NEJM Case: Brain, Heart, and Parsimony

Cardiology factors prominently in psychiatry and psychiatric care. I have been fortunate on many occasions to work with psychiatrists who were also cardiologists and to have access to outstanding cardiologists as consultants. That gave me a great appreciation for what was possible in the detection treatment of cardiac problems. It also help me appreciate the importance of treating psychiatric disorders in patients with cardiac problems. The recognition that some medications can cause problems and the need for ECG screening was another change in psychiatric practice. Prior to that knowledge, there were some medications that delayed cardiac conduction to the point that they are no longer used.

One of the commonest scenarios I currently see is at the interface of anxiety and the effect it has on the heart. About 20 to 30% of the people I see have severe anxiety and panic attacks. About two thirds of them have made at least one trip to the emergency department because they thought they were experiencing a heart attack. They are generally young people with limited cardiac risk factors. When I asked them about the symptoms that led them to the ED, the most common answer is “my heart was pounding out of my chest and I thought I was having a heart attack”. Palpitations are another common symptom. They are harder to get at and people who have talked to cardiologists are better at describing them. I demonstrate by making an irregular thumping noise on my chest with my hand to indicate what it might feel like. The associated symptoms of panic attacks like swelling, lightheadedness, dizziness, chest tightness, shortness of breath, hyperventilation, and dizziness all reinforce the thought of a heart attack. Once the ED staff determine the patient is having a panic attack the way they are educated is critical in reducing ongoing symptoms. But that is another story.

An associated symptom in anxiety is what I like to call “cardiac awareness”. It happens in anxious people whether they have an anxiety disorder diagnosis or a stressor making them anxious. Laying in bed at night waiting to fall asleep many people can sense their heart beating without taking their pulse. They can sense other pulse points in the body and frequently they can sense large pulsations. This is a normal physiological process but anxiety can lead to a focus on it. I also lead to attaching other meetings to it such as the occasional palpitation is seen as evidence of heart disease leading to increased anxiety. In that situation it becomes very difficult to sleep leading to more anxiety and frequently - a faster heart rate the next day.

Cardiac pathology can compound the problem because there are various conditions like atrial fibrillation that can lead to people paying much more attention to their heart rate and rhythm. Atrial fibrillation is interesting in that regard because there are two management strategies. In a rate control strategy the person is given a medication to generally keep their heart rate less than 100 bpm but the rhythm could still be irregular and experienced as frequent palpitations. In a rhythm control strategy the person is either given a medication or treatment to maintain a regular sinus rhythm and palpitations would be much less frequent to nonexistent. Current thinking on treating atrial fibrillation is that the outcomes of both strategies are equivalent in terms of mortality but that patients with a rhythm control strategy rate themselves as having a higher quality of life.

That brings me to the New England Journal of Medicine case listed in the references below.  This case continues a recent trend in incorporating more psychiatric expertise into these cases with psychiatrists as discussants. The patient was a 62-year-old man with depression and anxiety. The depression dated back 15 years with onset after he learned that his wife had cancer. His wife eventually died. Whichever psychiatrist are about seven years and eventually found that citalopram and clonazepam are effective. He continued with his primary care physician and eventually discontinued the citalopram. He was seen by one of the discussants due to recurrent anxiety depression and lethargy. Vital signs were noted to be abnormal with an irregular pulse of 130 bpm blood pressure 108/75. An ECG was done that showed new onset of atrial fibrillation. 

Echocardiography showed an enlarged left atrium and left ventricle, low normal LV ejection fraction, mild left ventricular hypertrophy, and no valvular disease. The subsequent ECG showed a prolonged QTc interval of 466 ms. At a subsequent visit he had an additional significant stressor also had started to binge drink. At that time he had weekly panic attacks that correlated with increased alcohol intake. When he was seen in the psychiatric clinic had weekly panic attacks that consisted of “racing heart, lightheadedness, restlessness, shaking, and generalized weakness and so the episodes lasted for several hours. A family history of depression and suicide was noted. He was noted to be drinking 4 to 6 standard drinks per week with occasional binges. Aripiprazole was added to the clonazepam and citalopram.

The patient subsequently had a near syncopal episode three weeks later I was noted to be hypertensive and tachycardic. The ECG showed atrial fibrillation and sinus pauses of six and seven seconds. A permanent pacemaker was placed in the metoprolol was discontinued.

He was noted to be improved on the psychiatric medication changes but the metoprolol is discontinued because of fatigue. Three weeks later he had increasing anxiety and the feeling that his heart was racing and “thumping” in his chest and that he was excessively worried. They aripiprazole was increased at that time.

Like most of these cases there is a differential diagnosis exercise included and the discussant in this case is a psychiatrist.  The exercise focuses on the fact that the central symptoms in this case-anxiety, palpitations, racing heart, restlessness, and fatigue are not specific for cardiac or psychiatric diagnosis. In fact all DSM diagnoses included criteria to rule out any medical causes of the syndrome. In this case all the usual suspects are discussed. From the medical side hyperthyroidism, return atrial fibrillation, dilated cardiomyopathy, Torsade de pointes, and rare medical causes are discussed. The duration of the patient’s symptoms rules out a lot of the acute causes. From psychiatric standpoint panic disorder, substance intoxication, and substance withdrawal were the primary considerations. The discussant Dr. Chen uses the term that we don’t hear enough of lately and that is parsimony specifically “The best diagnosis would parsimoniously explain the patient’s symptoms and the time course of his illness”. He concludes that there is a clear correlation with discontinuing metoprolol and experiencing recurrent atrial fibrillation.

From a cardiology standpoint the decision was made to improve rhythm control with sotalol and the rationale for choosing that agent was provided. He experienced a decrease number of episodes of atrial fibrillation that he was correlating with anxiety.

The discussion highlights the correlation of anxiety with atrial fibrillation. That anxiety is a product of experiencing the palpitations and also can be an etiological factor in the episodes of atrial fibrillation. Depression and anxiety also predict who experiences more severe symptoms of atrial fibrillation. Patient medications also discussed in terms of the prolonged QTc interval. The authors comment on the FDA warning about QTc prolongation with higher doses of citalopram. They point out that although citalopram prolongs QTc interval more than other antidepressants there is little evidence that it leads to torsade de pointes or sudden cardiac death. They also point out that the literature shows that when this warning led to decreasing the dose of citalopram the result was no worsening of cardiac outcomes but less than optimal psychiatric outcomes including more frequent hospitalizations and increased sedative hypnotic prescriptions.

Overall this was an excellent discussion of the cardiology-psychiatry interface. Psychiatrists are likely to see increasing numbers of patients with atrial fibrillation. I currently see number of patients who are taking multiple cardiac medications. Any patient with this degree of complexity it is important to discuss the possibilities in order to determine the likely sequence of events. In patients with cardiac risk factors who are hypertensive and appear to be describing panic attacks caution is necessary to make sure that there are no underlying cardiac conditions that need to be attended to. As illustrated in this case I have seen patients with severe panic attacks (but no atrial fibrillation) due to the abrupt discontinuations of metoprolol. In patients who have recently discontinued antihypertensive therapy and have panic attacks - clarifying whether there has been any exposure to beta blockers is important.  

Another relevant factor in this patient's demographic is that the sympathetic tone of the peripheral nervous system in humans seems to increase with age. That may predispose older populations to tachycardia, palpitations, hypertension, and anxiety either directly or indirectly by experiencing the cardiac symptoms.

Being able to make an assessment and determination of patient stability, whether or not they need urgent care, what further testing is needed, and what further referrals are necessary is a skill that every psychiatrist should have.

George Dawson, MD, DFAPA

Reference:

1: Chen JA, Ptaszek LM, Celano CM, Beach SR. Case 9-2019: A 62-Year-Old Man with Atrial Fibrillation, Depression, and Worsening Anxiety. N Engl J Med. 2019 Mar 21;380(12):1167-1174. doi: 10.1056/NEJMcpc1900140. PubMed PMID: 30893540. Full Text

See also for the critical references in this case.



Graphics Credit:

The human heart line drawing in the above graphic is from Shutterstock per their standard agreement.

More On Takotsubo

I posted previously on Takotsubo cardiomyopathy and an association with antidepressant therapies.  That occurred in the context of a patient with the condition that I recently treated.  At times when there is a condition that is prominent on your mind and you tend to notice it immediately as you review the literature.  In this case I noticed it in the New England Journal of Medicine as this weeks Case Records of the Massachusetts General Hospital.  If you plan on reading the case - please do that first before reading the summary that follows. Like most of these cases it is a textbook description of the way experts should think about complicated diagnoses.  I will naturally focus on what I think are the high points for psychiatrists.

The patient described was a 55- yr old woman with a history of thyroid cancer but no other chronic illnesses.  She had a history of Stevens-Johnson syndrome from cefadroxil.  She was did not smoke, drink, or use other intoxicants.  She was married and employed.  Four months before the index episode she was jogging and had pounding in the chest, diaphoresis, and nausea for about 40 minutes.  She was seen in a local ED and a mildly elevated troponin [0.055 ng/ml] that increased at 11 hours 0.415 ng/ml] , 4 normal ECGs, normal echocardiogram, and normal coronary angiogram.  A subsequent MRI scan was done and was normal.  The presumptive diagnosis was exercise related supraventricular tachycardia.  She was prescribed a beta blocker and ASA and discharged.

She resumed jogging and eventually stopped the beta blocker.  Four months later while skiing, she developed palpitations, dyspnea and weakness. she was assisted off the mountain, but developed nausea, emesis, chest pain, and shortness of breath.  In the local emergency department she was tachycardic, tachypneic, and normotensive. Her oxygen saturation was 84% on room air.  Troponin I [11.000 ng/ml] and N-terminal- pro-B-type natriuretic (NT-proBNP) [15,159 pg/ml] levels were elevated.  Bedside cardiac ultrasonography showed severe left ventricular dysfunction with apical ballooning.  She was transferred to a tertiary care center for suspected cardiogenic shock.  At that center she was noted to be critically ill and received all of the measures necessary to treat the shock including mechanical ventilation and pressors alternating with antihypertensive treatment episodes. A left ventricular assist device (LVAD) was placed. She was subsequently transferred to MGH.

There she was noted to need continued need for treatment of heart failure.  Infectious agents for myocarditis were ruled out.  Femovenoarterial extracorporeal life support was added to improve cardiac output and also because the LVAD was causing significant hemolysis.  The patient's cardiac status improved on day 3 and an endomyocardial biopsy was done when the extracorporeal life support was removed.  That biopsy was consistent with myocardial injury, myocardial toxicity, mechanical stress and treated myocarditis.  Acute myocarditis was ruled out.

A clinical diagnosis of takotsubo (stress) cardiomyopathy was made.  A consultant discussed the limited differential diagnosis of apical ballooning not associated with coronary artery disease and the associated etiologies as:

1.  Recurrent apical ballooning syndrome
2.  takotsubo cardiomyopathy
3.  Acute myocarditis
4.  Coronary vasospasm
5.  cocaine induced coronary vasoconstriction
6.  thrombosis with endogneous fibrinolysis before angiography

Several etiologies (1,2,5) may depend on similar hypersympathetic mechanisms caused by exercise, neuropsychiatric disorders,  psychiatric medications, or intoxicants causing catecholaminergic effects.  Takotsubos was described as an increasing cause of acute non-ischemic cardiomyopathy in patients admitted with acute chest pain syndromes.  In one series the disorder accounted for 7.5% of all admissions with acute chest pain.  Eventually the patient is diagnosed with pheochromocytoma as the cause for takotsubos, the adrenal tumor is resected, she regains normal cardiac function and her recovery is uncomplicated.  The staff at MGH has done another outstanding job of solving a complex medical problem and saving a crtically ill patient.

How does all of this apply to psychiatrists?  I am sure that there are some people out there who are irritated just to see a psychiatrist talking about medicine.  Well I will tell you:

1.  Cardiotoxicity of catecholamines: 

I think we have been lulled into thinking that anxiety and even panic attacks won't kill you so why worry about that patient with elevated vital signs or persistent tachycardia that won't go away?  Granted - very few of those people will develop takotsubos and even fewer will have a pheochromocytoma.  I have treated several people with takotsubos and none with a pheochromocytoma - so if I had to guess I would say the cardiomyopathy is much more common in clinical practice.  Once you know that vitals signs (including pulses) need careful monitoring and caution needs to be exercised if medications are being added that might add to the catecholaminergic burden.

Over the years I have encountered very many patients with persistent tachycardia and otherwise normal electrocardiograms showing sinus tachycardia. The general sequence of events at that point it to assess for causes of the tachycardia and obtain Cardiology consultation to look for inappropriate sinus tachycardia and suggest treatment if that condition is found (2).  Persistent tachycardia can lead to left ventricular hypertrophy and cardiomyopathy but that is typically rare.

I have discussed these cases with many Cardiology consultants who tell me that sinus tachycardia is "not normal" there are just no guidelines about what to do about it, especially if there is no obvious cause.  Using beta-blockers just to treat tachycardia seems like an arbitrary decision on their part based on whether the patient experiences any distress from palpitations.  Psychiatrists use beta-blockers for the same indications as well as the physical manifestations of performance anxiety.   

2.  Monitor vital signs, troponins and get timely Cardiology assessments: 

You might find yourself in an environment where you have to go the extra mile to get help from medicine or cardiology.  I found myself in a situation with patients who had chest pain and instead of transfer to medicine the decision was made to keep the patient on the psychiatric unit and measure troponins.  That is the main reason I included the troponins in the above summary.  Even the mildly elevated and trending higher troponins may be an indication of some type of milder myocardial damage. It might even be useful to discuss with the consultant that takotsubo might be a consideration.

3.  Potential risk factors for takotsubos should be considered in all patients who are assessed:

From the list in the differential there are a wide range of catecholaminergic insults that psychiatric patient may incur including prescription and street stimulants (amphetamine, methamphetamine, cocaine, synthetic cannabinoids, JWH compounds, synthetic psychedelics), antidepressant compounds and atomoxetine, intoxication and withdrawal states (3), sleep deprivation, seizures (4) and physiological factors like extreme physical or emotional distress. It is very common to see one or more of these factors present during patient assessments and in that case, a cardiac review of systems should be done.  I am cautious to not start a new drug with potential cardiac side effects until sinus tachycardia has resolved.

4.  A diagnosis of takotsubos needs to be considered in the discharge plan:     

In today's treatment environment of getting people out of the hospital as soon as possible or not admitting them in the first place acute stress induced cardiomyopathy takes on a different meaning.  In the NEJM case, the patient had the unexpected burden of catecholamines from a pheochromocytoma that had obvious toxicity on cardiac function and she recovered uneventfully once definitive treatment was completed.  What if you are a treating psychiatrist and you know your patient has this diagnosis?  The decisions that need to be made include discontinuing any potentially toxic psychiatric medications and preventing damage from other sources of catecholamines.  This is relevant if it is highly likely that the patient will be in a stressful environment or is highly likely to use some of the toxic medications.  The discharge plan needs to be modified accordingly.

That is my proactive approach to sinus tachycardia and takotsubos when it is identified.  It should be apparent that I do not take a passive stance when it comes to potential medical problems in my patients, especially when it directly affects psychiatric care and the recommended treatment plan. You don't have to be an expert in ECG or managing complex cardiac conditions but you do have to recognize when your patients health status is compromised. Saying that there has been "medical clearance" by another physician is not enough.  This approach does help define the medical skill set that every psychiatrist needs to possess. In these cases knowledge of basic cardiac conditions, basic ECG skills, and how the medical and psychiatric treatment plans need to be modified is a requirement.


George Dawson, MD, DFAPA


References:

1:  Loscalzo J, Roy N, Shah RV, Tsai JN, Cahalane AM, Steiner J, Stone JR. Case 8-2018: A 55-Year-Old Woman with Shock and Labile Blood Pressure. N Engl J Med. 2018 Mar 15;378(11):1043-1053. doi: 10.1056/NEJMcpc1712225. PubMed PMID: 29539275.

2: Homoud MK.  Sinus tachycardia: Evaluation and management.  Piccini J Editor. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on March 18, 2018.)

3: Spadotto V, Zorzi A, Elmaghawry M, Meggiolaro M, Pittoni GM. Heart failure due to 'stress cardiomyopathy': a severe manifestation of the opioid withdrawal syndrome. Eur Heart J Acute Cardiovasc Care. 2013 Mar;2(1):84-7. doi: 10.1177/2048872612474923. PubMed PMID: 24062938.

4: Kyi HH, Aljariri Alhesan N, Upadhaya S, Al Hadidi S. Seizure Associated Takotsubo Syndrome: A Rare Combination. Case Rep Cardiol. 2017;2017:8458054. doi: 10.1155/2017/8458054. Epub 2017 Jul 24. PubMed PMID: 28811941.




Graphics Attribution:

"Levocardiography in the right anterior oblique position shows the picture of an octopus pot, which is characteristic for Takotsubo cardiomyopathy."

Hammer N, Kühne C, Meixensberger J, Hänsel B, Winkler D. Takotsubo cardiomyopathy - An unexpected complication in spine surgery. Int J Surg Case Rep (2014). Link Used per open access license.

Conventions:

There does not appear to be a consensus on the spelling of takotsubo and whether or not it should be capitalized or not.

The NEJM Depressed and Recovered Surgeon Commentary

In the March 1, 2018 edition of the New England Journal of Medicine is the story of a surgeon and told by that surgeon about lifelong depression and severe depression that required both involuntary treatment and electroconvulsive therapy.  The essay has been widely hailed on Twitter and elsewhere as a story that illustrates the problems in medicine as well as problems when physicians develop mental illnesses and need treatment.

The first few paragraphs are written in an interesting style reminiscent of one of my all time favorite books Zen and the Art or Motorcycle Maintenance (ZAMM) by Robert M. Pirsig.  In that book. Pirsig details a very personal and spiritual journey on a motorcycle trip across the northern USA from Minnesota to California.  He describes his journey through life at that point including his academic failures and accomplishments.  He talks about the relationships with the people on the trip including his son, another couple, and the friends they are scheduled to meet along the way.  He explores Eastern and Western philosophy and discusses personal difficulties that he has had along the way, including a psychiatric admission to a hospital and a series of electroconvulsive therapy (ECT) that left him delirious, confused, and obliterated a previous alter ego - Phaedrus. Much of his discussion focuses on threads he recalls about Phaedrus and the problems he encountered.

I started reading this book when I was in the Peace Corps in about 1976.  I say started because if you are like me and many other people - this book had a profound effect on you and you kept reading it.  I was reading it a decade before I finally became a psychiatrist.  I was discussing it with enthusiastic fellow Peace Corps volunteers - very energetic and bright people.  Like a lot of people, I look back on that as a very exciting part of my life.   I really don't have any regrets and don't miss those days.  I can still recall them with a great deal of excitement.  When people ask me what I got out of the Peace Corps - I always tell them that meeting and relating to the people I was with was the best part of the experience.  ZAAM  was part of that for me and it still is.

My first read through the book was chilling when I read the passage about ECT:

"He (Phaedrus) was dead. Destroyed by order of the court, enforced by transmission of high-voltage alternating current through the lobes of his brain. Approximately 800 mills of amperage at durations of 0.5 to 1.5 seconds had been applied on twenty-eight consecutive occasions in a process known technologically as "Annihilation ECS." A whole personality had been liquidated without a trace in a technologically faultless act that has defined our relationship ever since.  I have never met him. Never will."

Reading about it later confirmed that Pirsig had been hospitalized and treated with ECT.  He was misdiagnosed with schizophrenia and eventually diagnosed with depression.  He apparently had more than one course of ECT.  I thought about Pirsig's description of ECT in ZAAM.  The ECT would have happened about a decade before he wrote the book.  In many biographic pieces, Pirsig is described as having a genius IQ, high in that range.  He wrote a book that some reviewers equated to Moby Dick  - commonly seen as one of the greatest American novels.  After the book he moved from his job as a technical writer to an academic and was in the English department at the University of Minnesota for a number of years.

I thought about the description of ECT a lot as I learned it as a resident and referred many patients to our ECT consultants for treatment.  In one of the very first cases, I saw a patient depressed and completely immobilized in a coronary care unit by severe depression.  He was unable to eat and he was dying.  In those days we had few medications that we could safely give him and even they would not work fast enough.  When he consented to ECT, he got significantly better, started eating and within two weeks was back home.

Dr. Weinstein's article is a more matter-of-fact presentation. The Pirsig paragraph is a little dramatic and obsessive.  I can speculate on what happened during the ECT treatment and what happened to Phaedrus, but I won't.  Another element barely mentioned but easily overlooked in both pieces is that treatment was involuntary.  Both patients were ordered by a court to be in a hospital and accept the treatment offered.

Going into my career as a psychiatrist, it is common to have reservations about both ECT and involuntary treatment.  You don't have a lot of time to think about it because of the illness severity of the people you are treating.  In my career on inpatient settings it was common to be seeing people who had attempted suicide or homicide and barely missed completing the act.  I have treated many people who were admitted to hospitals because they had killed someone due to a severe mental illness.  I have also been called years after leaving a clinical setting to be informed about the suicide or homicides committed by patients that I had treated.  An even larger group of patients required treatment because they were unable to function and they were starving to death, not able to take care of their medical needs, or had judgment so poor that they were at high risk of accidental injury or death.  The only way any of these patients got better was with medical treatment by psychiatrists including antidepressants, antipsychotics, lithium, and electroconvulsive therapy.

To those people who are thankful that Dr. Weinstein published his experience in the NEJM, I agree with that opinion.  But to me as an inpatient psychiatrist who saw all of the people that are too ill to be included in clinical trials of antidepressants and in many cases too ill to consent to treatment there is a much bigger lesson here.  That lesson is that involuntary treatment, antidepressant medication, mood stabilizing medication, antipsychotic medication, and electroconvulsive therapy all work.  If you are a person with a severe disorder, see a psychiatrist who prefers treating severe problems. If you are a concerned family member, make sure that involuntary treatment is an option.  If it is not, find out why the county you live in is not protecting the most vulnerable people in our society.

But most of all don't let the the media circus about whether antidepressants work or all of the problems with psychiatric medications throw you off.  Psychiatrists know what they are doing and they are good at their job.  Health care corporations and governments do their best to restrict access to psychiatrists but this current paper is evidence why this access is critical and needs to greatly increase.

Nobody should be disabled by severe depression.  Nobody should die from it. The only acceptable outcome is complete recovery of a stable mood and ability to function.       


George Dawson, MD, DFAPA




References:

1: Weinstein MS. Out of the Straitjacket. N Engl J Med. 2018 Mar1;378(9):793-795. doi: 10.1056/NEJMp1715418. PubMed PMID: 29490178.

2:  Robert M. Pirsig.  Zen and the Art of Motorcycle Maintenance.  Bantam Books, New York.  Copyright 1974 by Robert M. Pirsig, p. 77.


Graphic Credit:

The photo at the top of this post is downloaded from Shutterstock and licensed per their standard agreement.

HITECH Editorials in the NEJM...

Since my Labor Day message to colleagues dovetails so well with these editorials, I did not want to miss the opportunity to comment on them.  They appear to be written by people with policy interests in this information technology takeover of clinical medicine.  They are mildly critical but totally miss the mark on what a catastrophe this government roll out has been.  The question any taxpayer should ask is why any other outcome would be expected.  Software and network implementations world wide and at the level of the US government have led to colossal failures.  Multibillion dollar investments  that at some point were abandoned.  The only difference in this case is that the government is not the actual client.  The federal approach to health care - apart from the brief foray of FBI agents raiding physicians offices to see if they made any coding violations is to set up payments for proxies and let them hash things out with providers.  The primitive approach of marginal incentives that are really weighted as penalties is supposed to facilitate the whole mess.  The mess would get implemented either way if you ask me.  There are tens of thousands of executive and mid level health care executives chomping at the bit for a project like this to mismanage.  And they have mismanaged it well.  Government leverage makes it difficult to refuse.

The initial editorial by Washington and  co-authors (1) focuses on the success of getting hospitals and physicians on the electronic health record (EHR).  They present a graphic showing the steep increase in EHR use over the 2004 to 2015 decade.  The acute care hospital curve ends at essentially 98-100% for certified EHRs and office based practices are at 90%.  The article rightly points out that physicians have borne the brunt of the implementation and how physicians are frustrated by the lack of "actionable information generated by these systems".  The article discusses the need for the "seamless flow of electronic information" in a couple of places.  It describes how EHR could be useful in research.  It ends  on a vague note that there is still a lot of work to be done and maybe that will happen some day.

The second piece by Halamka and Tripathi (2) starts out on a more realistic note.  Top down implementation gave physicians inadequate tools and then blamed them for being reluctant.  Technically physicians were not reluctant because they did not have a choice.  In most systems, administrations made all of the purchasing decisions, overhyped the software, and let it be known that contrary opinions were never appreciated.  It was up to physicians to learn how to use the stuff no matter how time consuming it was.  They point out that some measures were enacted on top of the clinical workload that made the situation worse.  They include the longest sentence I have recently seen in a journal article but it does cite a fair number of the problems a lot of the problems:          

"Soon physicians were expected to provide high-quality and empathic care in a 12-minute visit while weaning themselves from paper-based workflows, entering the numerous structured data elements required for meaningful use, rolling out new HIPAA privacy notices, implementing security protections for new electronic data, learning and incorporating new ICD-10 billing codes, and convincing their patients to use patient portals and secure e-mail, all while avoiding safety and malpractice issues." (p 907).

At one point they make the argument that health care organization have moved to "value-based purchasing".  Was that applied to the EHR?  Is there anyone today who would suggest that any EHR that is currently sold in this country is a value based proposition or is there as a result of HITECH legislation?  In their conclusion they suggest that now all of these systems are installed - the government can afford to pull back simplify requirements and let market effects shape some of the metrics like interoperability.  They suggest that returning control to the customers is a path to "recapturing the hearts and minds of our clinicians."

The government heavy aspect of these editorial pieces cannot be denied.  It is more of the same "we are from the government and we are here to help you whether you want us to or not."  Here are a few aspects of this roll out that the HITECH legislation either missed or made a lot worse:

1.  Incredible cost - 

Enterprise wide systems are incredibly expensive both upfront and for the annual licensing and maintenance fees.  That does not include any modification of the system - that will typically cost more.  Once a health system has bought in - it is difficult to shop around and come up with a better deal.  In some areas one company has a monopoly on the enterprise.  In many cases the systems are marketed as being a lot more easy to use than they are.  Support is huge in the implementation phases and drops off in a hurry.  Subsequent modifications - even if they are easy to make cost large sums of money.  In some cases the vendors demonstrate whiz bang technology like seamless integration with voice recognition systems.  The customers often find out that those options don't work well with their systems or are available as a high priced option.

In many organizations the EHR budget (combined with other federal costs cutting measures) is a fixed drain on the budget.  If revenues fall, lay offs can occur just to keep the EHR running.  In private practices, the up front and monthly licensing fees are no less of a burden.  There are some "free" EHRs that are funded by advertising or research but no standard comparison or guidance for any clinic that needs to implement one.  The total budget of these costs would be interesting to see, but I have never been able to find a good reference.  Health systems typically describe their margins in the low single digits.  If that is true and EHR system costing tens of millions up front with tens of millions in maintenance costs is clearly a tremendous drain on the system.

2.  IT implementation is poor -

I don't know what percentage of physicians has seen their EHR rolled out in a way that does not optimize clinical utility.  Working physicians need the most rapid route to incorporate the EHR into their work flow.  That includes software that works, software that is efficient, and ideally software that is smart enough to allow individual physicians to analyze trends in the same patient or groups of patients that will allow better diagnosis and treatment.  The IT implementation is also frequently biased toward administration rather than clinicians.  Many clinicians are surprised to find that someone is counting their mouse clicks as a way to measure productivity and the EHR charts they access are monitored.  This is another significant cost that nobody ever seems to discuss. The most egregious implementation error is when a software change is made on the fly and the physicians are given a heads up with no training.  They are expected to learn the software change with no training.  I have always found the illusion of assistance with the EHR interesting.  For the first few months there are always superusers and the factory reps clamoring to help you out.  They gradually fade into the background and you are left with a very poor piece of software.          

3.  Software quality is poor - 

As far as I can tell current EHR programs are designed to deliver lab and imaging data, generate documentation and reports, and perform a billing and coding function.  They do a fair job with the labs and imaging details. Documentation is very labor intensive and poorly done.  It adds hours per day to the physician's work flow and has necessitated the hiring of scribes and retired physicians just to keep up with the documentation tasks.  It is common that EHRs cannot be accessed by outside physicians and when that happens - the printout sent to those physicians is poorly structured and extremely content poor.

On the authorship side - a basic goal should be to produce a document fairly quickly that appears to have been written by an intelligent being.  As anyone who has read EHR entries or reports that is not typically the case.  There are extremes at either end.  You can find notes that are basically a series of check boxes or you can find 18 page notes where the author imported everything that they could into the note because that is one of the few things (in some EHRs) that you can do quickly.  Neither approach is helpful in terms of continuity of care or developing rational treatment for a patient.  Having used EHRs for the past 15 years - I can attest to clunky editing and incompatibility with voice recognition systems as being major drawbacks.  The text fields of some EHRs only work with their own microscopic and very slow editing tools.  It is impossible to set a cursor anywhere in the field to produce the document.  Using this twenty times a day when you are used to working with functional word processors is maddening.  Some systems of care set a font that looks like it is out of the 1950s and that is how the final document appears.

Every physician was appointed (under penalty of law) to be their own billing and coding specialist.  Sure every hospital and clinic has some billing and coding specialists but today they are there basically to audit the work of physicians.  In the EHR this translates to a tedious search for the diagnoses, listing them in the right priority, and signing off on the diagnostic and billing codes.  This can take up to an additional 20 mouse clicks per encounter.  Even if you can do that in 2 minutes - times 4000 encounters per year - that equals another 133 hours per year. That is work added just to maintain the EHR.  Before the EHR, billing and coding could be completed in about 10% of the time.

All the time physicians are engaged in these inefficient EHR based practices they are hearing how the EHR is such an advance in efficiency and productivity.              

4.  Hardware infrastructure/software is running 24/7 - 

Before the modern EHR, there were a limited number of workstations per hospital and most of them were shut down at night.  Now there are thousands of workstations and storage arrays in large organizations running 24/7.  They can't be shut off because of frequent software updates.  Nursing and medical staff can easily be observed spending most of their workday at computers rather than talking with patients and families.  Before the current EHR, physician would typically look at a computer screen to review the labs and possible the MAR (record of meds given).  Now starting at a computer screen most of the time is the norm.  The EHR dominant approach has increased the electrical bill and reduced time spent with patients at the same time.     

5.  A question of security - 

There have been well publicized leaks of large numbers of patient files and more recent ransomware attacks.  Security in most software systems has historically been an afterthought.  I have not seen any specific problems with EHR software but this tip sheet from CMS points out the potential complexity of the situation.  The security problem is also more urgent for healthcare sites that are under more stringent privacy requirements like 42 CFR Part 2.    

Those are a few of my ideas about the rapid deployment of the EHR.  Unlike the authors I am very skeptical of any drastic improvements on the horizon.  If you can't make an EHR that will produce a coherent report with information content at least equal to an old admission or discharge note that is a major problem.  If you can't produce an EHR that allows for some intelligent analysis of data without going through the entire record and reading every text note that is a major problem.  Sure - access to labs is nice, but we had computer access to labs before the EHR.  Patient access is also nice, but let's be honest - it is limited and doesn't address what patients really want - quality health care.

About the only thing that I agree with the authors on is that the physician needs to be put back into the loop.  But that hides the very basic fact that physicians were intentionally taken out of the loop thirty years ago when politicians decided that they could be replaced by managed care administrators.

When you look at it from that perspective the massive problems with the current EHR - make perfect sense.

  

George Dawson, MD, DFAPA



References:


1:  Washington V, DeSalvo K, Mostashari F, Blumenthal D. The HITECH Era and the Path Forward. N Engl J Med. 2017 Sep 7;377(10):904-906. doi: 10.1056/NEJMp1703370. PubMed PMID: 28877013.

2:   Halamka JD, Tripathi M. The HITECH Era in Retrospect. N Engl J Med. 2017 Sep7;377(10):907-909. doi: 10.1056/NEJMp1709851. PubMed PMID: 28877012.

NEJM Review of Generalized Anxiety Disorder

There was a review of Generalized Anxiety Disorder (GAD) in this week's New England Journal of Medicine by Stein and Sareen (1).  I just did a bit of a critical review of the concept here and thought I would look at what these authors had to say.  

They start the review with a clinical vignette of a 46 year old married woman with insomnia, headaches, back pain, and excessive worry about a number of daily stressors.  She is also drinking alcohol on a daily basis to "self-medicate".  She is described as a person who comes in frequently for appointments.  After reviewing the phenomenology,  comorbidity, and differential diagnosis - the authors come back to this case and apply what is in the review.

Their review of the diagnosis does highlight a few things that are problematic about the diagnosis.  The key diagnostic feature is chronic excessive worry.  The worry has to be there for at least 6 months.  In their review of other psychiatric causes of anxiety they omit diagnoses that can cause short term worry or anxiety - the adjustment disorders.  They point out that GAD is more common in primary care clinics where it usually presents with a chief compliant of somatic problems rather than excessive worry.  They discuss major depression as a common co-occuring condition and suggest that anhedonia may be a distinguishing symptom for depression.  They also describe anxious depression as episodic depression superimposed on chronic anxiety.  There is no mention of the low diagnostic reliability of the disorder and why that might occur.  I think that any psychiatrist who sees GAD over time experiences the same problem that occurred in the DSM-5 field trials, the diagnosis can seem to change between visits from GAD to major depression, even in the absence of any new stressful life events.  Critics of psychiatry frequently cite this as a problem with DSM-5.  I think that DSM-5 does a good job with the symptom descriptors, but we don't know why this change occurs and I have not heard anyone talk about it like it is a real phenomenon.

Alcohol use is described as a common co-morbidity with 35% of people with GAD "self-medicating."  I put that term in quotes because it suggests that alcohol can actually be used for the purpose of medication.  What really occurs is that over time the person becomes more anxious and sleep deprived because of the negative effects of alcohol on sleep, baseline anxiety, and baseline mood.  Practically everyone I talk with who has an alcohol use disorder can recognize this pattern and modify any remarks about self-medication to "feel better for a few hours" or "knock myself out and forget about my problems".  There is also the issue of alcohol use being the cause of an anxiety disorder rather than temporary relief.  While I am on the topic of substance use and GAD, at one point the authors make the statement: "Data are also lacking on the use, usefulness, and safety of medicinal marijuana for generalized anxiety disorder" (p. 2066).  Many if not most anxious people are averse to the use of marijuana for anxiety.  Initial use of marijuana typically causes a drop in blood pressure with a compensatory tachycardia.  Tachycardia especially if there is a noticeable accentuation of heart beats is not tolerated well by patients with anxiety.  Many have had panic attacks.  Others have cardiac awareness and are sensitive to any changes in heart rate or intensity.  Many people tell me they thought that marijuana was effective for anxiety, but over time it seemed to make them more and more anxious, they developed panic attacks, and they had to stop using it.  These features combined with a tendency of patients to stop talking to their primary care physicians about substance use are good reasons to heavily educate them about these problems at the earliest possible time.

The authors take a risk factor analysis approach to looking at historical features that can also be associated with the diagnosis.  They point out that they are nonspecific and amy be associated with other psychiatric diagnoses.  I would encourage a more developmental approach, looking back at the first recollection of anxiety - usually at some point in childhood and how that developed in the childhood environment.  It is fairly common for the patient to describe one or both parents being anxious and how that was transmitted to them  eg. ) "I started to worry about the same things my  mother worried about" or "I started to worry about my mother because she was worried all of the time - I worried that something was going to happen to her."  Those learning patterns associated with adult anxiety are fairly common and may explain the low heritability (15-20%) of the disorder.  The authors do discuss one feature that is important in this context and that is intolerance of uncertainty.  Clinically that translates to excessive and at times catastrophic worry about uncertain situations.  They are unsure about the biological or experiential origins of the symptom.  I think the important part is that with a careful enough history and sometimes collateral information the learning aspects of this bias can be examined and it can be unlearned in therapy.

The authors advocate for a stepped approach to treatment and I certainly agree.  This approach would include an initial medical assessment to look for common medical conditions that can cause anxiety followed by education about anxiety and lifestyle changes to address sleep, exercise, caffeine intake and alcohol use with monitoring response to those interventions.  Those first two phases could be accomplished at the initial visit.  If those initial interventions don't help moving on to "low intensity psychological interventions" like self-help books, computer-assisted psychotherapy, and support groups.  The next step up is more intensive psychological interventions like individualized cognitive behavioral therapy (CBT) or pharmacological management based on the patient's preference.  The highest level of care would include pharmacotherapy and more intensive CBT alone or in combination with other therapies (psychodynamic or acceptance and commitment therapy (ACT)).  The practical issue with this 4 step algorithmic approach to care is that it is generally not available in primary care settings.  In many of those settings, the patient is screened with the Generalized Anxiety Disorder 7-item questionnaire (GAD-7) and the patient is treated with a medication.  This is viewed as "cost-effective" care by managed care systems because an inexpensive prescription and a 20 minute appointment with a physician is apparently much more "cost effective" to the organization than maintaining computerized psychotherapy or educational and monitoring systems.  There is also the largely undetermined effect of the patient taking a completely passive role in their care.  There is a significant difference between a patient who is actively engaged in lifestyle changes and self education and one who expects a complete cure from a pill.  The actively participating patient has better outcomes.   

The authors include a table of 16 medications used to treat GAD.  They point out that the effects of medication are modest at best and no single medication has better efficacy.  They discuss vilazodone as a promising medication in clinical trials and do not include it in the list.  My current prescribing information says that it is FDA approved only for major depression, but only 4 of the 16 drugs on the list are approved for GAD: paroxetine, venlafaxine XR, duloxetine, and buspirone.   The authors comment on the practice of using hydroxyzine for GAD and suggest not to use it.  I am in complete agreement with that recommendation and think that any anti-anxiety effect comes from the non-specific sedating effect of antihistamines.  The side effect profile is also not very favorable.  They point out the benzodiazepine paradox with GAD - they are recommended for short term (3-6 month) use but the condition is chronic.  There is even more subtlety there.  Some early studies of GAD treated with antidepressants suggests that patients needed to take the medication only 30% of the time over ten years of treatment.  I don't think you will see a similar study with benzodiazepines and I think it has to do with the behavioral pharmacology of the drug.  The single-most important issue when it comes to benzodiazepines is the informed consent and letting the patient know that they are taking a potentially addictive drug.  

The  authors are silent about the fact that GAD may be the most heterogenous of all of the DSM-5 categories.  In October and November of this year, I went to three excellent conferences.  One of the central themes was phenotypic diversity in DSM-5 categories and what it implies for biology and genetics.  GAD seems to offer some of the best clinical features for distinguishing intermediate phenotypes and I outline a few in my previous post.  There are problems with a diagnostic category that says "excessive worry" is a discriminating feature and ignores real physiological markers like persistent tachycardia, hypertension, body mass index, and hyperarousal at the time of sleep.   This also points out how basic science can drive clinical diagnoses in psychiatry and hopefully at some point in the near future we will see this kind of research.

    

I think that we have gotten as much as we can out of the GAD diagnosis at this point and it is time to break it down into what can be more reliably observed. 

George Dawson, MD, DFAPA

References:

1: Stein MB, Sareen J. Generalized Anxiety Disorder. N Engl J Med. 2015 Nov 19;373(21):2059-68. doi: 10.1056/NEJMcp1502514. PubMed PMID: 26580998.

Moral Bias

Lisa Rosenbaum's final installment of her three-part conflict of interest series in the NEJM is out and full text is available online for free.  My associations and observations in response to the first two can be found here and here.  As a student of bias and rhetoric, reading Dr. Rosenbaum's series has been a breath of fresh air both on its own merit, but also relative to the grim anti-industry and anti-physician bias that permeates the popular press and medical settings these days.  The hypocritical nature of many of these comments was always obvious to me, but there was only very qualified support for anyone who did not see all physicians (especially psychiatrists) as tools of the pharmaceutical industry.  But the types of moral and ethical biases that Rosenbaum highlights goes far beyond the issue of free lunch from a pharmaceutical rep.  It shakes the very foundation of a system of evaluation based on weak empirical evidence or pure politics as I have pointed out many times on this blog.  At some level it is such a stunning expansion of many of the old NEJM editorials, it seems surrealistic that these articles have been published.  But on the other hand, the page below this last article invites readers to participate in a poll on the ".....suitability of three potential authors to review articles for the Journal."  Combined with the fact that these articles have a series editor that suggests to me that this may be all part of a social media-like initiative to attract interest to the NEJM.  On that basis, I expect a full gamut of future authors including the more typical opinions equating the appearance of conflict of interest with conflict of interest and suggesting zero tolerance for contact with industry.

This article starts out with commentary on the medical school "anti-pharma animus".  The organization of American medical students apparently grades medical schools on the basis of how free from pharmaceutical company influence their conflict of interest policies and environment are.  She gives a quote from a medical student to illustrate the mind-set involved in at least some members of this movement, namely the need for "pure" information to medical students.  Some early critics of Rosenbaum's article cite this as anecdotal data but that misses the point.  Her point is that this kind of mind-set exists and it is one of a number of mind-sets that makes the ethical climate around conflict of interest an unreasonable one.  She also points out that the rhetoric associated with this statement clearly indicates that this is a moral argument and at that point the psychology of moral arguments may apply.  From the perspective of medical education, is it better to take an insular approach and suggest that all research can be assessed by looking at the funding source or should medical students be taught to read and critique research independent of funding source?  A study quoted one of Rosenbaum's previous article suggests that internists are able to look at research abstracts and classify them according to research rigor, but that the introduction of funding source forces a re-evaluation with a bias against industry funded research.

The article progresses to talk about the psychology of moral argumentation at that point and a set of arguments that I have summarized in the table above.  I think it is also instructive to address one of the early arguments about the Rosenbaum essays and that has to do with evidence and the use of evidence in arguments.  In order to look at that, it requires a quick look at the type or argument, whether it is a scientific or non-scientific argument and whether the corresponding type of evidence exists.  I think there is no doubt that Rosenbaum's arguments are moral arguments rather than scientific ones.  As such they seek to address the ethical climate around conflict of interest.

There are two aspects of the concept of ethical climate that are missing from Rosenbaum's analysis.  The first is the ethical climate as a way to control physicians.  The best example during my career has been managed care and the research that supported it.  Like today's collaborative care research, the early managed care research was focused on the idea that it was more "cost-effective" than fee-for-service or treatment as usual.  In both cases (collaborative care and managed care), the research was generally done by advocates of the proposed methods.  Thirty years later, any objective analysis on the effect of managed care on psychiatric services will show that it has been devastatingly negative.  Bed capacity has been shut down, the criteria for inpatient care is "dangerousness" rather than any specific medical indication, people are clearly discharged from hospitals based on optimizing meager DRG based payments rather than medical indications, detoxification and addiction services have practically been eliminated from most hospitals,  only a small percentage of hospitals have psychiatric services, state hospital systems have also been shut down, and the only place where psychiatric care has increased has been county jails and prisons.  That entire system wide change for the worse was based on a moral argument of cost-effectiveness rather than scientific research.  Once that ethical landscape was established physicians could simply be shouted down with the slogan: "Times have changed - you are no longer in charge."  I doubt that any physician who heard that slogan was ever in charge of anything.  It was political rhetoric, designed to elicit an emotional reaction in the people taking over and the physicians they ultimately came to control.  Nobody thought that cost effectiveness was the same thing as cost shifting to correctional systems.

The second aspect is the explicit control of physicians by managed care companies and a conflict of interest that greatly exceeds that of any other industry.   Rosenbaum's three articles are all focused on the pharmaceutical or medical device industries.  There is no mention of the managed care industry or its spinoffs, despite the fact that it controls the medical care of over 80% of Americans.  As I have consistently pointed out, the theoretical concerns of the affiliations of authors on research papers about drugs or medical devices is nothing compared with a managed care company that tells your physician that you need to be discharged from a hospital or use a particular medicine that the physician is not recommending.  In the case of psychiatric care, that company is free to make even more life altering decisions such as denying a patient with a drug addiction any functional detox services, deciding that a patient with significant suicide risks can be treated on an outpatient basis, or maintaining a person in a disabled state with minimal treatment options for a complete recovery.  The regulatory environment that concentrates that much power in an industry that can generate profits by denying care is a complex story, but it all started with an ethical environment  that blamed physicians for the high cost of health care.  That physicianscold environment has too many elements in common with the pharmascold environment to ignore.  In both cases there is a predominate moral bias that greatly oversimplifies the problem and at least in the case of managed care leads to clear long term adverse consequences.              

The good news is that these articles have been published along with the evidence that moral reasoning can be seriously flawed and associated with biases.  Rosenbaum's focus has clearly been on the relationship between physicians and the pharmaceutical or medical device industry.  She has discussed her personal experience as a Cardiologist and how it has affected her largely in terms of interventions, statin therapy, and as a potential consultant to the industry.  Psychiatry has been an easier target for the same biases and rhetoric that she lists in her article.  I pointed it out in a Washington Post article where the narrative was clearly skewed to fit the idea that psychiatry was corrupted by Big Pharma and attempting to make it easier to diagnose depression in order to sell more antidepressants.  That article included selected information to make it seem like the American Psychiatric Association was the only professional organization to make advertising profits from Big Pharma.  The suggested quid pro quo for advertising revenue should be absurd to anyone familiar with advertising but it was not to this reporter.  But the real issue was that the DSM does not recommend treatment anyway and the majority (80%) prescribers who treat depression don't use a DSM-5 or even care about what it says.  Less formal approaches adopt a similar scolding moralistic tone toward psychiatry that is possible only by ignoring the deficiencies in other medical fields and idealizing them while devaluing psychiatry.

I think that Rosenbaum's articles are must reads, especially for psychiatrists who may be unfamiliar with rhetoric, moral reasoning, and politics.  That may be why physicians in general have been inept in mounting any kind of a counterattack against political strategies that work by changing the ethical climate.  These articles provide some points for discussion.   Watching the counterattacks will also be instructive.      


George Dawson, MD, DFAPA

1: Rosenbaum L. Beyond moral outrage--weighing the trade-offs of COI regulation. N Engl J Med. 2015 May 21;372(21):2064-8. doi: 10.1056/NEJMms1502498. PubMed PMID: 25992752.

Bias Cuts Both Ways

Lisa Rosenbaum's second article (1) in a series of three appeared in the New England Journal of Medicine this week.  It continues the theme that bias is more complicated than following the money (or pens or pizza slices).  It was interesting to note the response to the original article.  On at least one blog a poster apparently Googled Dr. Rosenbaum in order to point out all of her potential conflicts of interest.  It probably would have been more relevant to look at the standard International Committee of Medical Journal Editors disclosure form on file at the NEJM.  But it does provide a good example of one of the references in this week's piece - financial disclosure (or in this case suspicion) as an ad hominem approach to evaluating science.  In a similar vein, one of the authors of a previous NEJM editorial pointed out that the science has to stand on its own merit independent of disclosures or credentials.

The initial part of the article points out a fact that has always seemed pretty obvious to me.  Association is often used to suggest that there are significant meaningful conflicts of interest.  The oft quoted statistic is that 94% of physicians have "relationships with the industry".  This includes counting drug samples or donuts in the workplace as a significant relationship.  One of my previous employers decided that all hospital employees should participate in "donut rounds" and not just the physicians.  I viewed this as a pseudo-egalitarian managed care tactic, but by definition that means that 100% of the employees at that hospital had a "relationship with the industry".  The article also points out that physicians who request drugs be included in a formulary are also more likely to have industry relationships than not.  I have a history of being on two separate Pharmacy and Therapeutics (P&T) Committees of a major healthcare system and a major hospital where the overriding biases were drug cost and deals with pharmaceutical companies.  There were major changes on a year to year basis due to price differences in the cost of commonly prescribed drugs and they were often based on the flawed assumption that all drugs in the same class are equivalent.  On the other hand if an exclusive deal could be made, that company might also be able to combine that with a preferred deal for a more common drug.  It was a curious situation where decisions that were supposed to be science based were not.   The P&T Committee was biased by the managed care industry operating strictly on a cost basis.

I decided to part ways with the P&T Committee on the day we were presented with forms to fully disclose all of our finances to assure there were no conflicts of interest.  The usual hype about how we were all cherished guardians of the public trust was included.  I thought about it for a second and looked around the room.  There were approximately 15 MDs and 4 PharmDs on the committee.  Some of the brightest and most well read staff in the organization.  I ran the hypothetical through my mind: "What are the odds that if I owned stock in XYZ Pharmaceutical that I could convince my 20 colleagues that it was a good idea to put their most expensive drug on the formulary just based on my word?  What are the odds that I could overcome the predominate bias of the financial well being of the company that employed all of us?  What are the odds that if I accomplished those first two unattainable goals that I would actually see a profit in my XYZ Stock?"  I also thought about the drug approvals that we did based solely on public relations considerations.  Drugs that were practically worthless, but that were demanded by advocates for incurable diseases.  The explicit decision was that we did not want to run afoul of some of the very vocal advocates for those illnesses.  It would be bad public relations and press.  I looked back at the 5 page disclosure form and decided that I was not going to play that game.  I was not going to pretend for one second that I needed to be vetted by an organization that apparently saw itself as destined for sainthood.  I walked away at that time.  I had long been familiar with the other bias listed in the Rosenbaum article and how any disclosure at a CME presentation could result in mockery or discreditation.  It is difficult enough to present the pertinent information to an audience who may want to be entertained without being the butt of jokes as a sponsored presenter.  Any way you look at it my behavior was a reaction to a modern day witch hunt mentality and I was not about to be declared a witch.  Even beyond that, I was not the only "clean" person in the room.  Getting heavy handed about a conflict of interest disclosure as a public relations gimmick after many of us had already figured it out 20 years ago was more than a little insulting.

Rosenbaum also discusses a previous study from the NEJM (2) that as far as I can tell has not received press anywhere else.  In this study, the authors designed identical fake clinical trial report abstracts of studies with varying methodological rigor.  The studies had three possible funding disclosures - the pharmaceutical industry, the NIH or none.  In this experiment the internists involved in the study were less likely to read the entire report, less likely to prescribe the study medication, and less likely to see the experiments as rigorously conducted if they were sponsored by industry rather than the NIH.  They were half as likely to prescribe medications recommended in an industry sponsored trial than an NIH sponsored trial.   The authors were naturally concerned that physicians would be skeptical of even high quality but industry sponsored trials and that might slow the acceptance of that information in clinical practice.

In an interesting study done by the industry that same year,  a team (3) at the biotechnology firm Amgen  examined 53 studies that were considered to be 'landmark' preclinical studies in the field of oncology.  The goal was to see if they were reproducible.  The findings could be confirmed in only 6 or 11% of these papers.  The non-reproducible research led to hundreds of secondary articles and in some cases led to research that exposed patients to agents that resulted directly from the original research.  A team (4) at Bayer HealthCare did a similar review of preclinical studies to identify potential drug targets and concluded that only 25% of the work was reproducible.   That same article referenced the general industry rule that up to 50% of published results from academic settings cannot be reproduced in an industrial lab.  The Amgen and Bayer HealthCare studies suggest that is really an underestimate of what amounts to academic bias.  A common criticism leveled by Big Pharma critics is that they have benefited from all of the taxpayer funded basic science research at the NIH.  These studies suggest that there are plenty of problems with that research independent of funding stream and that they are less rather than more likely to lead to drug discovery.

In addition to unique information to examine the issues of bias (the author lists many more),  she also points out the origin of the word Pharmascolds (5) as those who "vilify the medical products industry and portray academics working with it as traitors and sellouts".  The authors here describe an inadequate public response from both the companies and the physicians who were criticized.  The full text of the reference is available online.

This is another highly informative article by Rosenbaum which demonstrates that analyzing conflict of interest is not as easy as some members of the press and some professional critics make it out to be.  She gives a great example of an 85 year old woman who needs an aortic valve replacement and what the considerations might be based on the characteristics and biases of two different Cardiologists assessing this situation.  It is even more complex in a setting where some would be quick to refer the woman to a hospice service.  In my experience outlining all of the potential biases in that situation is a significant task and one that few physicians would attempt.

Some day a more measured discussion of conflict of interest might provide a better approach.  Until then be skeptical of any critics who suggest that it is inappropriate for a physician to have a relationship with the pharmaceutical or medical devices industry just based on the face of it.  And for any physicians out there who want to take the most conservative path to avoid unwarranted criticism, stay out of the Sunshine Act database.

        


George Dawson, MD, DFAPA        
                   

1:  Rosenbaum L. Understanding bias--the case for careful study. N Engl J Med. 2015 May 14;372(20):1959-63. doi: 10.1056/NEJMms1502497. PubMed PMID: 25970055.

2:  Kesselheim AS, Robertson CT, Myers JA, Rose SL, Gillet V, Ross KM, Glynn RJ, Joffe S, Avorn J. A randomized study of how physicians interpret research funding disclosures. N Engl J Med. 2012 Sep 20;367(12):1119-27. PubMed PMID: 22992075.

3: Begley CG, Ellis LM. Drug development: Raise standards for preclinical cancer research. Nature. 2012 Mar 28;483(7391):531-3. doi: 10.1038/483531a. PubMed PMID:22460880.

4:  Prinz F, Schlange T, Asadullah K. Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov. 2011 Aug 31;10(9):712. doi: 10.1038/nrd3439-c1. PubMed PMID: 21892149.

5:  Shaywitz DA, Stossel TP.  It's time to fight the 'pharmascolds'.   Wall Street Journal.  April 8, 2009.    http://www.wsj.com/articles/SB123914780537299005 accessed on May 17, 2015.

Indignation Bias

"Moral indignation in most cases is 2% moral, 48% indignation, and 50% envy." - Vittorio De Sica


The New England Journal of Medicine has started a new series on conflicts of interest that should prove to be enlightening if the rest of the articles are as good as the first one.  In this article, Lisa Rosenbaum, MD  takes on typical cases that appear to be straightforward conflict of interest cases and thoroughly debunks the common thought process.  She provides a clear link between the outrage over the behavior of the pharmaceutical industry and an indignation based approach to regulation and conflict of interest considerations.

In the first example she looks at the issue of the 2013 cholesterol guidelines and the expansion of the target population for statin therapy.  There was the standard New York Times editorial by two physicians who concluded that the guideline "would benefit the pharmaceutical industry more than anyone else."  They referenced an article by one of the authors on the frequency of statin side effects that was later withdrawn due to an overestimate of the frequency of side effects.  They challenged the credibility of  the guideline writers suggesting that they needed to be free from "influence, conscious or unconscious".  Rosenbaum reviews the checks and balances in place for the writing of this guideline in a manner reminiscent of my analysis of a Washington Post commentary on the DSM-5 diagnosis of depression.  In both cases, the safeguards in place are overlooked, the benefit to the pharmaceutical industry  overestimated, and the authors of these critical articles are never challenged.  She asks the important question: "So why the rush to conclude that the guidelines were an industry plot?"  It is also interesting from the perspective of psychiatry where the field would never get that kind of break.  The question for psychiatry is:  "Why the rush to judgment to conclude that the guidelines were a plot between psychiatrists everywhere and industry?"

The Jesse Gelsinger case was examined next.  Mr. Gelsinger was an 18 year old man with ornithine transcarbamylase deficiency.  He volunteered for a research protocol examining gene therapy for the disorder.  The ethical considerations included the fact that the researchers were advised that it was not ethical for them to test the protocol in affected babies who might benefit if it was successful because that would be considered coercion.  There was also an issue relating to the reporting of a complication of the therapy by basic science researchers.  Rosenbaum points out that after Jesse Gelsigner's death due to the research, the popular explanation for what happened was that the lead researcher had an equity position in a gene-therapy company.  There were numerous safeguards in place including a lack of a direct connection between sponsorship of the trial, a university prohibition of the lead researcher in patient enrollment or interaction,  and that same researcher asking a colleague to be the lead investigator in that trial.  The research had also been approved by more than one Institutional Review Board (IRB).  Most IRBs require a review of the scientific merit of the research before considering it on ethical grounds.   Since this was a protocol for the first human experiment in gene therapy, the vetting was unusually rigorous:

"The OTCD gene therapy protocol and the associated consent document underwent extensive review including IRBs at three institutions, the Recombinant DNA Advisory Committee, the Oversight Committee of the General Clinical Research Center of the University of Pennsylvania, and the FDA."  (reference 2)

 Please read the entire paper on line for the complexities of this case.  For the purpose of the NEJM article the relevant section had to do with Wilson recommendations of why the appearance of conflict of interest maybe all that counts.  After disclosing everything that he did  to minimize financial conflicts of interest Wilson concludes:

"I conclude that it is impossible to manage perceptions of conflicts of interest in the context of highly scrutinized clinical trials, particularly where there is a tragic outcome....." (reference 2, p 155).

That is where Rosenbaum's article gets interesting.  She introduces a concept that gets very little play in clinical medicine and one that has not had much play in psychology until the past decade and that is emotional reasoning.  There are physiological and evolutionary reasons why emotions play a large role in day to day reasoning.  In patients with a pathological loss of emotional reasoning there are significant problems in day-to-day decision making.  Diagnostic reasoning in medicine on the other hand is often described as a purely intellectual  process.  Psychiatrists  encounter this in our colleagues.  I can recall for example, confronting a Cardiology resident with the fact that her agitated patient did not have an acute exacerbation of bipolar disorder like she suspected and  did not need transfer to Psychiatry, but in fact had just had a stroke and was aphasic.  "What the hell do you know about strokes?  What do psychiatrists know about neurology?"  she stated forcefully as she rapidly escalated herself.   I calmly back pedaled and said: "Get your attending to confirm the findings and the diagnosis and if he doesn't - call me back.  But right now your patient has aphasia and has right upper extremity weakness and needs to go to the Neurology service."  Within an hour that patient was under the care of the Neurology service.  My point being that level of emotion or in this case emotional biasing really doesn't show up in any of the case records or diagnostic reasoning in the New England Journal of Medicine.  Everything is cool, dry, and pure Bayesian analysis.

Rosenbaum likes the work of a social psychologist Robert Zajonc who was one of the pioneers in this area.  If most decisions begin with a feeling, what persisting feeling may be there in the case of decisions about conflict of interest.  She had previously cited numerous legal infractions and penalties against most of the major pharmaceutical manufacturers.  It should not be surprising that the persistent emotional decision making involving that industry is going to be rather negative and miss the complexities and information that runs counter to that emotion.  I think back to one of the basic admonitions of grandmothers everywhere from my generation: "If there is one thing I can't stand it is a liar!"  I reflected on that over the course of my years in medicine as I realized that the reality is that everybody lies and they lie all the time.  But if you are indoctrinated to that rule and you have a definite emotion associated with it, you should be able to predict the direction of the decision.  You only have to look as far as Cognitive Appraisal Theory (4) for the predictable results when anger is that emotion.  To make it real, in the case of ongoing problem with the pharmaceutical industry you will see their responsibility as high and any adverse outcomes as being totally in their control.  You will be very certain about your decision, irrespective of what the reality is.  One example previously mentioned is the idea that the new cholesterol guidelines would be a windfall for the pharmaceutical industry when the vast majority of the prescriptions are for generic statins.  There will be a contamination effect on everyone associated with those companies and as long as the underlying emotion persists the associates will be predictably condemned with the same level of certainty and any negative events will be perceived as being under the complete control of the individuals involved.  There can be no unanticipated adverse outcomes or complications.        

The most concerning aspect of this kind of emotional bias is that people seem to be completely unaware of the fact that they have been swept up in it.  To them, their decisions all seem reality based.  The biasing effect in emotional reasoning has the same predictable effect in paranoid psychotic states, road rage, and Little League parents.  It is certainly alive and well in practically all aspects of public opinion when it comes to psychiatry.  Many blogs and Internet sites seem nothing more than a lens to focus rageful commentary against the profession, and further indignation if any psychiatrist dares to speak out against many of these practices.

I think indignation bias explains a lot, particularly attitudes toward psychiatry but also overly rigid thinking in the case of complex decisions and unpredictable negative outcomes.  It has allowed an irrational connection between Big Pharma and psychiatry and for many people to profit from focusing anger against the profession.  And per Dr. Rosenfeld it is not conducive to rational regulations of the industry, but it seems that at least the marketing end of those businesses seem content to see their "pushback" as being the cost of doing business.  Even marketers could benefit from educating themselves about the negative future effects of emotional decision-making against their industry.


George Dawson, MD, DFAPA


References:


1:  Rosenbaum L. Reconnecting the Dots - Reinterpreting Industry-Physician Relations. N Engl J Med. 2015 May 7;372(19):1860-1864. PubMed PMID: 25946288.

2:  Wilson JM. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol Genet Metab. 2009 Apr;96(4):151-7. doi: 10.1016/j.ymgme.2008.12.016. Epub 2009 Feb 10. PubMed PMID: 19211285.

3:  Lerner JS, Li Y, Valdesolo P, Kassam KS. Emotion and decision making. Annu RevPsychol. 2015 Jan 3;66:799-823. doi: 10.1146/annurev-psych-010213-115043. Epub 2014 Sep 22. PubMed PMID: 25251484.

4:  Lerner JS, Keltner D. 2000. Beyond valence: toward a model of emotion-specific influences on judgment and choice. Cogn. Emot. 14(4):479.



Supplementary 1:  According to UpToDate, the gene therapy trial mentioned in the above reference was cancelled after the death of Jesse Gelsinger.  He was the 19th patient in the trial and metabolic correction of the other 18 patients did not occur.  (Topic 2923)

Supplementary 2:  Image used at the top of this post is a Shutterstock standard license download.

Supplementary 3:  Quote from Vittorio De Sica is from Stereophile June 2015, p 125.

More on Geriatric Depression and Overprescribing Antidepressants in Primary Care

A recent article in the New England Journal of Medicine adds some more epidemiological data to the issue of the treatment of geriatric depression.  The centerpiece of the article by Ramin Mojabai, MD is a graphic that is a combination of data from the National Survey on Drug Use and Health or NSDUH and the U.S. National Health and Nutrition Examination Survey or NHANES.  His central point is that the majority of people diagnosed with depression in primary care clinics do not meet diagnostic criteria for major depression.  The actual numbers for the elderly are 18% of those diagnosed with depression and 33% of those diagnosed with major depression actually have a diagnosis of major depression as assessed by rating scales or structured interviews.  The bar graphs in the A panel illustrate that most people over the age of 35 who are taking antidepressants do not meet criteria for major depression.  The opposite is true for the 18-34 year olds where antidepressant prescriptions are less than the prevalence of depression.  Panel B illustrates that the prevalence of people who were told by their clinician that they had depression and did or did not meet criteria for major depression.  In all cases the clinicians involved estimated non-major depression as being more prevalent than major depression.  Can we learn anything from these graphs?

The striking feature in Panel A is the dissociation of the total number of people taking antidepressants from the people with a diagnosis of major depression.  I can see that happening for a couple of reasons.  I would expect the number of people who are stable on antidepressant therapy to accumulate over time.  Most of them would have major depression in stable remission and would no longer meet the criteria.  A related issue is the atypical presentations of depression with increasing age.  I have seen many cases of depression presenting as pseudodementia, Parkinson's syndrome, and polyarthritis or a similar chronic pain syndrome.  In all cases, the symptoms responded to antidepressant medication but they would not meet criteria for major depression and most often the evaluation would resemble an evaluation for a medical problem.  There is also the problem of depression in the aging population who have a form of dementia.  At the upper end of this age distribution that may involve as many as 5% of the 65 year old population and they are likely overrepresented in primary care settings.  Lastly there is the problem of suicide in the elderly.  I reviewed a recent paper in the American Journal of Geriatric psychiatry that documented a decreased risk for suicide in elderly men and women who were taking antidepressants and the increased suicide risk in that group.  It is likely that many primary care physicians are concerned about that higher level of risk and this may influence prescribing for this group.  The other interesting comparison is that using different methodologies the ballpark antidepressant use in the elderly in Denmark approximates the antidepressant use on the US.  It is probably a few percentage points lower, but the study in Denmark used a more robust marker of antidepressant use (refilling the actual prescription) rather than survey questions.

The author addresses the issue of antidepressants being used for other applications like headaches and chronic pain chronic pain and states from an epidemiological perspective that two thirds of the prescriptions are for "clinician diagnosed mood disorder."  The standard used in this study of DSM major depression criteria is too strict to use as a marker for antidepressant use since there are other valid psychiatric indications that primary care physicians are aware of and treat.  Panic disorder, generalized anxiety disorder, social anxiety disorder and dysthymia are a few.  There are also more fluid states like adjustment disorders that seem to merit treatment based on severity, duration, or in many cases by the fact that there are no other available treatment modalities.  These are all possible explanation for the author's observation that the majority of people diagnosed with depression in primary care clinics do not meet criteria for major depression.

Diagnostic complexity is another issue in primary care settings.  Patients are often less severely depressed, have significant anxiety, may have an undisclosed problem with drugs or alcohol, and have associated medical comorbidity.  In an  ideal situation, a diagnosis of depression is not necessarily an easy diagnosis to make.  It takes the full cooperation of a patient who is a fairly accurate historian with regard to symptom onset and dates.  They are harder to find than the literature suggests.  The epidemiological literature often depends on lay interviewers using structured interviews like the DIS or SADS to make longitudinal diagnoses.  This approach will not work for a large number of patients and a significant number will not be able to recall events, dates, medications or prior treatments with any degree of accuracy.  With that level of uncertainty, antidepressant prescription often comes down to a therapeutic trial so that the patient and physician can directly observe what happens between them as the only available reliable data.

The  author notes that the primary intervention for depression in primary care is the prescription of antidepressants.  He talks about the ethical concerns about exposing patients especially the elderly to antidepressant drugs if it is not warranted, but he is using the major depression diagnosis here as the standard for treatment.  He makes the same observation that I have made here that mass screening for depression is not warranted based on the concern about false positives.  That stance is supported by the Canadian Task Force on Preventive Health Care.  The U.S. Preventive Services Task Force recommends screening "when staff assisted depression care supports."  My position is that screening, especially in medical populations is problematic not only from the false positive perspective but also because the screening checklist is often used as the diagnosis and an indication for starting antidepressant medications.  Screening checklists are also political tools that are used to manipulate physicians.  The best example I can think of is using serial PHQ-9 scores as a marker of depression treatment in primary care clinics even though it has not been validated for that application. As an extension of that application the PHQ-9 is used as a quality marker in clinics treating depression over time even though there is no valid way to analyze the resulting longitudinal data.

The author makes recommendations to limit the overuse of antidepressants and uses the stepped care approach with an example from the UK National Institute for Clinical Excellence or NICE.  These guidelines suggest support and psychoeducation for patient with subsyndromal types of depression.  A fuller assessment is triggered by very basic inquiries about mood and loss of interest.  Amazingly the PHQ-9 is brought up as an assessment tool at that point.  More monitoring and encouragement is suggested as a next step with a two week follow up to see if the symptoms remit spontaneously.  Medications are a third step for longstanding depressions or those that do not remit with low level psychosocial interventions.  An expert level of intervention is suggested for patient with psychosis, high risk of suicide, or treatment resistance.  That seems like a departure for NICE relative to their guideline for the treatment of chronic neuropathic pain.  In that case the referral for specialty care was contingent on a specific prescribing consideration (opioids) and the pain specialist was considered the gatekeeper for opioid prescriptions in this situation.  Antidepressants are seen as overprescribed drugs but no gatekeeper is necessary.  I suppose the argument could be made that there are not enough psychiatrists for the job, but are they really fewer than pain specialists who prescribe opioids for chronic neuropathic pain in the UK?  

This model is only a slight variation on the Minnesota HMO model of screening everyone in a primary care clinic with a PHQ-9 and treating them as soon as possible with antidepressants.  The driving factor here is cost.  With a month of citalopram now costing as little as $4.00 - there is no conceivable low level psychosocial intervention that is more "cost effective".  I have also been a proponent of computerized psychotherapy as a useful intervention and it is not likely that the Information Technology piece needed to deliver the psychotherapy would be that inexpensive.  Another well known correlate of depression in the elderly is isolation and loneliness.  I was not surprised to find that there were no interventions to target those problems since it would probably involve the highest cost.  In the article standard research proven psychotherapies were recommended on par with the medical treatment of depression, but the question is - does anyone actually get that level of therapy anymore?  My experience in assessing patients who have gone through it is that it is crisis oriented and patients are discharged at the first signs of improvement.  That may happen after 2 or 3 sessions.

I doubt that the stepped care approach will do very much to curb antidepressant prescribing.  This study suggests that overprescribing is a problem using a strict indication of major depression.  There are always problems with how that is sorted out.  I have not seen any studies where a team of psychiatrists goes into a primary care clinic and does the typical exhaustive diagnostic assessment that you might see in a psychiatric clinic.  It would probably be much more relevant to the question at hand than standardized lay interviews or checklists.  There is also a precedent for interventions to curb over prescribing of medications and that is the unsuccessful CDC program to reduce unnecessary antibiotic prescriptions.  If clear markers of a lack bacterial infection can be ignored, what are the chances that an abstract diagnostic process will have traction?

And finally the stepped care interventions seem very weak.  This is a good place for any number of professional and public service organizations to intervene and directly address the psychosocial aspects of depression in the elderly.  Public education on a large scale may be useful.  The psychoeducation pieces can be included in relevant periodicals ahead of time rather than as a way to avoid the use of medications.  Environmental interventions to decrease isolation and loneliness is another potential solution.  From a medical perspective, if the concern is medication risk every clinic where antidepressants are prescribed should have a clear idea of what those risks are and how to assess and prevent them.  Patients who are at high risk from antidepressants should be identified and every possible non medication intervention (even the moderately expensive ones) should be exhausted before the prescription of antidepressant medication.   Primary care prescribing patterns that potentially impact the patient on antidepressants should also be analyzed and discussed.  A focus on risks and side effects can have more impact on the prescription of antidepressants than psychosocial interventions and waiting for the depression to go away.


George Dawson, MD, DFAPA


Supplementary 1:  Permission and credit for the graphic:

"From New England Journal of Medicine, Ramin Mojtabai, Diagnosing depression in older adults in primary care. Volume No 370, Page No. 1181, Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society."