn’t really care. With the EHR all of those staff were replaced. I was not only doing their jobs but now I was legally responsible for any billing errors and the suggested penalties were high. All of this additional work and responsibility was directly transferred to physicians through the EHR.

The only real bright spot from the EHR was the ability to see imaging studies, electrocardiograms, and laboratory results as soon as they were available. It took years to get that implemented to the point it worked effectively.

Are there workarounds to successfully use the EHR without burnout, depression, and excessive work? I think that there are. The last few years I have been seen by ophthalmologists who were retinal specialists and an otolaryngologist or ENT physician. In both cases these positions were using a scribe or a third person in the room who documented the history, exam, findings, and treatment plan as indicated by the physician. In the case of the retinal specialist he was working with an ophthalmology fellow and made corrections to that examination by directions to the scribe. The same thing happened with the ENT physician but in that case the scribe was also an RN who could provide more details about the suggested treatment plan. In both cases the physician walked out of the room at the end of the encounter with no further documentation burden. That led one of my colleagues to point out that the only reasonable workaround for the EHR problem is to use two people - the physician and a scribe or staff person who could also function as a scribe.

That led to my idea about the Physicians Preservation Act at the top of this post. It addresses all the flaws in the system that were brought about by heavy lobbying and Congressional advocacy for a burdensome inefficient electronic documentation system. As I pointed out in a 2015 post, the system has never lived up to claims of efficiency or savings even when physicians started to do the work of four or five people. This entire administrative structure is there to produce excessive documentation that nobody reads. There is also a massive environmental cost since the system must operate through thousands of networked personal computers that in many cases are operating 24/7 along with the associated data storage facilities. 

My suggested solution is a compromise between the likely inertia of the current EHR system and the politics that keep it in place and the massive burden it places on physicians and their families. There are just too many special interests in Congress keeping this system afloat. The question is how long can the country afford to lose doctors because of it.

My guess is not too much longer.

George Dawson, MD, DFAPA

Cardiac Screening In Psychiatric Patients

There is a paper that just came out (1) that I consider a must-read for all psychiatrists.  Some experts might qualify that and say that it is only necessary to know the subjects if you are treating the medically ill, the elderly, pediatric patients, patients with cardiovascular disease, or patients with cardiac risk factors. The problem with those qualifications is that you have to know everything in this paper (and others) in order to make that determination. Beyond that you have to been trained in how to determine if your patient is seriously ill or not. In the case of all medical specialists, serious illness generally means treatment by another specialist or in a more intensive setting. For that reason, the cardiac aspects of care in this paper are required knowledge.

Three of the authors of this paper are cardiologists, two are psychiatrists, and one is a clinical pharmacist. They have produced a very practical document on identifying problems with tachycardia, QTc prolongation, sudden cardiac death, myocarditis, and dilated cardiomyopathy.  They provide very specific endpoints and suggest some basic intervention that can be done before the patient is referred to cardiology. Examples would be assessment of tachycardia, suggested treatment thresholds, common treatment interventions like beta-blockers and calcium channel blockers, and referral to cardiology if there is a progression to other cardiac symptoms, nonresponse to the initial therapy, or an arrhythmia beyond sinus tachycardia. They provide similar guidance on the other common conditions and relate them to second-generation antipsychotics (SGAs). 

All of the authors are from the United Kingdom.  I am not familiar with the standard settings for practicing psychiatry in the UK, but in the US there is a high degree of variability. For example, in practicing on inpatient settings it is not a problem to order ECGs or even stat ECGs. Echocardiograms and other imaging studies of the heart are easily obtained as well as cardiology consultation. In a previous inpatient setting where I practiced, I requested a cardiology consultation for a young woman with a QTc of 520 ms who required treatment with antipsychotic medications. She was seen immediately and an electrophysiology study was done. After that study I was advised by cardiology that I could safely treat the patient with olanzapine. At the other end of the spectrum, I know there are psychiatrists reading this who have no access ECGs, medical testing, or cardiology consultants. They are often practicing in an office that lacks a sphygmomanometer or staff routinely checking patient vital signs. Many of those office settings are essentially nonmedical and any psychiatrist practicing there - would need to bring in their own equipment and probably take their own vital signs.  A basic standards would be that every practice setting for psychiatry in the country should have the tools to make the measurements recommended in this paper, but I am not aware that any standard like that exists.

The second obstacle to realizing these guidelines is the way electronic health records (EHR) are set up. Major organizations and the EHR companies themselves produce templates that are typically designed for business purposes rather than medical quality. A visit to a psychiatrist in that organization results in that template being filled out with a business rather than a clinical focus. In other words, sections of bullet points are completed based on what coders believe will capture the necessary billing from insurance companies. One of the key sections is often the review of systems (ROS). Because these documents are not designed by physicians and there are no uniform standards, a functional review systems is often not there. In the case of cardiac symptoms, there needs to be a clear section that encompasses all the symptoms described by the authors in this paper. As an example, take a look at the cardiac symptomatology that I recorded in this post and the modified extended review of systems that I typically ask patients about.

Any inpatient or outpatient assessment done by a psychiatrist should include a thorough medical history, a review of systems that is focused on medical rather than psychiatric systems, a set of vital signs including noting whether or not the cardiac rhythm or pulse is regular or irregular and a further description of the irregularity.  A focal exam for additional heart and lung findings and determination of pulses and peripheral edema may be indicated.  The take home point is that this history taking combined with a few additional findings should be all that is necessary to order further tests like an ECG, refer for an acute assessment, or refer to a primary care physician or cardiologist for further assessment.  If the patient is being followed for the metabolic complications of SGAs, there may already be a fasting blood glucose, and lipid profile in the chart to assess additional risk factors.  Over the years I have also found that recording a theory about why I think the patient is symptomatic is also very useful.  In my practice that has ranged from medication side effects to an acute myocardial infarction.

With those issues we can proceed to consider the assessments and treatments recommended by this group. I am not going to repeat the content of the paper here.  I recommend that any interested psychiatrist or psychiatric resident get a copy of this paper and study it in detail if you are not already familiar with the concepts. I will list a few of the points that I found to be interesting after doing these assessments for a long time.

Tacycardia is a common problem in psychiatric patients and the population in general. Here the authors were focused on tachycardia as a side effect of SGAs and haloperidol.  They produced a table showing the incidence of tachycardia across a number of SGAs and haloperidol and illustrate that clozapine by far has the highest prevalence of tachycardia. In the table haloperidol, asenapine, and sertindole at the lowest incidence of tachycardia at about 1%. They point out this problem is generally self-limited but it suggests a number of investigations that should be considered before monitoring for improvement over time. The recommended treatments (bisoprolol, ivabradine) are not recognizable medications for physicians in the US. In the US, beta-blockers are commonly used. They suggested treatment is predicated on whether patients are symptomatic or not with palpitations. Although UpToDate describes sinus tachycardia as a benign condition with no worse outcome than a control group, this tachycardia is drug-induced. My main concern with persistent drug-induced tachycardia is tachycardia induced cardiomyopathy. My other concern is that common causes of tachycardia in the patients I see include excessive use of caffeine (alcohol, or other substances), deconditioning, and sleep deprivation. Establishing a baseline prior to any of these prescriptions is important.  There is always a lot of debate about whether or not electrocardiogram should be done. I agree with the authors that the ECG is an inexpensive screen and should be done to make sure that it is a sinus rhythm. Another bit of information that may not be available is whether the pulse is irregular or not. Many clinics have automatic blood pressure and heart rate measuring devices and not all of them make that determination.

The section on the QTc interval was interesting because the authors provide very clear guidance on measuring QTc, the problems with that measurement, and very clear guidelines on what to do about that measurement. They cite the threshold for stopping or reducing treatment with QTc prolonging agents as an interval greater than 500 ms or relative increase of greater than 60 ms. They also use the American Heart Association definitions of prolonged as QTc > 450 ms in men and > 460 ms in women.  They point out that the most common calculation of QTc (Bazett’s formula) overcorrects heart rates greater than 100 BPM and they suggest that other formulae may be used for that situation. Like many psychiatrists I have ordered hundreds of ECGs for determining baseline cardiac conduction. The vast majority have been normal. The ones that were not - were typically unrelated to the medication I was prescribing. Many conduction abnormalities were related to increasing age and latent cardiac problems. The other common scenario where I am concerned about cardiac conduction is polypharmacy. It is possible for a person to be taking multiple medications for psychiatric indications - all of which may affect cardiac conduction. The drug interaction software for most EHRs as a very low threshold for this type of interaction.

The myocarditis section of this paper was very interesting. In Table 1 - the authors included prevalence figures for myocarditis in the same table where they documented the prevalence of tachycardia for each medication. The figures are based on isolated case reports. The review the controversy about clozapine and widely variable reports of incidence. The incidence quoted for Canada and the USA was 0.03%. Different criteria used to diagnose myocarditis was considered an important point of variance. A set of clinical criteria is provided in the paper as well as when to refer to a cardiologist. In addition to the ECG, serum troponin, C-reactive protein, echocardiogram, and cardiac MRI are considered. The referral indicators included elevated troponin, CRP, and abnormalities at echocardiogram. My interpretation is that psychiatrists in the US who have access to those measures and ready access to cardiologists could potentially use those markers. The most reasonable approache is to be able to recognize the symptoms of myocarditis clinically and be able to refer the patient to cardiology were most of the testing could occur. The clinical description of myocarditis in the paper sounded very similar to typical viral myocarditis with chest pain, dyspnea, flu-like illness, fever, and fatigue. These are nonspecific symptoms especially during influenza season. The clinician has to have a high index of suspicion based on treatment with clozapine. The paper contains an ECG tracing of saddle -shaped ST elevation considered to be a finding consistent with myocarditis. It was visible in most leads.

The approach to dilated cardiomyopathy was very similar in terms of recognizing the symptoms of congestive heart failure and the necessary investigations. There was guidance and when to request an echocardiogram based on BNP and in NT-ProBNP measures as well as when referral to cardiology was indicated. The standard of care in the US is the psychiatrist recognizing what is happening but not treating dilated cardiomyopathy. In most clinical with limited resources, this is a good reason to have a referral relationship with a primary care clinic - especially one that can do the testing on site. There are many primary care and even urgent care clinics that cannot do the testing suggested in this paper.

In the case of myocarditis and dilated cardiomyopathy, the question of whether a patient should be re-challenged if they need the offending medication and their underlying cardiac condition has improved. The authors suggest close consultation with a cardiologist at that point. Given the data my own practice has been to not re-challenge with the offending medication but to try a different treatment modality. The concern in the article is that the patient’s ability to function from a psychiatric standpoint may require use of that specific medication. I do not think that enough is known about the outcome of either condition to resume the original medication, but if favorable outcome studies or case reports exist, I might revise that opinion.

All things considered this is an outstanding article on the cardiotoxicity of SGAs. The graphics in the paper also excellent with management flow diagrams and well-designed tables.  The authors restate that cardiotoxicity is very low.  It is the job of every psychiatrist who prescribes these medications and others to make sure that patients are monitored for these complications. There is always a question of what constitutes adequate informed consent when we are talking about a potential complication rate of 0.03%. At that level it is certainly possible that many psychiatrists have never seen these complications and never will. I think it is reasonable to let people know that medications they are taking can cause rare but potentially serious side effects including death. The informed consent issue was not touched on in the paper but a day-to-day practice it is an important one.  From a practical standpoint I generally advise people that if they are taking a medication with rare but potentially life threatening side effects, they have to take all physical symptoms seriously. Physical symptoms cannot be attributed to common explanations like colds, the flu, or gastroenteritis.

This paper had a very specific focus and it did not touch on the other metabolic and neurological complications of these medications that require additional screening.  One of the reasons I posted my ROS document on this blog was to make ti easy for any clinic or psychiatrist to build their own template with the relevant questions needed for their own patient population. 

For some psychiatrists and clinics the work in cardiac screening just got a lot harder.  For others who have been doing all of this for decades - there will be very little difference.

George Dawson, MD, DFAPA

References:

1:  Sweeney M, Whisky E, Patel RK, Tracy DK, Shergill SS, Plymen CM.  understanding and managing cardiac side effects of second-generation antipsychotics in the treatment of schizophrenia. Br J Psych Advances 2019: 1-15.

2:   Patel RK, Moore AM, Piper S, Sweeney M, Whiskey E, Cole G, Shergill SS, Plymen CM. Clozapine and cardiotoxicity - A guide for psychiatrists written by cardiologists. Psychiatry Res. 2019 Jul 24:112491. doi:10.1016/j.psychres.2019.112491. [Epub ahead of print] Review. PubMed PMID: 31351758.

Recent Opinion About Diagnostic Heterogeneity – Gets It Wrong

There was an opinion piece about categorical diagnosis in psychiatry and diagnostic heterogeneity that was published in Psychiatric Research weeks ago (1), that generated a lot of controversy.  The controversy started when an online publication characterized the article as showing that Psychiatric Diagnoses Found to Be "Scientifically Meaningless".  The author of that article subsequently posted that the article was written by science undergraduates re-purposed as science writers.  If this was supposed to be investigative journalism it failed at several levels not the least of which is the apparent conflict of interest by the authors. Instead the internet article basically quotes the authors as factual and scientific rather than a rhetorical opinion piece.  What follows is my take on the Psychiatric Research Article.

The first sign of bias that a reader may encounter in the original article is right in the abstract. The concluding sentence reads:

“A pragmatic approach to psychiatric assessment, allowing for recognition of individual experience, may therefore be a more effective way of understanding distress than maintaining commitment to a disingenuous categorical system.” (my emphasis added).

When I read this sentence, it was difficult for me to believe that peer reviewers for a psychiatric journal could allow it to pass. In one sentence the authors are allowed to distort and discredit psychiatric clinical methods and diagnostic methods that have been carefully developed for over a century.  I won’t belabor the definition of “disingenuous” but it is safe to say that the expenditures in terms of brainpower and money as well as the transparency of the process make the production of the DSM 5 one of the more rigorous approaches to a diagnostic system in medicine. The people sitting on the DSM 5 committees for each section were acknowledged experts in their fields with decades of experience and published research.  Production of the DSM-5 was also a multiyear process that took 14 years to develop prior to its publication in 2015 (2).  During that time there was a multiyear grant that sponsored 13 international conferences on specific diagnostic issues.  Guiding principles and conceptual issues were examined.  Public input was solicited. Hundreds of clinicians and researchers were involved.  There was transparency about potential conflicts of interest. It was not just an intense effort – it was a unique diagnostic effort in terms of overall vigor and resource utilization.   Describing the output of all of this work as “disingenuous” and getting that in print lead me to question the peer review and editorial process.  Are the editors and reviewers ignorant of the effort that went into the diagnostic categories or don’t they care? It is clear that the authors of this article don’t.

The second red flag in the paper to anyone familiar with typical antipsychiatry arguments is the mention of Foucault and the suggestion that psychiatric classification occurs within wider sociocultural developments and that these roots have resulted in diagnostic heterogeneity.  In fact, Foucault’s observations of psychiatry were inaccurate at the time and have not held up at all over the course of time. The authors seem to ignore the actual reasons for categorical diagnosis in the first place and list none of those references.  Practically all modern DSM work can be traced back to the reference generally referred to as the Feighner criteria (3).  Reading those papers, clearly describes categorical diagnosis as a work in progress and the importance of diagnosis. The authors also describe five phases for the validation of psychiatric diagnoses.  They have this comment on diagnostic heterogeneity:

“In the absence of known etiology or pathogenesis, which is true of the more common psychiatric disorders, marked differences in outcome, such as between complete recovery and chronic illness, suggests that the group is not homogeneous. This latter point is not as compelling in suggesting diagnostic heterogeneity as is the finding of a change in diagnosis. The same illness may have variable prognosis, but until we know more about the fundamental nature of common psychiatric illnesses, marked differences in outcome should be regarded as a challenge to the validity of the original diagnosis.” p 57.

These authors suggested 5 phases to establish the diagnostic validity of psychiatric illness including the clinical description, laboratory studies, delimitation from other disorders, follow-up studies, and family studies.  There are entire texts dedicated to some of these markers on epidemiology and family studies.  One of the mandates of the DSM-5 committees was to review all of this data and compile it into the most clinically useful form.  In the interim they happened to pare the total number of diagnoses from a maximum of 297 in DSM-IV to 157 in DSM-5 (see reference 2, p xxiii).  This is the basis of categorical diagnosis – not the narrative of a philosopher.

Contrary to the idea that the current authors and the like-minded authors they have referenced have discovered diagnostic heterogeneity it has been widely acknowledged from the outset and by all current psychiatrists. There are no surprises here especially for people trained as physicians. Practically every complex biological illness is heterogeneous with heterogeneous outcomes as well as polygenic etiologies.  Their Foucauldian criticism also ignores the fact that the Washington University group was based on empirical research as opposed to the psychoanalytic process of the day.
 

The example of the empirical approach is illustrated by tracing the development of Major Depression criteria from 1950 to 1980. In fact, many in that group were highly skeptical of psychoanalysis as a possible diagnostic process at all. As they started to publish research article, one of their original articles was highly edited by a psychoanalyst/editor to remove any reference to the term diagnosis. 

The second acknowledged aspect of psychiatric diagnosis and treatment that is given short shrift by the authors is the issue the value of both diagnosis and formulation or as Kendler, et al discuss:

“However, neither we nor, we think, the developers of the criteria would claim that assessing operationalized diagnostic criteria is all there is to a good psychiatric evaluation. While critical, a diagnosis does not reflect everything we want to know about a patient. Our diagnostic criteria, however detailed, never contain all the important features of psychiatric illness that we should care about.” (see reference 4 p. 141.)

The authors’ research method is an exercise in subjectivity.  They basically read five chapters in the DSM 5 (schizophrenia spectrum and other psychotic disorders, anxiety disorders, bipolar and related disorders, trauma and stressor related disorders, and anxiety disorders) and use a technique called “thematic analysis” “to code themes or patterns of meaning across diagnostic categories being analyzed, with a particular focus on the heterogeneity or differences across types of diagnostic criteria.”  You don’t need an advanced research seminar to figure out what is wrong with that picture. Here is a group of psychologists several of whom make a career out of criticizing psychiatry and who are building a case that psychiatric diagnoses are inferior to their own vague diagnostic system using a qualitative technique that even their reference (5) refers to as having “no particular kudos as an analytic method – this, we argue, stems from the very fact that it is poorly demarcated and claimed, yet widely used”.  What outcome would any objective observer expect?

The combinatorics argument:

The authors make it seem like large combinations of diagnostic features mean categorical diagnoses are problematic.  Although they don’t say it explicitly - referring to more diagnoses greater than the number of stars in the solar system - suggests improbability.  But do large combinations of number preclude reasonable human use?  A chess board for example has an 8 x 8 square configuration and by some estimates - 10¹³⁷ moves are possible.  And yet players at all levels seem to be able to negotiate a chess board and determine win, lose or draw.  Master players can develop strategies that make them more likely to win.  Is there similar evidence that diagnoses with large combinations can be managed the same way?  What follows is a mixed table of a psychiatric diagnosis (PTSD) that yields a large number of combinations of diagnostic criteria on the left, a dimensional scale for depression (DEP) from a standard psychological test (MMPI), two different criteria for systemic lupus erythematosus (SLE), and criteria for asthma. Qualifiers for each column are listed at the bottom.

Disorder	PTSD (1)	MMPI-DEP (2)	SLE (ACR) (3)	SLE (SLICC) (4)	Asthma (5)
Criteria	Presence of 1 (or more) of the following symptoms: 1. 2. 3. 4. 5. One or both of the following symptoms: 1. 2. Two (or more) of the following: 1. 2. 3. 4. 5. 6. 7. Two (or more) of the following: 1. 2. 3. 4. 5. 6.	15/26 items	4 of 11 criteria: 1. 2. 3. 4. 5. 6. 7.   A or B 8.   A or B 9.   A or B 10. A or B or C or D 11. A or B or C or D or E	4 of 17 criteria including at least 1 clinical criterion and 1 immunologic criterion; or biopsy proven lupus nephritis: 1.   A or B 2.   A or B 3.   4.   A or B 5.   A or B 6.   A or B 7.   A or B 8.   A or B 9.   10. A or B 11. 12. 13. 14. 15. 16. A or B 17.	1. A or B or C or D 2. A1 or A2 or A3  or B or C
Minimal Combinations	3,150	7.726160e6	330	2,380	36
Total Possible Combinations	636,120	7.726160e6 + 5.311735e6 + 3.124550e6 + 1.562275e6 + 657800 + 230230 + 65780 + 14950 + 2600 + 325	12,555	321,489	46

Footnotes:

1.  This column is from the reference: Galatzer-Levy, I.R., Bryant, R.A., 2013. 636,120 Ways to have posttraumatic stress disorder. Perspect. Psychol. Sci. 8, 651–662.

2.  I have several opinions from different psychologists on the current use of this MMPI scale and the raw cut-off scores. I understand that there are different raw scores for men and women. I can recalculate this scale based on any numbers that may be deemed more reliable. Just email them to me along with the evidence.

3.  American College of Rheumatology (ACR) classification criteria for Systemic Lupus Erythematosus

4.  Systemic Lupus International Collaborating Clinics (SLICC) proposed revised classification criteria for Systemic Lupus Erythematosus

5.  There are numerous endophenotyping classifications for asthma.  It is clear at this point there is no comprehensive system of clinical classification.

What can be observed from this table?   

Apart from waxing poetically they seem to not recognize that common psychological approaches scale to an even larger extent – much greater than 10¹⁸. I have also demonstrated that the way diagnostic criteria are worded makes a big difference in counting word combinations.  Just using the DSM phrasing “or more” greatly increases the number of combinations.  Criteria designed like the SLE criteria as a series of “A or B” choices that greatly reduce the number of possible combinations.  On the other hand dimensional criteria like a single scale from a popular psychological test – greatly increases the number of possible combinations because that scale is a many n and many k.  Using a 15/26 item scale results in 10⁷ combinations.  Using that as a ball park estimate for the other clinical scales results in numbers far larger than used by the authors to criticize categorical diagnosis.  The other aspect of this table is that less combinations is not necessarily better. With asthma for example, these numbers are based on very basic diagnostic criteria.  There are at least 2 other 6 item endophenotype systems and an additional cough variant asthma, but currently experts in the field have not developed a way to incorporate that level of clinical complexity into diagnostic criteria that would be useful to clinicians. Low number of combinations of diagnoses criteria are not necessarily better than higher numbers – especially when the disease complexity is not captured.  

The second issue with combinatorics is that they are not predictive of anything. Great strides in treating post-traumatic stress disorder have occurred in the past 30 years using criteria with a high number of combinations.  That obviously does not preclude patient selection or monitoring in clinical trials of either psychotherapy or pharmacotherapy. It does not prevent the successful diagnosis and treatment of patients in clinical settings in many cases where severe and potentially fatal psychiatric illness exists.  As an example, delirious mania had a fatality rate of 75% in 1849 in the United States (7). That number has fallen to zero with psychiatric treatment based on categorial diagnosis and the clinical training of psychiatrists to recognize severe illness. Many of those improvements have occurred in the past 30-50 years. 

  

In the authors selection strategy, large sections of the DSM 5 that clearly disprove the author’s contentions are omitted. The elimination of Neurocognitive Disorders, Sleep-Wake Disorders, and Substance Related and Addictive Disorders for example also eliminates biological markers and autopsy validation of criteria of diagnoses.  Table 1 (p. 482 of DSM-5) contains 127 discrete categorical diagnoses across 10 categories of substances. 

But the larger misunderstanding here is that what the authors disparage as heterogeneity is an expected part of medicine. Every physician knows that no two patients with asthma, benign prostatic hypertrophy, or gout are the same. There are a collection of illness features with some overlap but no truly homogeneous categories – even in clinical trials that attempt to minimize it. Biological systems especially the brain are designed to scale in various ways including based on combinatorics of various biological elements.  The author’s use of the term quadrillion, happens to be the estimated number of synapses in the brain but that is just a starting point of how systems in the human brain can scale.  The endothelial system in the human body has more cells than the brain and massive heterogeneity that allows for regulation of the vascular beds the human body. The hematopoietic and immune systems have similar levels of scaling that could also result in very large number of combinations. In none of these cases do the number of combinations of cell types, connections, tissue behavior, or descriptions preclude diagnoses, research or treatment.  A very small sample of this heterogeneity is suggested by the table below.  

Heterogeneity In Normal Functioning And Disease States In Human Biology (very partial list)

Endothelial cells	Diabetic nephropathy
Hematopoietic Stem Cells	Hepatitis C virus
Neuroendocrine Neoplasms	Ischemic Stroke
Leukemia - Clonal and Intraclonal cell types	Prostate Cancer
Aphasia syndromes	Mitochondrial Myopathies
Atrial Fibrillation Syndromes	Asthma
Immunodeficiency syndromes	Coriticobasal Degeneration
Diabetes Mellitus Type I and II	Viral Syndromes
Congestive Heart Failure	Cryptospridium genus and species

The authors ignore clinical heterogeneity that physicians have to address in their patients every day.  Very few physicians see clinical trials subjects as patients requesting assistance. That means comorbid physical illnesses, variations in patient tolerance of medical and psychological interventions, pharmacokinetic and pharmacodynamic factors, heart disease, liver disease, renal disease, substance use disorders, traumatic brain injuries, old age, pediatric age, suicide risk, aggression risk, impaired functional capacity, and even pregnancy have to be addressed in patients being seen every day by psychiatrists and adjustments have to be made. Only physicians schooled in heterogeneity would be able to treat those people.  Only physicians schooled in heterogeneity would realize that the people in clinical trials are rarely the people being seen in the office.  

In conclusion, the authors have a poor understanding of diagnostic heterogeneity and why it is a central part of medicine.  Some of their arguments are similar to arguments offered up by the critics of Kraepelin in the early 20^th century.  Other arguments - like the combinatorial ones reflect a poor understanding of biological systems and how they scale as well as a lack of understanding of medicine. Physicians know for example that diagnostic models are not completely explanatory, that over time - the explanations change, but that science exists at some level of that explanation or treatment. That is the nature of biological as opposed to physical systems. Anyone interested in these issues can find a rich literature out there that describes these problems and even the involved philosophy. Unfortunately, only one of the authors referenced (out of 28) is written by anyone authoritative in that area.

The only disappointment greater than an article like this being published is the fact that it was published in the journal Psychiatric Research.  It has little to do with psychiatry or research and it is shocking that the obvious problems with article were overlooked. On the other hand, this journal was never at the top of my reading list and this may be why.

George Dawson, MD, DFAPA

References:

1: Allsopp K, Read J, Corcoran R, Kinderman P. Heterogeneity in psychiatric diagnostic classification. Psychiatry Res. 2019 Sep;279:15-22. doi: 10.1016/j.psychres.2019.07.005. Epub 2019 Jul 2. PubMed PMID: 31279246.

2:  Black DW, Grant JE.  DSM-5 Guidebook. American Psychiatric Publishing, Arlington, VA: pp 543.

3: Feighner JP, Robins E, Guze SB, Woodruff RA Jr, Winokur G, Munoz R. Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry. 1972 Jan;26(1):57-63. PubMed PMID: 5009428.

4: Kendler KS, Muñoz RA, Murphy G. The development of the Feighner criteria: a historical perspective. Am J Psychiatry. 2010 Feb;167(2):134-42. doi: 10.1176/appi.ajp.2009.09081155. Epub 2009 Dec 15. PubMed PMID: 20008944.

5: Braun, V., Clarke, V., 2006. Using thematic analysis in psychology. Qual. Res. Psychol. 3, 77–101. https://doi.org/10.1191/1478088706qp063oa.

6: Kendler KS, Engstrom EJ. Criticisms of Kraepelin's Psychiatric Nosology: 1896-1927. Am J Psychiatry. 2018 Apr 1;175(4):316-326. doi: 10.1176/appi.ajp.2017.17070730. Epub 2017 Dec 15. PubMed PMID: 29241358.

7: Bell, L., 1849. On a form of disease resembling some advanced stage of mania and fever. Am. J. Insanity 6, 97–127.