The Prostate Is On The Wrong End - Why Should We Worry?

There is always a lot of news about the prostate these days.  It has become the poster child of the evidence based crowd.  Just last week I saw the headline: "Men are more likely to die in a structure fire than from prostate cancer." This is all part of the political approach to epidemiology that emphasizes that even though most men will develop some type of prostate cancer by the age of 85, they are likely to die of other causes.  Therefore PSA screening is not useful because it leads to more invasive procedures with complications like prostate biopsy and then procedures with even more complications like radical prostatectomy. The sordid aspect of this business has been pointing out the options that several celebrities who made decisions about prostate cancer and therapies.  Depending on the side you take - you will cheer the representative decision.  I noticed that the celebrities who died from prostate cancer including misdiagnosis are omitted from that equation.

In clinical practice, young men with recurrent prostatitis have always been a red flag for me. They often end up on very long courses of antibiotics and seem to have chronic symptoms.  The symptoms don't match descriptions of acute prostatitis that are more similar to an acute urinary tract infection. The anatomy of the male urinary tract often needs to be reviewed, especially the relationship of the prostate and the urethra.  I have treated many young men who were very angry at their Urologists because of these chronic symptoms even though they were not medically explained.  If I see these situations today - I typically call the Urologist and suggest treatment only for a clear cut case of prostatitis and whether they have noticed any changes in the patient's behavior.

My focus in this post is bladder outlet obstruction and all of the associated phenomenon due to benign prostatic hyperplasia.  According to UpToDate (10) it is more common in men and  10% of men greater than the age of 70 and 1/3 of men over the age of 80 will develop it.  Treatment is necessary to prevent renal complications, bladder dysfunction, infection and in severe cases delirium.  I don't intent to focus on the urological treatment - only as required to explain the situation.  I am more interested in what happens with this disorder and how the presentation may appear to be psychiatric.  I think that this is a neglected are in the literature.  Please send me any references that I may have missed.

The neuroanatomy and physiology of micturation is a complicated process.  At the local level, micturation is innervated by both the sympathetic and parasympathetic nerves.  The sympathetic efferent innervation inhibits  β3 adrenoreceptors to relax the detrussor muscle of the bladder and activates α1 receptors at the level of the urethra.  Parasympathetic efferent innervation activates M3 muscarinic receptors in bladder smooth muscle and motor neurons stimulate acetylcholine nicotinic receptors in the external urethral sphincter to cause contraction.  Relaxation of that sphincter muscle is facilitated by postsynaptic parasympathetic neurons that release ATP and nitric oxide.  The efferent arm of micturation requires close coordination of that combination of motor and sympathetic nervous system components.

The afferent side of this function begins at the level of the bladder epithelium.  These cells have complex signalling functions that can lead to local vascular and muscular responses in addition to sensory information being sent to higher centers. Bladder epithelium and underlying myelofibroblasts may function to send a stretch signal as the bladder fills. The actual mechanism that initiates that signal was not clear from the review I read.  A local acetylcholine based mechanism was thought to led to local bladder contractions.  This was thought to be the reason that antimuscarinic agents were used for bladder spasticity.   

This process was not delineated very well until about the past 10-15 years.  A combination of brain imaging during micturation and neuroscience techniques applied to determine the anatomic pathways.  One of those techniques was the application of pseudorabies virus to the wall of the rat  bladder.  This technique leads to retrograde transport of the virus into affected structures.  Viral markers go to structures in both the peripheral and central nervous system. A wide variety of cortical and subcortical structures are involved including the raphe nuclei, locus ceruleus, red nucleus, periaqueductal grey area, pontine micturation center, and cerebral cortex are involved.  The parasympathetic excitatory reflex pathway  is presented in the diagram below (1).

The circuits controlling continence and micturation are shown below. The diagram on the left is the storage reflex consisting of negative feedback to inhibit detrusor contractions and increase urethral sphincter activity. In the voiding phase intense afferent activity in the spinobulbospinal reflex pathways passes the pontine micturation center. That leads to descending parasympathetic activity stimulates detrusor muscle and inhibits urethral sphincter activity at the bladder outlet. Associated structures at the brain level have been suggested by functional imaging studies. The central mechanism suggested is release of tonic inhibition of the micturation center by the frontal cortex. Some of the associated structures are important limbic structures and have connectivity to other organ systems by sympathetic tracts. 

In the case of BPH, there is increased intraluminal pressure in the proximal urethra or bladder outlet. This alters the set point of the system. Voluntary voiding occurs but at higher residual volume and detrussor pressure. That leads to typical symptoms of frequent voiding, decreased urine flow, and small volumes. In extreme cases total obstruction can occur on at least a temporary basis requiring temporary catheter insertion to maintain urine flow. 

Getting back to psychiatry, let me illustrate the relevance of the problem. 

Case 1: JD - a 68 yr old man in fairly good health until about 3 months earlier. At that time he started to experience profound sleep problems. He has obstructive sleep apnea (OSA) and uses CPAP - but his parameters looking at the AHI and air leakage are unchanged. He now has frequent nocturnal panic attacks that awaken him.  Upon waking his heart is pounding and he has palpitations. He purchased a single lead hand held ECG device that takes a 30 second rhythm strip and recorded one ventricular premature contraction in 30 seconds. He consulted both his pulmonologist and cardiologist involved in the original OSA diagnosis. The pulmonologist looks at his CPAP parameters and concludes that he does not need another sleep study. The cardiologist tells him that these VPCs are benign and there is nothing to worry about. JD is concerned because this is a definite change in his health status and neither physician is concerned. 

He went in to see his primary care physician who examines him and jokes about the cardiac-bladder connection. He does a prostate exam and concludes that his prostate is "about the 90th percentile". No further evaluation or treatment is recommended. 

His wife notices that he is sitting up in a chair in the bedroom a lot more at night. He explains that he is having palpitations and is very anxious at night. His wife tells him to see the psychiatrist who is treating her for panic attacks. He makes an appointment and goes in about 2 weeks later. 

The psychiatrist does a complete history and sleep assessment and concludes that these are not typical panic attacks. JD recalls a number of dreams where he is running, exerting himself, or very fearful in the dreams. He awakens with his heart pounding and experiencing the irregular beats. As soon as he is able to void, the tachycardia and palpitations resolve. The psychiatrist thinks they are related to the episodes of urinary frequency and urgency associated with BPH and that therapy targeted to address the bladder outlet obstruction will lead to a resolution of the sleep problems and panic attacks. Since seeing his primary care physician JD has acquired a wrist watch with a vibrating alarm. He uses it to wake himself up at 2AM and 4AM and finds that pre-emptive bladder emptying greatly reduces but does not eliminate the nocturnal panic attacks entirely. The psychiatrist refers JD to a Urologist. He is assessed and treated with tamsulosin - an alpha blocker that relaxes smooth muscle fibers in the bladder neck and prostate. Taking the medication results in a significant improvement but not a normalization of bladder emptying. JD is back to voiding once a night. He has no nocturnal panic attacks or dreams where he is fearful or exerting himself.

The background and case illustrate a few points. Now that micturation is no longer a black box in the brain, the affected structures and the types of symptoms that can be generated need to be considered. It is an easy mistake to treat what seems like a panic attack like a panic attack - especially when previous physicians have not been impressed enough to work up or treat the problem. Nocturnal panic attacks in a 68 year old man with no previous psychiatric history suggests that there are possible medical causes for these symptoms and in this case it was bladder outlet obstruction. The closest syndrome to account for the findings in this case is cystocerebral syndrome - typically delirium in elderly men with acute urinary retention where no other cause can be identified (3-9). Decompressing the bladder typically results in resolution of the acute confusion. That has led several of the authors to postulate that an adrenergic rather than anticholinergic mechanism is involved. I don't not have access to all of these papers and cannot tell if the authors documented some of the problems noted in the case described here (tachycardia, palpitations, VPCs, anxiety and panic) but they are all presumptive hyperadrenergic mechanisms. 

Whether sleep disturbance, panic attacks, and eventual delirium can all occur in the same men with bladder outlet obstruction is not known at this point. That progression of symptoms seems to make sense but it is not well documented and may just be another syndrome waiting for better characterization.  One of the main differences may be the post void residual volume.  In the case presented here that was about 200-300 ml.  In the literature on cystocerebral syndrome there is usually urinary retention and a much larger volume - often 1 liter or more.  

Until then BPH and the associated lower urinary tract symptoms (LUTS) are markers that psychiatrists and sleep medicine specialists need to pay close attention to - especially if it comes with insomnia, panic attacks and palpitations. 

George Dawson, MD, DFAPA

References:

1: Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci. 2008 Jun;9(6):453-66. doi: 10.1038/nrn2401. Review. PubMed PMID: 18490916.

2: Griffiths DJ, Fowler CJ. The micturition switch and its forebrain influences. Acta Physiol (Oxf). 2013 Jan;207(1):93-109. doi: 10.1111/apha.12019. Epub 2012 Nov 16. Review. PubMed PMID: 23164237.

3: Shirvani N, Jimenez XF. Cystocerebral Syndrome: A Case Report and Review of Literature and Mechanisms. J Am Geriatr Soc. 2015 Dec;63(12):2645-2647. doi: 10.1111/jgs.13851. PubMed PMID: 26691712.

4: Washco V, Engel L, Smith DL, McCarron R. Distended bladder presenting with altered mental status and venous obstruction. Ochsner J. 2015 Spring;15(1):70-3. PubMed PMID: 25829883; PubMed Central PMCID: PMC4365850. 

5: Saga K, Kuriyama A, Kawata T, Kimura K. Neurogenic bladder presenting with cystocerebral syndrome. Intern Med. 2013;52(12):1443-4. PubMed PMID: 23774572. 

6: Young P, Lasa JS, Finn BC, Quezel M, Bruetman JE. [Cystocerebral syndrome]. Rev Med Chil. 2008 Nov;136(11):1495-6. Spanish. PubMed PMID: 19301784. 

7: Waardenburg IE. Delirium caused by urinary retention in elderly people: a case report and literature review on the "cystocerebral syndrome". J Am Geriatr Soc. 2008 Dec;56(12):2371-2. doi: 10.1111/j.1532-5415.2008.02035.x. Review. PubMed PMID: 19093953. 

8: Blè A, Zuliani G, Quarenghi C, Gallerani M, Fellin R. Cystocerebral syndrome: a case report and literature review. Aging (Milano). 2001 Aug;13(4):339-42. Review. PubMed PMID: 11695503. 

9: Liem PH, Carter WJ. Cystocerebral syndrome: a possible explanation. Arch Intern Med. 1991 Sep;151(9):1884, 1886. PubMed PMID: 1888260. 8: Blackburn T, Dunn M. Cystocerebral syndrome. Acute urinary retention presenting as confusion in elderly patients. Arch Intern Med. 1990 Dec;150(12):2577-8. PubMed PMID: 2244775.

10: Glen W Barrisford GW, Graeme MS, Steele S. Acute urinary retention.  O'Leary MP, Hockberger, RS Editors. UpToDate. Waltham MA: UpToDate Inc.  http://www.uptodate.com (Accessed on March 30, 2018.)


Graphic Credits

Both neuroanatomy and urology graphics in this post are from reference 1 and posted here:

Reprinted by permission from Nature/Springer: Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci. 2008 Jun;9(6):453-66. doi: 10.1038/nrn2401. Review. PubMed PMID: 18490916. License number  4319020942759

The graphic of the empty sample cup is from Shutterstock per their standard licensing agreement.

Take Your Meds

"It might be because I have severe ADHD.  It might be because it was jet fuel.  I don't try to draw the line".  - Stimulant user rationalizing use.


The above comment was made by a young man in the new Netflix documentary "Take Your Meds" about stimulant medications (but mostly Adderall).  Fortunately or unfortunately depending on your viewpoint - physicians are still charged with the task of drawing the line.  I don't typically like watching documentaries, but since this is my area of expertise I thought I would watch this one.

From the outset, it was apparent that the real downsides of using tremendously addictive drugs were not going to be emphasized.  This was a sanitized version of abusable drugs.  It was stated that prescription stimulant users were a class apart from methamphetamine users.  There seemed to be an implicit message that in an egalitarian society - if the methamphetamine users had access to stimulants they would be better off. If we all could get access to performance enhancing drugs like stimulants the world would be a better place.  A neuroscientist known for this kind of social commentary made some remarks basically stating that prescription stimulant use is another example of class factors in addiction.  In this case because over half of the story was performance enhancement - that class argument was also made.  Are those lower socioeconomic kids losing out because they don't have access to this performance enhancement?  Probably not because the film makers don't present any data that performance enhancement actually occurs.  It is the idea of performance enhancement. 

A modicum of of common sense and medical use was introduced.  They showed a very concerned pediatrician treating children of mothers who had some expertise in the field and nothing seemed to help their sons than stimulant medications.  In one scene the pediatrician spends a time convincing one of these teenagers that it is up to him to take the medications. I do not know how doctors can have those conversations in awkward examination rooms with the unexamined identified patient sitting on an exam table and the doctor just standing there talking.

We meet a number of individuals over the course of the documentary.  The first is a new college freshman.  She is the first to comment the competitiveness/ performance enhancing aspect of stimulants - namely "Everybody here is on them.  They are traded and sold.  In order to be competitive I have to be on them."

We meet a former professional football player who starts taking them.  We learn about how great he felt and how much of an advantage it seemed to make in all aspects of his play and in overcoming injuries.  We learn that in the NFL, if you are a player you can get an exception to play with stimulants and take them if a doctor says that you have ADHD and then only the prescription written by the doctor.  In this case the prescription was for Vyvanse 70 mg per day with 2-10 mg Adderall as needed on top of the Vyvanse.  The Adderall was occasionally increased to 20 mg twice a day in addition to the Vyvanse.  Either way he is taking more than the recommended total amount of stiumlant per day.  One day before the game, the player in this case ran out of his usual stimulants and took Concerta (methylphenidate) from another player.  Concerta had a different profile on toxicology screening and as a result he incurred a 4 game suspension.  The details of what happens next are not clear but we see him when he is not longer playing professional football and has moved on with his life.  In an interesting postscript, he talks about the conflict of being a different person on stimulants and what it means to take credit for what that person does.

We meet a Wall Street researcher and coder.  We get opinions on what coders think of using stimulants to write code and their aspirations to write perfect code.  He paints a picture of what it is like to work for a large investment concern.  A room full of people on computers, expected to work very long hours and get rapid results.  If additional time is needed, the plan is to take stimulants and get the work done.  One night he declines stimulants, leaves work and the guy next to him stays there and at some point has a seizure from stimulants.

The common threads are the idea that stimulants are used as performance enhancers to be more competitive in academic and business environments. The idea is that every student and worker is expendable and if they can't do the job, somebody else will step up and do it therefore stimulants are necessary.  Some seem annoyed by the charade of having to convince a doctor that they have ADHD in order to get a stimulant prescription.  They would prefer just to get it without any medical diagnosis.  Hallucinogens are brought up as additional performance enhancing agents - especially microdose hallucinogens.

There are the usual suggestions that this is a pharmaceutical marketing phenomenon.  There is a brief discussion of America's first amphetamine epidemic and how the Controlled Substances Act was used to shut it down.  The producers do mention that adult prescriptions for stimulant medications now exceed the prescriptions for children. They touch on problems with a totally subjective (first-person report) and a lack of clear objective markers for a diagnosis - but not the amount of fraud that goes on to get these prescriptions.  Nobody ever points out for example, that none of these otherwise high functioning adults would qualify for the diagnosis on level of disability alone.                 

The only small bit of scientific data in the film was the work done by Farah, et al (1) who looked at the performance enhancing properties of amphetamines in health college students.  Across a large number of neuropsychological variables it seems that the only one that was significantly improved was the persons perception of their performance.  In other words, there was no objective sign that their performance was enhanced on cognitive testing but the subjects all believed they were performing better. There is more data that the performance enhancing aspects of stimulants are overblown.

That is certainly my experience interacting with amphetamine users for the last 30 plus years.  I caught the tail end of the first epidemic and starting seeing obese patients on high dose amphetamines.  Even though they had not lost a pound and were still very obese, they insisted on staying on high dose stimulants and were fearful they would gain weight if they stopped.  In those days it was not uncommon to get a call to the Emergency Department because there was a narcoleptic patient there form another state who was taking high dose stimulants (> 100 mg/ day of amphetamines) for narcolepsy.  My job was to figure out if the patient really had narcolepsy or they were lying to get stimulants.

Today my job is a little more subtle.  Adults are operating from many levels of misconception about both stimulants and ADHD.  Today I rarely meet an adult who does not think they have ADHD - even if they have a superior level of academic and vocational achievement. In some cases they have been swayed by the non-specific effects of stimulants - "I took my son's Adderall and for the first time I was able to focus and read well."  In many cases they are influenced by professionals who have heard about the high heritability of ADHD and interpret this to mean if they diagnose a child with ADHD it means the parents and in some cases the grandparents have it.  I have seen generations diagnosed this way.  I  work in the addiction field and everyone who is addicted to stimulants believes that they cannot live without them. They get quite angry if they are not supplied.  That same population is in withdrawal form using very high doses of prescription or non-prescription stimulants and they also present with a residual ADHD that cannot be distinguished from ADHD but it is due to acute and chronic changes from stimulant overuse.  Last but not last, the medical and potential medical complications of amphetamine use need to be carefully determined.  Hypertension, cardiac changes,  arrhythmias, and movement disorders are all fairly common in people who overuse stimulants.

 These are a few of the major points that the Netflix documentary leaves out.  It touches a few of the high points but like most media pieces it gets too focused on human interest stories.  Historical lessons like what happened during the First Amphetamine Epidemic seem to be lost.  When that ended in the 1970s even the rock bands of that era were sending the message that "Speed kills!"  Addiction is more likely to happen if it is taken because for performance enhancement.  Any time a person operates from the perspective that taking a medication will greatly enhance their performance, it is difficult to not think that "more is better."

If you are a bottom line person, I think you will be disappointed if you want to learn some science about ADHD and stimulant treatment in this documentary.  You will hear a few sound bites but not much more.  If your interest is more in the pharmaceutical industry selling stimulants and marketing them excessively, you will also get the superficial story.  There is much more detail on annual prescriptions and trends.  On a historical basis, I produced a timeline extracted from a history of America's first amphetamine epidemic that covers everything in the film and more without the film clips of Jack Kerouac.  If you are an addiction specialist like I am, I think there is a message there that most of the prescriptions for adults are not for ADHD but for some type of cognitive enhancement and the basis for that is thin.  That is a good take away message, but the real downside is not that apparent.

That downside is addiction.  Compulsively using stimulants to the point that your life, your relationships, and your health are destroyed is as possible with prescription stimulants as it is with methamphetamine.  Both are sold on the street by the same dealers.  Contrary to what you read in the press or pick up in this film all it takes is exposure to amphetamines and the right genetic make-up to create an addiction.  Having true ADHD, or the right socioeconomic standing, or willpower doesn't protect you against addiction.  Once an addiction to prescription or nonprescription stimulants occurs it is a very difficult problem to recover from.  Unlike opioids and alcohol - there are no known medications to assist in recovery. 

So like most treatments in medicine, stimulants need to be cautiously applied.  Indiscriminate use for performance enhancement does not seem like a good idea to me because it will cause proportionally more addiction and the cognitive gains across the population are minimal mostly restricted to the  perception that you are doing much better than you are. 

Not a good reason for taking stimulant medications unless you really need them.


George Dawson, MD, DFAPA
 





References:

1: Ilieva I, Boland J, Farah MJ. Objective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people. Neuropharmacology. 2013 Jan;64:496-505. doi: 10.1016/j.neuropharm.2012.07.021. Epub 2012 Aug 1. PubMed PMID: 22884611.

2: Smith ME, Farah MJ. Are prescription stimulants "smart pills"? The epidemiology and cognitive neuroscience of prescription stimulant use by normal healthy individuals. Psychol Bull. 2011 Sep;137(5):717-41. doi: 10.1037/a0023825. Review. PubMed PMID: 21859174

3: Bagot KS, Kaminer Y. Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review. Addiction. 2014 Apr;109(4):547-57. Review. PubMed PMID: 24749160.

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.

Bedless Psychiatry and A Recipe for Remaining Bedless

There is no better marker of the rickety psychiatric infrastructure in the USA than the lack of psychiatric beds.  A close second is how those beds are utilized to basically run patients in an out to maximize hospital profits. It seems like I have said it a thousand times on this blog but I will say it again - hospitals make money by getting psychiatric patients out in advance of the diagnosis related group (DRG) time limit.  These days that it is about 3-4 days. If management believes that the psychiatrist is not discharging people fast enough - they will turn up the heat on them to do so by using either a designated case manager or somebody who sits in team meetings and reports that psychiatrist to his or her superiors if the patients are not out by a maximum of about 6 days.

There are huge problems with that business approach to psychiatric care.  The first is patient complexity. Severe psychiatric disorders place people at risk for significant medical problems and often psychiatric care cannot proceed until those medical problems are stabilized.  During my career for example I had terminal cancer patients and patients with uncontrolled diabetes mellitus and hypertension admitted directly to my care because they had a major psychiatric disorder.  Substance  use disorders complicate at least half of the admissions and psychiatric care typically has to wait until a patient is detoxified from an intoxicant.  Very ill patients with schizophrenia and mood disorders who received outpatient treatment cannot be treated and stabilized in 4-6 days.  Specific problems like suicide risk and delirium often take many weeks of care.  Although brief stays can be useful in the case of event or intoxicant related crises the length of stay on psychiatric units is basically an arbitrary number of days determined by bean counters rather than doctors. They do no reflect clinical reality.

That brings me to the commentary by Sisti, Sinclair, and Sharfstein (1).  They lost me then they had me and then they lost me completely.  My first criticism is the title "Bedless Psychiatry-Rebuilding Behavioral Health Service Capacity."  Ironic that the authors use the managed care buzzword "behavioral health" to suggest that the bed crisis can be addressed by the same carpetbaggers that designed the current system.  I can appreciate a political turn of a phrase as well as the next rhetorician, but in the case it falls very flat.  The only way to address the bed crisis and the destruction of the mental health care infrastructure in this country is to get rid of managed care and all of their buzzwords.  There is no way that companies paid well for rationing care and kicking unstable people out of psychiatric hospitals are going to solve that problem.

From there the authors do an adequate job of describing the problem of a sharp drop in bed capacity in addition to the absurdly short lengths of stay.  They depend on data that may have another agenda.  In a recent post in this blog, I looked at the drop in state hospitals beds in Minnesota and the Medical Directors commentary on why that will never be reversed.  The same organization that authored the report used by the authors to describe the drop in beds (National Association of State Mental Health Program Directors (NASMHPD) is on record stating that "Building more inpatient bed capacity to meet demand is unsustainable".  State Mental Health Program Directors are all accountable to state politicians and generally run state mental health programs like managed care companies do.  They ration services and limit access to treatment. It is cost effective from their perspective to leave large blocks of people untreated. Better yet put them in jail and give them a baloney sandwich everyday instead of the à la carte fare that medical and surgical patients have come to expect in customer satisfaction based hospitals.  This conflict of interest and lack of interest in looking at whether bed capacities are too low is a bias that any reader of the report should be aware of.   They also consider OECD data and suggest that psychiatric bed capacity in the USA is 4th from the lowest bed capacity in the countries studied.

They go on to discuss the "types" of beds  and suggest that the notion that bed capacity may be too abstract.  They favor bed descriptions based on the function of the unit that they reside on - forensic, acute care, intermediate, and long term care.  They discuss beds in the grey zones between corrections and mental health.  For example in my discussion of the Minnesota situation, I did not include beds operated by the Minnesota Sex Offender Program (MSOP).  That program houses 726 clients at two large facilities or about three times the state bed capacity for all of the committed patients with mental illness in the state.  In a bizarre end run around psychiatry, sex offenders in the state are essentially granted mental illness status.  This occurs in order to allow the state to indefinitely commit them.  MSOP clients are essentially never discharged while committed patients back up and crowd local hospital psychiatric units and shut them to new admissions while they are waiting to be transferred into the state hospital system.  The argument about no new beds at the state level does not apply to sex offenders.

The authors close by saying the concept of a psychiatric "bed" may need to be "jettisoned" in order to more accurately address the needs of patients and system capacity.  They end with the idea that "targeted payment reforms" are necessary to increase psychiatric bed capacity.  I think that they have it wrong on both accounts.  We have had 30 years of "incentives" that really are not incentives.  The DRG payment itself was allegedly a payment for what was the average amount of care for a particular diagnosis.  Instead, it became a way that managed care companies could game the system while they rationed care.  It may not be as easy to determine (another bean counter bias) - but looking at the flow though systems and where services are short is a better idea.  Classic examples are outpatient psychiatrists who are not able to refer one of their outpatients to an inpatient unit in the same system for purposes of detox, electroconvulsive therapy, or stabilization.  Whenever that happens it should be taken as a sign that health plan needs to improve their bed capacity.

Bed quality is as least as important as bed inventory.  Beds are worth less if there are problems with the physical structure or staffing problems.  Beds are worth less if a therapeutic environment cannot be maintained. Beds that can contain aggressive behavior are generally at a premium because fewer people can work in that setting. In every state there are only a few psychiatric units that will address aggression as a psychiatric problem.  Specialty units to treat depression, bipolar disorder, schizophrenia, substance use in addition to mental illnesses, or medically ill psychiatric patients are rare.  There appears to be no interest in either the quality or specialty side.  DRG payments create an incentive to get people out as soon as possible and provide the lowest level of quality.

A very basic comparison with any systems of high quality beds that address the medical problem with state of the art care is instructive. Any middle aged person in the US who presents to the emergency department with chest pain who has cardiac risk factors will be admitted to a telemetry unit, get the necessary blood testing, and (if all of those tests are negative) will probably get an echocardiogram and cardiac stress test before they leave the next day. That same person presenting to the emergency department with hallucinations or mania or severe depression or delusions will only be admitted unless they are determined to be "dangerous".  The standard definition of dangerousness being "imminent risk of harm to yourself or others."  Dangerousness is the managed care approach to psychiatric hospitalizations.  It contaminates emergency assessment and it contaminates what happens on the inpatient side.  When the overriding treatment dimension is dangerousness - inpatient units become holding tanks where nothing therapeutic occurs. Patients sit around and look at one another all day long waiting for someone to proclaim that they are no longer dangerous - so they can be discharged.  Beds that operate under this punitive model should probably not be counted. 

The authors' commentary seems to continue the same policy wonk approach that has contaminated practically all medical journals - basically a number of administrators sitting around and speculating.  Unfortunately we know that a lot of bad ideas get started this way. We also know that hypotheticals and incentives have have been the order of the day for a generation and that very process knocked out bed capacity and led to all of this low quality care.

To improve the bed capacity it will take a psychiatrist who is aware of the problems and how they can be addressed in each state.  Being on the ground as the inpatient beds and any quality they had were rationed away would be a plus.  Knowing how to build increased capacity and quality is the best possible approach. 


George Dawson, MD, DFAPA



References:

1:  Sisti DA, Sinclair EA, Sharfstein SS. Bedless Psychiatry—Rebuilding Behavioral Health Service Capacity. JAMA Psychiatry. Published online March 14, 2018. doi:10.1001/jamapsychiatry.2018.0219

Graphics Credit:

The above picture of an abandoned state hospital bed is downloaded from Shutterstock per their standard licensing agreement.

There Is No Joy In Medicine

At least not nearly as much as there used to be.

I read a comment by a medical student recently who said that he found nothing in medical school - none  of the clinical rotations to be enjoyable at all.  As I looked back on it, at the interpersonal level there is a lot of subjectivity.  Although it was never stated personalities could make or break a rotation.  There was none of the anonymity of sitting is a large lecture hall and passing three or four tests.  As a medical  student, most of the teams I was on consisted of me, an intern, a resident and occasionally a more senior resident and one or more attending physicians.  Just as in real life, it was common to find people who really did not want to be on those teams.  They were fulfilling some sort of obligation.  As in real life, it was fairly common to be on a team where someone did not like you and if they were personality disordered could make your life a living hell.  But that was relatively rare.  As a medical student, the job was to keep your head down, not make any waves and absorb as much information as possible.

And some of those rotations were a dream.  A perfect combination of senior staff who knew they were there to teach, did a great job of it, and went the extra mile to be as cordial as possible to everyone in the process.  I have written about the last team I was on in medical school as an example.  The Renal Medicine team of of Milwaukee County Medical Center and Froedert Hospital in Milwaukee.  In those days there were three senior attendings who were also Professors in the medical school.  They ran an inpatient unit, outpatient clinic, and hypertension clinic. They also covered all of the inpatient consults. There was an associated group that took care of transplant and dialysis patients and all of the complications.  As a medical student my job was to do the initial patient interviews on the consults and present it to the team and round with the team on all of the inpatients.

It was an inspiring team to be a part of. One of the senior Internal Medicine residents was a guy who I had worked with before.  He was bright and had an incredible sense of humor. The most senior attending would give us all a hard time, but you could tell he was joking.  I never saw him lose his temper.  We were typically putting in 10-12 hour days with both patient care and didactics.  There was scheduled teaching time every day and plenty of teaching on the case presentations. Everyone was interested in the work and flexible. On my absolute last day of medical school the Internal Medicine resident told me they were swamped with admissions.  It was 6 PM and he knew I was graduating the next day.  He let me know that and then asked me if I could see 2 consults that needed to be staffed.  I did and felt good about it.  I lived about 1/2 mile away across the golf course sized county grounds and was ecstatic that night for completing medical school and that rotation.

Enjoyable rotations were not limited to medicine specialties.  I had plenty of contact with neurosurgeons in the same hospital.  The Neurosurgery residents had a grueling schedule starting as second year residents where they were basically on call every night.  They were in surgery in the morning and had to assess and treat acute emergencies in a very hectic emergency department.  The also ran a neurosurgery ICU.  On that service we rounded every morning and tried to get all of the work done on hospitalized patients by  11 AM.  The rest of the day was typically spent dealing with one emergency after another. The head of neurosurgery did not say much and appeared to be brusque, but he was an outstanding surgeon and teacher in the operating room.  We also had Radiology rounds every Saturday morning where he would review all of the imaging studies done on our patients in the previous week. That was a two month rotation for me and very enjoyable.

When I think of the common elements in those rotations that made them implicitly joyous - a few things stand out:

1.  They were intellectually rigorous:

There was no dispute that the teachers and professors knew the field inside and out and were interested in discussing it.  My only regret is that as a medical student - you really don't know enough to ask the best possible questions - at least I didn't.  My standard procedure was to study the problems that were being addressed in detail and in retrospect it might have been easier to ask a lot of questions.  Teaching occurred in detail and at length every day.  It was routine.

2.  They managed their own services:

These days practically all hospitalized patients are managed by hospitalists. Hospitalists will call in specialists as needed, but they basically assess the patient and leave a note in the chart.  People will say this is more efficient and have that same argument about primary care physicians not seeing their own patients in the hospital - but a lot is lost in the process.  Teaching is an obvious casualty. Are you going to learn more about a patient who is on your service 24/7 or one who you drop by and leave a note for the hospitalist team?  I have seen medical students following consultants around and they often look bewildered.  As a team, there is a sense of belonging and typically a place to hang your hat and discuss the work every day.

3.  There was no outside interference by the business world:  

The hospital landscape has become bizarre relative to the hospitals I trained in. Instead of morning rounds - you might see a team of physicians in a "huddle" in the morning.  That huddle may contain non-medical staff and administrators who have no role in patient care. There are really there to manage physicians. Some might tell physicians when to discharge patients.  Others are just there to report what physicians are doing to senior management.  Let me clarify that these are not multidisciplinary treatment teams. I had 20 years of those teams meetings that were clinically focused and then one day there was a case manager in that group and she was reporting what I was doing to a hostile medical director who threatened to override my decisions. At a team level there was an equally malignant administrator trying to undermine the relationship between medical and nursing staff.  It is clear from my medical school experience that none of the managers were necessary and they made the clinical situation much worse. Add utilization review and prior authorization done by companies with an obvious conflict of interest and the hospital landscape suddenly becomes a complete nightmare.  I found myself in the position of needing to go though 2 hours of prior authorization time in order to discharge patients on the same medications that they came in on. In other words the medications were already authorized but I had to do it again.

4: Physicians weren't treated like criminals:  

Physicians tend to not be very good with politics and have a short memory but I don't.  In the 1990s, a billing and coding system was introduced that was supposed to capture physician work and provide commensurate reimbursement.  Unfortunately the inventors of this system did not realize that it was totally subjective and far too detailed. In the only study ever done on the validity of the system, the chance that any two coders could agree on the same billing code was a coin toss. In the meantime, at some point during that decade my hospital colleagues and I were cloistered in a lecture hall and told that any mistakes on our documents were a crime and if a billing statement went out based on that crime - we could be prosecuted under federal racketeering charges. In the meantime, the FBI was raiding doctors offices and trying to make documentation errors into a federal crime.  Eventually the federal government must have seen this was a bit heavy handed and they turned enforcement over to compliance monitors in organizations.  I was awarded the "best documentation" one year by a compliance officer and the next year it was the worst. Over that year, I had made no changes to my documentation. Today there is a mountain of worthless documentation that takes each physician about 3-4 extra hours per day to produce that is the direct result of this initiative. If I was back on my neurosurgery rotation - the document would have been 3-4 handwritten lines.

5: Everybody was an expert - not pretending to be one:

Fake medical news is common across all social media.  Journalists commonly print the story that they want rather than reality.  A common story on this blog is is how physicians were bought off by (often trivial) gifts and this led to inappropriate prescribing and massive drug company profits. It was a good story while it lasted and some media is still trying to push it but when gifts to physicians were eliminated, the USA still has by far the most expensive pharmaceuticals in the world.  There are even more provocative headlines out there that don't pass the smell test.  It is in the best interest of click-bait journalists and business administrators to make it seem like knowledge in medicine is relative and anyone can possess it.

6:  Clinical care was cohesive and not fragmented: 

Business innovations in medicine leave a lot to be desired.  When the field is structured around the ideas of business managers and some of these problematic ideas are published as commentaries in prestigious medical journals - adequate care becomes an increasingly remote possibility.  On the services I mentioned patients were triaged to receive the state of the art care of the day.  They did not end up seeing a series of physicians or providers who had no clue about how to address the problem and hoping to see the appropriate specialist.  In fact one of the most embarrassing developments of managed care was the idea that they were going to put specialists out of business or install a gatekeeper to see who gets referred to a specialist.  There are ample examples on this blog of the importance of seeing the appropriate specialist without having to deal with any administrator erected obstruction.  The main fracture in medicine at this point has been the destruction of the psychiatric infrastructure and the incarceration of the mentally ill.

Just a few obvious reasons why my most joyous experience in medicine happened in medical school over 30 years ago.  I think it could all be distilled down to the basic truths of autonomy, professionalism, a singular patient focus, an intellectual approach to the field, and doing the right thing. That is when you have hard working physicians who enjoy the work and are not burned out.  Medicine is currently creaking under the weight of bad ideas from politicians and bureaucrats and all of the associated rationalizations.

It is no wonder that I often find myself thinking about my old renal medicine and neurosurgery teams and whether future physicians will ever be able to capture that joy again.

It is no wonder that when Grace Slick sings with conviction over my Bluetooth player that I am focused on those first 4 lines.......



George Dawson, MD, DFAPA




Graphics Credit:

Photo licensed directly from Gijsbert Hanekroot Fotografie. Title below:

Jefferson Airplane Perfornm Live At Kralingen Festival
ROTTERDAM, NETHERLANDS - JUNE 26: Grace Slick and Jorma Kaukonen from Jefferson Airplane perform live at Kralingen Festival in Rotterdam, Holland on June 26 1970 (Photo by Gijsbert Hanekroot/Redferns)


Lyrics:

From the song Somebody To Love performed by Jefferson Airplane.  Words and music by Darby Slick.


Supplementary:

Interested in Grace Slick photos from around the time of the release of this song. Contact me if interested.

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.

Drinking Your Way To Your 90s.

The headlines recently have been unmistakable:

Drinking alcohol key to living past 90, study says

Drinking Tied To Long Life In New Study

Drinking alcohol increases longevity more than exercise, according to study

Alcohol more important than exercise for living past 90, study claims


Could these headlines be true?  After all, wasn't there a recent headline that said drinking alcohol was the largest single modifiable risk factor for dementia (1)?  Buried in some of those headlines are also secondary stories about political decisions that did not go well for the producers of some alcoholic beverages.  France's Health Minister Agnès Buzyn - a physician stated recently that alcohol is alcohol.  She went on to say that contrary to what French citizens are taught to believe about the health effects of wine it is no  different than drinking beer or distilled spirits and it is bad for health.  I think that we have been in the midst of a tremendous  amount of hype about alcohol, the specific types of alcohol, secondary natural products, the purported metabolic effects and the effect of alcohol on longevity.  The current headlines were the only ones I can recall where the positive effects of drinking alcohol was estimated to be on par with exercise.

I come at the problem from the perspective of an acute care and addiction psychiatrist. For 22 years, I worked at a tertiary care center that was also a Level 1 Trauma Center and it contained a burn unit.  At one point our medical director surveyed our admissions and determined that at least 50% across the entire hospital were there because of drugs or alcohol.  We saw every type of injury and chronic illness due to intoxicants and the patients with those insults often had markedly shorter life spans than expected.  How could alcohol use extend life?  Why was it seen as a common finding? Most importantly - why were all of these headlines surfacing right now?

Some of the articles named Claudia Kawas, MD and her work in the 90+ Study and Leisure World Cohort Study as the source for the headlines (2-4).  The Leisure World Cohort Study (LWCS) followed a group of 8,371 women and 4,828 men from a media baseline age of 74 for a period of 28 years or until death.  The group was located in a retirement community and were described as predominately white, middle class and well educated.  They were sampled at intervals with questionnaires that asked about their dietary habit including beverage intake in terms of alcohol and caffeine containing beverages and other types,  a number of activity levels, and total amount of exercise.  A large number of papers resulted from this study and are still being written as the continuation study of the members that survived into their 90s.  Dr. Kawas gave a presentation at a recent American Association for the Advancement of Science (AAAS) meeting on some of her findings and that appears to be what the headlines based on.

 From the LWCS group, there were several notable findings.  In terms of activity level (2), any activity of 1/2 hour per day or more reduced mortality risk 15-30%.  A broad range of exercise of various levels of intensity and whether they were done inside or outside.  Level of activity at age 40 was a predictor of activity in old age.  Relative Risks (RR) for all cause mortality were calculated for the activities and their duration. as well as the time spent.  After 3/4 of an hour per day the RR effect tapered off.  Sedentary activities like watching television had no significant impact on the RR.  The greatest observed risk occurred when activity levels were reduced due to injury or illness.  They found no survival advantage for a high activity level (1+ hours per day) compared to a moderate level of 1/2 to 3/4 hours per day.

The same group looked at the issue of alcohol intake in the LWCS group.  In their introduction they note that 4% of the annual mortality in the world is caused by alcohol.  They review some of the previous literature and the purported J - or - U shaped mortality curves for alcohol consumption - meaning higher mortality rates for abstainers, lower mortality rates for moderate drinkers (1-2 standard drinks per day), and higher mortality rates for higher levels of drinking. The response choices on the survey were for 1, 2, 3, and 4 or more drinks per day.  They also broke the sample down based on their responses drinking surveys in 1992 and 1998 to to stable non-drinkers, stable drinkers, starters, and quitters based on comparing their survey answers.  Three quarter of the sample drank.  Two drinks a day conferred a 14-16%  in decreased mortality irrespective of the type of alcohol.  At follow up there were more non drinkers than at baseline (36% versus 26%).  The quitters and starters acquired the expected mortality risks in each group.  They conclude that there was a small beneficial risk of alcohol on mortality of about 15% but qualify the result based on the study limitations.

The final dimension in this sample of the LWCS paper was a look at non-alcoholic beverages and caffeine content.  They looked a coffee, decaffeinated coffee, black or green tea, cola drinks (sugar or artificially sweetened), other soft drinks and sweetener combinations, and the amount of chocolate eaten (daily versus a few times per month.)  They found that there was a U-shaped mortality curve for caffeine consumption with peak protection at about the 100-399 mg/day.  They also found that consuming as little as one can a week of artificially sweetened soft drinks had a small increased risk of death (11-24%).  They looked at specifics and determined that 1-3 cups of regular coffee/day reduced mortality risk by 5-10% and drinking decaffeinated coffee or tea reduced risk by 5-9%.   Drinking sugar sweetened cola - had an 8% lower risk of death.  Infrequent chocolate users also had a reduced risk of death (3-9%).

Taken all together these three papers suggest that moderate levels of alcohol, caffeine, and activity are all consistent with longevity.  In order to look at the alcohol findings in perspective, I searched the literature for a meta-analysis of all of the alcohol x longevity studies and came up with an outstanding paper by Stockwell, et al  (5).  In it the authors look at and extensive analysis of existing alcohol effect on mortality studies and initially duplicated a J-shaped mortality curve based on 87 studies they included in their analysis.  They went back into that sample and corrected for abstainer biases such as including including former and occasional drinkers in the abstainer category.  They model four types of abstainer bias in their in the paper.  When those corrections are made or when only very high quality studies are used - the purported mortality advantage of moderate (1-2 standard drinks per day) - disappears completely.  I could not find any data from the LWCS studies used in this meta-analysis.  According to the author's selection criteria the LWCS data probably would have been eliminated because it was a cross sectional study.

That alcohol is not a heath food should not come as a surprise.  Any cohort of drinkers in their 90s suggests to me that they are biologically selected to survive the alcohol and that is probably why they are drinking into their 90s and not because of it.  Since the activity, caffeine, and diet soda effects noted in this study were collected using similar methodologies, that can be a cause for concern. The authors were careful to cite supporting data  and discuss the limitations.  Observational studies like the LWCS and 90+ Study add to the literature but it is necessary to keep these findings in perspective and consider the potential biases of the design.

At this time I have not found a similar meta-analysis for each of the other cases (activity level, caffeine consumption).

 

 George Dawson, MD, DFAPA


References:

All linked papers below are to free full text articles.


1: Schwarzinger M, Pollock BG, Hasan OSM, Dufouil C, Rehm J; QalyDays Study Group. Contribution of alcohol use disorders to the burden of dementia in France 2008-13: a nationwide retrospective cohort study. Lancet Public Health. 2018 Feb 20. pii: S2468-2667(18)30022-7. doi: 10.1016/S2468-2667(18)30022-7. [Epub ahead of print] PubMed PMID: 29475810.

2:  Paganini-Hill A, Kawas CH, Corrada MM. Activities and mortality in the elderly: the Leisure World cohort study. J Gerontol A Biol Sci Med Sci. 2011 May;66(5):559-67. doi: 10.1093/gerona/glq237. Epub 2011 Feb 24. PubMed PMID:21350247.

3:  Paganini-Hill A, Kawas CH, Corrada MM. Type of alcohol consumed, changes in intake over time and mortality: the Leisure World Cohort Study. Age Ageing. 2007 Mar;36(2):203-9. PubMed PMID: 17350977.

4:  Paganini-Hill A, Kawas CH, Corrada MM. Non-alcoholic beverage and caffeine consumption and mortality: the Leisure World Cohort Study. Prev Med. 2007 Apr;44(4):305-10. Epub 2006 Dec 29. PubMed PMID: 17275898.

5:  Stockwell T, Zhao J, Panwar S, Roemer A, Naimi T, Chikritzhs T. Do "Moderate" Drinkers Have Reduced Mortality Risk? A Systematic Review and Meta-Analysis of Alcohol Consumption and All-Cause Mortality. J Stud Alcohol Drugs. 2016 Mar;77(2):185-98. Review. PubMed PMID: 26997174.

The Abuse Potential of Gabapentinoids

I first started prescribing gabapentin in the 1990s, as part of an early attempt to see if it worked for bipolar disorder.  It was an off-label approach and did not have that indication.  At the time anticonvulsant approaches to bipolar disorder (valproate, carbamazepine) were being heavily used.  I was following a number of people who could not take lithium and on anticonvulsants and they seemed to do surprisingly well.  Gabapentin seemed to have significant advantages in terms of toxicity, it was well  tolerated by most people.  Unfortunately, it was completely ineffective for bipolar disorder and I stopped trying it almost immediately.

The next off label application that surfaced was for chronic pain.  Any psychiatrist is exposed to a number of patients with chronic pain or chronic pain and addictions, and it became apparent that it was being used successfully for chronic back pain, chronic headaches, and post herpetic neuralgia.  Over the next decade, gabapentin and then pregabalin was prescribed for chronic pain indications and people seemed to do reasonably well with it - even at relatively high doses.

At some point, physicians working in detox and the addiction field started to use gabapentinoids for chronic pain, anxiety, and withdrawal.  It is not uncommon to see patient with all of these problems who is not able to tolerate antidepressants for those symptoms or who needs more immediate relief.  In fact, in residential addiction treatment it is common to see patients come in on high doses of gabapentin for chronic back pain.   They are there for treatment of an opioid use disorder, but during that time have not escalated the gabapentin dose.

In the literature reports of gabapentin misuse have been surfacing over the past 5 years (1-7).  A large review (4) suggests that 1.3% of the treated population is at risk for gabapentinoid misuse with the number being much higher is some populations such as opioid users.  There is a report (3) that patients with opioid use disorder will attempt to augment the eurphorigenic effect of methadone in a similar way that they use benzodiazepines.  Benzodiazepine use with methadone in methadone maintenance clinics is a chronic and at times lethal problem.  There is a report from Norway (5) that gabapentinoids may be useful is reducing benzodiazepine use.  The report generally suggests that the abuse potential is low and greater for pregabalin than gabapentin.  There is an insurance database report (6) that looks at an overuse metric comparing gabapentinoids to other abused drugs.  Goodman and Brett (7) comment on the epidemiology of gabapentinoid prescribing, specifically an increase in gabapentin prescriptions from 39 million in 2012 to 64 million in 2016 with an associated doubling in the sales of pregabalin during the same period.  They attribute the increase to attempts to treat chronic pain without opioids in primary care, suboptimal non-opioid medications (acetaminophen and NSAIDs). They cite mixed evidence in clinical trials, side effects, misuse or diversion, and an excessive focus on pharmacological measures for pain as being concerns.       

Are there biases in these report?  There certainly are.  I don't have access to the full text of the most comprehensive paper (2), but I would be interested in looking at the actual numerator and denominator for their numbers and how much was based on actual pharmacovigiliance/pharmacosurveillance as opposed to case reports, case series and reports of complications.  The other issue is that all of these papers seem to come from the same publisher.  I have not encountered that before.

The only study that I could find that looked at the direct question of concomitant use of opioids and gabapentin came from Canada (8).  It studies a large group of patients on a database that records the prescriptions and looked at all opioid users that died of opioid related causes between 1997 - 2013.  The big picture is that there were a total of 2,914,971 opioid users during the study time frame and 6,745 died of opioid related causes.  Then by selection criteria they identified 1,256 cases and matched them to 4,619 controls. They defined gabapentin exposure as concomitant gabapentin use in the 120 days preceding the index date.  They also looked for a dose response relationship of gabapentin doses considered as low (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg daily).  They also did a comparison with nonsteroidal anti-inflammatory drugs (NSAIDs) used as an adjunctive pain medication instead of gabapentin.  Their results are summarized in the following tables excerpted directly from the article (click to enlarge):

 
As noted from the data and analysis, 12.3% of the controls and 6.8% of the cases were prescribed gabapentin in the 120 days, representing a 50% increased risk of death in the gabapentin treated cases.  In the case/control comparison both groups have roughly the same levels of mental illness but the case group had higher utilization of antidepressants (all types), benzodiazepines, and other drugs/CNS depressants. They were also taking substantially more high dose opioid therapy (>200 MME).  Higher dose gabapentin nearly doubled the risk. There was no added effect from NSAID use.  The authors conclude that caution needs to be exercised in deciding to prescribe this combination (opioids + gabapentin) and that if that decision is made it needs to be carefully monitored.  From my perspective I had some concerns about the controlling for benzodiazepine use in the case/control comparison and did not see any risk attributable to benzodiazepines.  The authors do cite a reference that led to FDA warnings about the benzodiazepine-opioid combination. 

Given the concerns about gabapentin why use it at all?  The main reason is that it is effective for some of the most difficult problems in medicine.  It is very difficult to see people with extreme anxiety and insomnia go for weeks without sleep and experience continuous panic attacks all day long.  When a person stops taking benzodiazepines that they have been taking for years that is a frequent result.  The same is true for people who have decided to stop drinking and suddenly have very high levels of anxiety and insomnia now that their baseline anxiety is back.  More to the point, unless something can be done to provide them with timely relief, relapse to drug and alcohol use is certain.  Finally does high levels of abuse by some patients with addictions suggest that the medication is unsafe?  It is probably safer then other medications in this population and extremely safe outside of those populations.  In either case safety depends on whether there is a physician involved or the medication is acquired from nonmedical sources.   

Standard practice with gabapentin should be to tell all patients (in addition to the usual discussion and detailed information) the following information.  I point out here that I do not prescribe pregabalin:

1.  Take this medication exactly as it is prescribed.
2.  Do not accelerate the dose of the medication.
3.  Do not mix this drug with alcohol or any other intoxicants or street drugs.  If a relapse occurs call to discuss and set up a plan as soon as possible.
4.  Do not stop the medication abruptly it needs to be slowly tapered.  There is a seizure risk if it is not.
5.  This medication is potentially addictive to some people. If you notice any tendency to take more of this medication than prescribed contact me immediately.
6.  This medication is monitored on the state Prescription Monitoring Program and all prescriptions are recorded even though it is not technically a scheduled drug at this time.

At least that is the way that I think it should be handled.  If I was still seeing a lot of patients with chronic pain on moderate to high doses of opioids I would add in a line or two about the the Canadian study (9) and greater chances of death from the gabapentin + opioid combination.  In my current practice, psychiatric treatment is split off from buprenorphine detox and maintenance treatment - but I still see a lot of patients on buprenorphine + gabapentin and can attest to the fact that in a controlled environment we have not observed the complications suggested by the Canadian study over a period of months.  None of these patients receive benzodiazepines or sedative hypnotics beyond a period of detox.  In fact, doing that study might be a significant contribution to the research.  It also probably means that those patients when they are discharged should hear that the risk of taking that combination may increase substantially in the outpatient setting.

There is plenty of politics and confusion surrounding the gabapentinoids issue.  It should not be surprising that this medication is showing up in the toxicology of opioid overdose victims. It should not be surprising that some people try to get "high" on it, even though the people doing that do not have typical ideas about the utility of medications. It should not be surprising that people try to use gabapentin like benzodiazepines to augment the effect of what they are using to get high especially opioids.  It should not be surprising that when some people decide to stop buprenorphine or methadone that they will buy somebody's gabapentin to try to treat withdrawal effects.  It should not be surprising that in some areas it is currency on the street (What can I get for a month's worth of gabapentin?).  It should not be surprising that it has become a political football in the social media on pain ("See it's not opioids as the problem - it is gabapentin") or the social media on weed ("See these are Big Pharma solutions, marijuana is much safer").  It should not be surprising that you can read about it on drug culture web sites where everyone is an expert pharmacologist and provides you with anonymous advice on how to get high. It should not be surprising that you can buy it online and have it delivered to your door, although you can never really be certain that it is the same stuff you get at Walgreens.  I am always amazed at how easy it is to sell some Americans drugs, if they think there is the slightest possible chance they can get high on it. That is also why it should not be surprising that children and teens will take it out of medicine cabinets - use it to get high and brag about it even though there were probably not high at all.

The features about the gabapentinoids that make sense to me is that they are medically useful  and have low toxicity, for people with nearly impossible problems in desperate situations.  It is a less toxic drug on the street than those mentioned in the above paragraph. Even then these drugs need to be carefully prescribed and closely monitored.  And even then some people will escalate the dose. There are no perfect solutions in medicine and in this area in particular - nothing seems to be coming down the pike.  The probability statement is always - does the use of gabapentin result in more people with improved symptoms, better quality of life and less addiction?  At this time unless presented with compelling evidence I would say that it does with the qualifier that its application needs to be carefully done by a physician who knows what they are doing and is aware of the potential for misuse. In  the current era, that can all be subject to the next social media fad.

There is not a big push by the pharmaceutical industry at this time to discover a drug that has limited toxicity that can be used for severe chronic pain, insomnia, and anxiety associated with addictive disorders.  There is also the question of what medications are being used for these problems if not gabapentin.  The answer is atypical antipsychotics (mostly quetiapine), hydroxyzine (a first generation antihistamine), and clonidine (primary use is hypertension and opioid withdrawal).  If the comprehensive toxicology of overdoses is available I would expect to see these compounds listed.  In any search of drug interactions both quetiapine and hydroxyzine are flagged as potentially affecting cardiac conduction. Clonidine can cause hypotension if used excessively and rebound sympathetic symptoms (tachycardia, hypertension, diaphoresis).  Looking at that group of medications gabapentin would appear to have the preferred side effect profile.

There also appears to be a big push to make gabapentin a controlled substance according to the Controlled Substances Act (CSA).  Pregabalin is currently a Schedule V drug (see page 14) or considered to have the lowest abuse liability.  Getting on that list depends on how the DEA currently sees the addictive behavior towards gabapentin versus pregabalin.  Putting a drug on Schedule V will probably have no impact on how it is used in medical practice or out on the street.  The fact that pregabalin is ranked so lowly is a sign of regulatory opinion on abuse liability.

That's my current opinion on the topic.  I may add more to this post in the future or to a post I am working on about the basic science of gabapentinoids.


George Dawson, MD, DFAPA


References:

1:  Schifano F. Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS Drugs. 2014 Jun;28(6):491-6. doi: 10.1007/s40263-014-0164-4. Review. PubMed PMID: 24760436.

2:  Chiappini S, Schifano F. A Decade of Gabapentinoid Misuse: An Analysis of the European Medicines Agency's 'Suspected Adverse Drug Reactions' Database. CNS Drugs. 2016 Jul;30(7):647-54. doi: 10.1007/s40263-016-0359-y. PubMed PMID:27312320.

3:  Baird CR, Fox P, Colvin LA. Gabapentinoid abuse in order to potentiate the effect of methadone: a survey among substance misusers. Eur Addict Res. 2014;20(3):115-8. doi: 10.1159/000355268. Epub 2013 Oct 31. PubMed PMID: 24192603.

4:  Evoy KE, Morrison MD, Saklad SR. Abuse and Misuse of Pregabalin and Gabapentin. Drugs. 2017 Mar;77(4):403-426. doi: 10.1007/s40265-017-0700-x. Review. PubMed PMID: 28144823.

5: Smith, R. V., Havens, J. R., and Walsh, S. L. (2016) Gabapentin misuse, abuse and diversion: a systematic review. Addiction, 111: 1160–1174. doi: 10.1111/add.13324.

6: Bramness JG, Sandvik P, Engeland A, Skurtveit S. Does Pregabalin (Lyrica(®) ) help patients reduce their use of benzodiazepines? A comparison with gabapentin using the Norwegian Prescription Database. Basic Clin Pharmacol Toxicol. 2010 Nov;107(5):883-6. doi: 10.1111/j.1742-7843.2010.00590.x. PubMed PMID: 22545971.

7: Peckham AM, Fairman KA, Sclar DA. Prevalence of Gabapentin Abuse: Comparison with Agents with Known Abuse Potential in a Commercially Insured US Population. Clin Drug Investig. 2017 Aug;37(8):763-773. doi: 10.1007/s40261-017-0530-3. PubMed PMID: 28451875.

8: Goodman CW, Brett AS. Gabapentin and Pregabalin for Pain - Is Increased Prescribing a Cause for Concern? N Engl J Med. 2017 Aug 3;377(5):411-414. doi: 10.1056/NEJMp1704633. PubMed PMID: 28767350.

9: Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W.  Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Med. 2017 Oct 3;14(10):e1002396. doi: 10.1371/journal.pmed.1002396. eCollection 2017 Oct. PubMed PMID: 28972983; PubMed Central PMCID: PMC5626029.

Graphics Credit:


Figure 2 about is excerpted directly from the work in reference 8 above per the Creative Commons Attribution License.  The authors are listed as the copyright holders.


Supplementary:

Publication from the above content?  If you are a psychiatrist or pharmacologist and think you can rework the above article into a publication.  Contact me and let's write that paper!