Adding Rather than Subtracting Bias - An Underlying Basis for Polypharmacy?

There was an interesting piece in Nature this week (1,2) about cognitive biases in complex problem solving.  The research psychologists asked subjects to solve problems of varying complexity and structure from the perspective of whether additional structures or steps were necessary or whether an optimal solution could be obtained by subtracting structures or steps. I will briefly describe each of the problems in the table below (pending permission to use one of their graphics).

Task	Description
Abstract grid task	Transform a grid pattern to make it symmetrical
Suggested changes to a large public university	Changes to improve the sense of community, enable student learning, and prepare students for a lifetime of service
Lego block structure	Improve the 8 or 10 block structure
Lego block structures	3 possible structures built from 12 blocks of a pool of 24 blocks on a 6” x 8” base.
Lego block structure	Revision of original structures made from a possible 20 blocks to make a 10 block structure
Lego block structure	Modify a Lego structure so that it can hold a brick over the head of an action figure in the structure
Read and summarize an article	Make a 6-8 sentence summary and then edit it to a shorter version
Read and summarize an article	Edit someone else’s summary and edit it to “omit needless words”
Day trip to Washington DC	Inspect a trip itinerary and suggest changes to improve it
Make a grilled cheese sandwich	Make a grilled cheese from 27 ingredients -
Modify a soup recipe	From 5, 10, and 15 ingredient soup recipes – modify from a list of ingredients and modify to improves the soup.

Inspection shows that the cognitive tasks cover many domains ranging from 2D and 3D visuospatial tasks, language tasks, and more theoretical tasks that involve speculative rather than confirmed outcomes. The authors suggest an all-encompassing definition: “the cognitive science of problem solving describes iterative processes to imagining and evaluating actions and outcomes to determine if they would produce an improved state.”(p. 258).  They define subtractive transformations as fewer components than the original and additive transformations as more components than the original.  The authors noted a bias in anecdotal literature to making conscious subtractive transformations and that suggested to them that strategy may be less common or undervalued. 

Across all experiments, the tendency toward subtractive strategies with the general instruction were lower but probabilistic.  For example, across all experiments, subtractions ranged from 21-41%.  A second set of conditions with subtle subtraction cues increased the rate of subtractive transformations to 43-61% across the same experiments.  At one point the researchers added a cognitive load task that was basically a distractor to use more attentional resources. In these conditions cognitive shortcuts are less accessible. Under those conditions subjects failed to identify a subtractive solution more frequently.  The authors also studied subjects form Germany and Japan suggesting that there is cultural generalizability of the additive over subtractive strategies.

The authors consider that the differences could be accounted for by generating a number of additive and subtractive ideas and selecting the additive or they simply default to the additive.  They elected to look at the default to the additive mode. They describe heuristic memory searches allowing for the timely access of relevant information.  They suggest a number of reasons what additive strategies may be favored including – the processing may be easier, semantic biases such as more being better, cognitive biases may favor the status quo or less change, and it may be more probable that additive rather than subtractive changes offer a better outcome.

This is an interesting paper from a number of perspectives.  First, it presents a cognitive psychology approach with no purported biological mechanisms. There are no functional imaging studies or brain systems described.  The theories and design of experiments depends on a psychological model of cognitive function. Second, the model is probabilistic.  Although the title suggests systematic overlooking of subtractive strategies, it turns out that many don’t and this bias can be modified by experimental conditions such as subtraction cues. Third, the effect of increased cognitive load can be demonstrated to increase the likelihood of additive rather than subtractive biases. Fourth, the biases extend across a number of domains including physical, social, and intellectual. Fifth, the authors suggest that there may be a number of “cognitive, cultural, and socioecological reasons for favoring the additive bias over the subtractive one.  Sixth, although the additive transformation was more likely to occur that does not mean it offers the best solution to the problem.  It may simply be the most commonly used solution. 

Real world experience illustrates how the additive transformations can be reinforced.  Advertising is a common one. The goal of advertising is basically to sell someone something that they don’t need or change their preferences for something that they do need to a different product.  If it works, it is an additive strategy on top of additive behavior.  If the product being sold affects other learning centers in the brain like reward-based learning that can lead to further additive effects. The photo at the top of this post illustrates another example.  This kitchen drawer for spoons and spatulas is a solution to the cooking problem of how many are needed to accomplish what the cook in this case needs to accomplish. The drawer is packed to the point where it barely closes and at that point, the cook is forced to reassess and decide about cleaning the drawer out and starting over.  Homeowners often forced to make similar downsizing or subtractive decisions after 20-30 years of additive ones and being forced with either space constraints or a smaller family.  

What about medical and psychiatric treatment?  I don’t think there is any doubt that additive transformations are operating. Most treatments that involve medication have a step approach with the addition of medications for symptoms that do not respond or partially respond to the initial treatment. This occurs after an explicit subtractive bias or at least a bias to maintain the status quo 20 years ago.  At that time, hospitals and clinics were reviewed based on criteria to limit the amount of polypharmacy defined as more than one drug from the same class. Today, polypharmacy is common.  Reference 3 below gives an example of polypharmacy defined as 5 or more medications taken concomitantly and hyper-polypharmacy was defined as 10 or more medications taken concomitantly in a 3-month sample of 404 geriatric patients with cardiovascular disease admitted to a hospital during 3-month period.  They found the prevalence of polypharmacy was 95%.  The prevalence of hyper-polypharmacy was 60%.  Most patients (77.5%) also had a potential drug-drug interaction.  Their suggestion be vigilant is a strategy discussed as being potentially successful in containing the additive strategies (2).  

From psychiatry, I am including a common problem that I encountered as a tertiary consultant.  That problem is what to do about a person with a depression that has not responded to high dose venlafaxine. There are geographic areas in the US, where very high dose venlafaxine is used with and without pharmacogenomic testing.  From the options listed in the diagram it is apparent that there are 4 additive (black arrows) strategies and 2 subtractive (red arrows). There is a robust literature on the additive strategies and not so much with the subtractive. As a result, it is common these days to encounter patients who have tried numerous combinations right up to and including “California Rocket Fuel” (4) of the combination of an SNRI like venlafaxine with mirtazapine.  The ways to analyze this situation, especially if there has not been any improvement are significant and depend a lot on patient preferences and side effects in addition to the lack of response. I have found that very high dose venlafaxine, can be sedating to a significant number of people and that they feel better when it is tapered.  I have also seen many people far along the augmentation strategies when tapering or discontinuing the venlafaxine was never considered. In some of these cases, the patient reports that venlafaxine is historically the only antidepressant that has worked for them in the past.

That brings up the issue of additive versus subtractive biases on the part of the patient. We have all been bombarded by pharmaceutical commercials suggesting the best way to mood stabilization is adding another medication – typically aripiprazole or brexpiprazole. In fact, those commercials speak directly to additive biases. It is often very difficult to convince a person to discontinue or reduce a medication that they have talked for years – even when careful review suggests it has been ineffective or creates significant side effects. 

Could a discussion of additive versus subtractive transformations be useful in those situations? There is currently no empirical guidance, but these might be additional experiments to consider for both prescribing physicians and the patients they are seeing. Certainly the expectations that they patient has for any given treatment needs to be discussed and whether that expectation is reasonable given their personal experience and the objective evidence. On the side of prescribing physicians, it is fairly easy to flag medication combinations that are problematic either from the perspectives of too many medications being used at once, physical and side effects not being analyzed closely enough, or medications being changed too frequently. Would discussing additive and subtractive strategies be useful in that setting?  Would a discussion of basic rules to address additive biases such as discontinuing a medication when it is replaced be useful?

Remaining vigilant that there are subtractive strategies out there is a useful lesson from this paper. Physicians are aware of the concept of parsimony and how that can be applied to medical care. Given the fact that the additive strategies are probabilistic and modifiable with conscious strategies – that should still prove to useful in containing polypharmacy.  

 

George Dawson, MD, DFAPA

Supplementary:

Another common additive strategy that I have encountered in the past 10 years is performance enhancement.  The patient presents not so much for treatment of a psychiatric problem but because they believe that adding a medication or two or three will improve their overall ability to function. Common examples would include:

1.  Presenting for treatment of ADHD (with a stimulant medication) not because of an attentional problem but because the stimulant creates increased energy and the feeling of enhanced productivity.

2.  Presenting for treatment of insomnia in the context of drinking excessive amounts of caffeine in the daytime and the caffeine is viewed as necessary to enhance energy at work or in the gym.  In some cases, stimulants are taken in the daytime and the idea is that the medication for insomnia would counter the effect of stimulants or caffeine taken late into the day.

3.  Taking anabolic androgenic steroids (AAS) and expecting to treat the side effects of mood disturbances, insomnia, anger, and irritability in order to keep taking the AAS.  Many AAS users also take other medications for this purpose as well as various vitamins, supplements, and stimulants to enhance work outs.

4.  Taking excessive numbers of supplements with no proven value and seeking to use medications for nondescript symptoms associated with the supplement use. In many cases, patients with psychiatric disorders are sold on elaborate mixtures of minerals and supplements with the promise that they address their symptoms.  In many cases it is difficult to determine if the associated vitamins and supplements interact with the indicated medical treatment or not.

All of these are additive strategies with no proven value that I have seen in the outpatient settings.  It is obviously important to know if the patient being treated is using these strategies.  There are often competing considerations – for example does the patient have a substance use disorder and are substance use disorders another predisposing condition to additive biases (I suspect they strongly are).

 

References:

1:  Meyvis T, Yoon H. Adding is favoured over subtracting in problem solving. Nature. 2021 Apr;592(7853):189-190. doi: 10.1038/d41586-021-00592-0. PMID: 33828311.

2:  Adams GS, Converse BA, Hales AH, Klotz LE. People systematically overlook subtractive changes. Nature. 2021 Apr;592(7853):258-261. doi: 10.1038/s41586-021-03380-y. Epub 2021 Apr 7. PMID: 33828317.

3:  Sheikh-Taha M, Asmar M. Polypharmacy and severe potential drug-drug interactions among older adults with cardiovascular disease in the United States. BMC Geriatr. 2021 Apr 7;21(1):233. doi: 10.1186/s12877-021-02183-0. PMID: 33827442; PMCID: PMC8028718.

4:  Stahl, SM . Essential psychopharmacology: neuroscientific basis and practical applications. Cambridge University Press, Cambridge 2000. p. 363.

 

Graphics Credit:

So far they are all mine.  Yes that is one of my kitchen drawers but I am fairly good at avoiding polypharmacy.  Click on any graphic to enlarge.

A Psychiatrist Takes An Overly Detailed Look At Endoscopy

 

I started typing this shortly after completing an esophagoduodenoscopy (EGD) and a screening colonoscopy. Starting at age 25 I have probably had a total of 4 EGD’s and 4 screening colonoscopies. About three weeks ago I started to experience dysphagia. During those episodes food fails to pass through the esophagus and causes pain.  In the extreme food does not pass at all and that leads to all the symptoms associated with esophageal obstruction. It is an extremely uncomfortable sensation that can lead to esophageal perforation and the need for emergency surgery. The last time that happened to me was about 25 years ago. Over the years I have had a couple of close calls but two recent episodes of near obstruction led me to going to see my primary care physician who set up the test.

My immediate association and worry was that I may have esophageal cancer. Three second-degree relatives and one first-degree relative had pancreatic cancer. It is rumored that my maternal great great grandfather died of stomach cancer. 2 second-degree relatives died of stomach cancer. All of the second-degree relatives had risk factors primarily cigarette smoking, but you can certainly develop cancer in the absence of risk factors and aging alone is a risk factor for cancer.  Since my first esophageal obstruction, I have not eaten beef (the source of the acute obstruction) and have also tried to avoid foods that have been implicated in G.I. cancers such as smoked and preserved foods as well as excessively hot beverages. I have never used tobacco products and do not drink alcohol. I have also tried increase foods that may be protective such as vegetables and tree nuts. The nuts were easy but vegetables require much more of an effort. I am one of those people that has an aversion to the taste of most vegetables, but for the past ten years I have been eating 2-3 vegetables per day.

Over the years of the screening colonoscopies, I always asked the gastroenterologist whether or not I should also have an EGD to see if there any after effects from the initial obstruction and dilatation. They all said that there was no reason to repeat it unless I had additional symptoms but that was never very satisfying response. Cancers of the esophagus and gastroesophageal junction are difficult to diagnose. Symptoms often do not appear until the cancer is advanced and not treatable.  One of the gastroenterologists seemed more concerned about the dilatation procedure. He advised me that the anatomy of the esophagus is multiple layers of transverse fibers and that dilatation procedures can disrupt that anatomy. He gave me a tip sheet on how to avoid dysphagia and esophageal obstruction by changing eating habits in some cases making sure that a mouthful of food is chewed at least 40 times.

The screening colonoscopies have generally been uneventful yielding one or two small noncancerous polyps per screening. That result led to the recommendation for screening every five years instead of every 10 years. Since the last screening I decided to greatly increase my fiber intake to 40 to 50 g per day and take additional wheat dextrin – 18-24 g/day.

As a psychiatrist who is as neurotic as the next person, I always reflect on how the neurosis affects my medical encounters. As a kid I had a high degree of death anxiety. I was always concerned that I had a fatal illness and that I would die within a year or two. In retrospect it is easy to think about how the family environment was the origin of those thoughts. I was exposed to relatives who are also very neurotic and preoccupied with health concerns. I had an aunt who died of pancreatic cancer in those days the entire family was involved in treatment largely because there was no coordinated blood banking and she needed transfusions from her siblings. At some point in my mid-to-late teens I realized my worries about dying were excessive because of the obvious fact that I was still alive. But old habits die hard. I am still very safety conscious about every possible hazard to the point that my wife says I am “paranoid.”  On an ongoing basis, I pay attention to every reference in the medical literature that might apply to my somatic concerns. The most recent examples are a commentary and an article in the New England Journal of Medicine (1,2) on the immunotherapy of esophageal cancer that was described as a major advance.  Over the years I have also tracked the complications in this area that were not related to cancer but more to scarring or fistula formation. None of this keeps me awake at night, it is what I do as normal activity.

The prep for screening colonoscopy is an ordeal. It seems to have become more of an ordeal over the years. By that I mean the prep went from an oral stimulant laxative and two sodium phosphate enemas to very large amounts of oral osmotic laxatives like polyethylene glycol 3350 ± additional salts (sodium sulfate, sodium chloride, sodium bicarbonate and potassium chloride).  Any Internet search for colonoscopy preps yields a wide range of recommendations and volumes. The clinic I was going to had the prep for people with chronic constipation that involved consuming the polyethylene glycol over two days (and additional osmotic and stimulant laxatives) and the one that I used started on 5 PM the night prior to a morning procedure.  I prepared 4 liters of a solution of Gatorade + polyethylene glycol 3350 (476 g). The instructions were to drink the first 3 liters at a rate of 237 ml (8 oz) every 10 minutes until gone and then wake up at 4:00 AM and drink the remaining liter – 4 hours before the procedure.

I describe this as an ordeal because just anticipating consuming that much salty fluid can create some anxiety, disgust, and anticipatory nausea. I typically drink fluid volumes every day right around 4 L, but the instructions here were to maintain additional fluid intake on top of the laxative.  I probably consumed an additional 5 L on top of the laxative (per the instructions).  The biology and chemistry of this procedure is interesting. For example, creating solutions rarely produces the original volume. The final solution can be smaller or greater than starting volume, but the difference is generally not factored into the final concentration. In this case, I found that final solution of polyethylene glycol 3350 and Gatorade was about 300 ml greater than 4 L so I discarded it to maintain the recommended volume.  There is also the question of the impact that osmotic laxatives have on fluid and electrolyte balance. Interestingly, the two main products used consist of one product with a combination of polyethylene glycol 3350 and additional electrolytes and one product that is pure polyethylene glycol 3350 mixed with sports drinks containing the additional electrolytes.  The former product contains warnings about use in patients who may have sensitivity to electrolyte imbalances like patients with seizures or arrhythmias.  I received some information about products that are more recent and easier to use including MOVIPREP^® and SUPREP^®. Both require the ingestion of much lower fluid volumes.

The main thing to remember about preparation for the colonoscopy is that the goal is to induce diarrhea and continue that until it is clear of fecal material. In my case that happened at about 1 AM following the initial 3 L ingestion. I seriously contemplated not drinking the additional leader at 4 AM but did not want to risk having to repeat the whole procedure again if the preparation was inadequate. As a result, I had diarrhea until about 8 PM the next night - about 10 hours after the procedures were completed.

The procedure itself was well coordinated and pandemic precautions remained in place. I had a negative COVID-19 screen two days prior to the procedure.  I was accompanied to the gastroenterology clinic and had to wear a mask throughout the entire procedure with the exception of the EGD. They placed the nasal prong oxygen cannula under my mask. All the nursing staff was masked. The gastroenterologist was wearing a large helmet like face shield in addition to a mask.  That reminded me of my positive affiliation with gastroenterologists. For years, I ate lunch with a group of 3-4 gastroenterologists and the occasional infectious disease specialist.  We typically discussed movies but at times the conversation would wander to hastas (the plant), politics, or medicine. They all had a good sense of humor. Whenever another gastroenterologist was brought up their humorous seal of approval was "He/she really knows their way around the colon!" They were all very likeable and had a great sense of humor.     

The endoscopy suite contained a wall of high-tech equipment. I was advised that the gastroenterologist would talk with me about informed consent. I reflected on that for a minute and realized that the last 10 surgeons and proceduralists that I have had contact with spend less time in aggregate talking about risks and benefits then I typically spend talking about antidepressant risks and benefits with the average patient. I don’t consider that to be a problem because as I have written before, desperate situations in medicine require desperate probability-based decisions and procedures. There are no guarantees.  In addition, I have treated patients who have had most of the known complications of both EGD and screening colonoscopy including perforations and the need for emergency surgery. I have also treated patients who have had spontaneous perforations of the esophagus for unclear reasons. My conversation with the gastroenterologist went something like this:

GE: “The risks of this procedure involve perforation and the need for emergency surgery, but that is rare. There is also some discomfort if we have to perform a dilatation. We will let you know what we find today and what the follow-up needs to be. Do you have any questions?”

Me: “My primary care doctor wanted me to let you know about my family history of G.I. cancer especially pancreatic cancer. He wanted to know if there was any additional screening that needed to be done?”

GE: “We generally do not do screening for pancreatic cancer. With your family history you might want to try to find a geneticist to see if you need any genetic screening. Your primary care doctor might consider a one-time CT scan of the pancreas.”

Me: “Regarding the dilatation, I saw gastroenterologist about 15 years ago who talked to me in detail about the anatomy of the esophagus and how repeat dilatations can disrupt the layered fiber structure of the esophagus. Is that a problem?”

GE: “Well I don’t know about that. If you have to eat-you have to eat. We have some patients who need to get the dilatation procedure every week.”

As we completed our conversation, the nurse advised me that she was going to induce “conscious anesthesia”. I clarified with her that was fentanyl and midazolam that I have taken many times in the past for these procedures. With my interest in consciousness, the idea of conscious anesthesia is something that I pay close attention to.  I missed the key opportunity with this session to ask the nursing staff what I behaved like under conscious anesthesia.  As soon as the anesthesia took effect the only recollection I have over the next 90 minutes was a nurse asking me about bradycardia and my reply was “it’s the beta-blocker”.  I woke up groggy and mildly ataxic. I put my clothes on and walked out to the elevator and left the clinic. The post procedure instructions said not to do anything that required a high level of thought or coordination for the next 12 hours. That is about how long it took the “brain fog” of the anesthesia to wear off. I always compare the current anesthesia to the first round I got at age 25. That combination of medication produced a paradoxical euphorigenic effect and about two hours of continuous laughter. It would be unwise of me to disclose that combination medications.

I can’t recall whether the gastroenterologist discussed the results with me or not but I was provided with two different sets of discharge instructions that read as follows:

Instructions after upper endoscopy (EGD) with biopsy:

Findings:

-Mild Schatzki ring - dilated

-Normal middle and upper third of esophagus. Biopsied to rule out eosinophilic esophagitis

-Normal stomach

-Normal examined duodenum

Instructions after colonoscopy:

-The entire examined: is normal

-The examined portion of the ileum is normal

-Repeat screening is recommended in 10 years

I could not have asked for a better result. No evidence of gastroesophageal reflux or Barrett’s esophagus. No significant esophageal strictures or ulcers. An upper and lower G.I. examination that is fairly unremarkable. That is very reassuring, but I doubt that it will have much impact on my focus on doing everything possible to prevent G.I. cancer and more esophageal problems. The colonoscopy result might indicate that my conscious move to a more high-fiber diet had some impact, but at this point I am questioning the issue of soluble versus insoluble fiber from the standpoint of metabolic and microbiome effects. Like most medical research there are no clear answers and so I am left with myself as an N=1 study and I have the help of an excellent internist.

As I recover, I am thinking about the afferent sensory innervation of the gut and the unusual sensations that it might be producing. I thought I might post a detailed synopsis here but will hold off for now. I think that many neurotic people adapt to some degree by what is currently described as mindfulness.  You get to a point in life where you realize you are probably excessively cautious and that you have to focus on and do many other things in a day. And you are able to do those things.  You adapt to the somatic concerns and there is no significant associated affect. In many ways it might just be another aspect of being goal directed or conscientious.

So I will take a break on that line of thought while I wait for a more detailed genomic analysis of possible risk factors for pancreatic cancer.

 

George Dawson, MD, DFAPA

 

References:

1:  Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, Feliciano J, Motoyama S, Lièvre A, Uronis H, Elimova E, Grootscholten C, Geboes K, Zafar S, Snow S, Ko AH, Feeney K, Schenker M, Kocon P, Zhang J, Zhu L, Lei M, Singh P, Kondo K, Cleary JM, Moehler M; CheckMate 577 Investigators. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med. 2021 Apr 1;384(13):1191-1203. doi: 10.1056/NEJMoa2032125. PMID: 33789008.

2:  Ilson DH. Adjuvant Nivolumab in Esophageal Cancer - A New Standard of Care. N Engl J Med. 2021 Apr 1;384(13):1269-1271. doi: 10.1056/NEJMe2101983. PMID: 33789017.

Graphic Credit:

That is the actual stuff that I drank in addition to another 4 liters of water, tea, and white grape juice.

Additional Credit:

I thank the gastroenterologist and staff involved in my care.  The experience was first rate.

Addendum:

The biopsy result came back negative for eosinophilic esophagitis.

Airborne Transmission - Once Again!

 

I thought I would take time for a rare celebration on this blog.  Most of my writing is about probabilities and uncertain outcomes. In many cases I am responding to the same tired arguments from people who don’t understand science, biology, medicine or psychiatry. Those positions generally result in some political attacks based on that lack of understanding or some specific political agenda. The position I am referring today is the airborne transmission of viruses. Although it seems like a straightforward scientific issue it has led to as much controversy as any psychiatric topic. Despite a significant amount of literature out there on airborne spread, there has been nothing but resistance to the concept.

Nowhere was the resistance more evident than the advent of the current SARS-CoV-2 pandemic. Initially the message was that the virus was spread by fomites or intermediate size droplets that fall within a few feet following a cough or a sneeze.  Accordingly, social distancing at more than a few feet, decontaminating hands and surfaces were recommended to counter this mechanism of transmission. Many experts claim that most respiratory viruses with very few exceptions are transmitted this way. Those same experts claim that airborne transmission of viruses in smaller droplets travelling much longer distances was controversial at best. All of those conflicting ideas led to recommendations for no masks in February of 2020 followed by recommendations for masks in the next two months.  The mask recommendations occurred in the context of widespread shortages of personal protective equipment (PPE) for health care workers.   

I posted my qualifications on the matter (2 Avian Influenza Task Forces earlier in this century, being subjected to multiple respiratory virus epidemics at work despite rigorous hand washing, and studying the available engineering and viral data, and lengthy discussions with HVAC experts) and began to write about it on this blog.  My perspective is clearly that respiratory viruses are airborne and therefore will not be stopped by handwashing alone, that there are clearly engineering approaches to stop respiratory viruses that will work much better than just handwashing, and that there should be a major research and development effort on environmental designs to minimize and even stop respiratory viruses in homes and public building. In fact, as I type this I have selected a UVC device to be installed in my home HVAC system and it will probably be installed in the next month or two.  Many of those posts on this blog can be found here or by using the search term “airborne” in the search box.

The victory lap today occurs with a press release from the CDC today that I consider a bombshell in terms of the airborne transmission concept.  The press release is a quick read but it highlights why surface contamination is unlikely to be a significant factor:

“Quantitative microbial risk assessment (QMRA) studies have been conducted to understand and characterize the relative risk of SARS-CoV-2 fomite transmission and evaluate the need for and effectiveness of prevention measures to reduce risk. Findings of these studies suggest that the risk of SARS-CoV-2 infection via the fomite transmission route is low, and generally less than 1 in 10,000, which means that each contact with a contaminated surface has less than a 1 in 10,000 chance of causing an infection.”

And further:

“The principal mode by which people are infected with SARS-CoV-2 is through exposure to respiratory droplets carrying infectious virus.”

This information has been slowly presented over the course of the past several months.  For example, Dr. Fauci mentioned on several news outlets that cleaning all of the mail and groceries was not necessary because it was not considered a main route of transmission. A logical inference from that statement is why there is a concern about any surfaces at all unless there is a person with a known infection close by.  And by extension, if surface contamination is not that much of a problem why the concern about accidentally touching your face?  As Dr. Fauci typically states we now have the science behind the transmission and the recommendations can be adapted to the new findings.

The CDC press release does not come right out and say airborne transmission.  They continue to say respiratory droplets are the predominate mode of spread and the old document on respiratory droplets says nothing about differentiating between moderate sized droplets that typically fall to the ground within a 6-foot radius of where they are generated or airborne droplets that are lighter, spread past 6 feet from the generation site and remain suspended for longer periods of time.

Some of the comments on the press release have been much more definitive. The only reference to this post has a good timeline on the airborne controversy and this quote from atmospheric chemist Jose-Luis Jimenez: “If we took half the effort that’s being given to disinfection, and we put it on ventilation, that will be huge.”  In the same reference Germany has invested a half billion dollars in improving ventilation and indoor air quality.

Overall, it appears that the CDC is slowly coming around to the idea that respiratory viruses are transmitted via airborne routes, but some resistance is still evident in the press release they link to an earlier non-descript respiratory droplet transmission document.  There are many potential advantages to fully backing the airborne transmission concept (in addition to the available science).  Research and development is at the top of the list. In an early blogpost, I pointed out that UV decontamination was routine in buildings when I was a kid in a small town in northern Wisconsin.  The currently available UVC is much safer and very effective for killing airborne biological particles. From a clinical trials perspective, deployment of these systems on a large scale and following the number of respiratory infections in facilities with and without the technology seems like a fairly basic experiment.

It is also interesting to consider the resistance. There is undoubtedly politics in science and that can be a factor. There may be a medical intervention bias. In other words, we need some magical intervention like a vaccine, antiviral medication, or general polypharmaceutical modality that can either cure or prevent the excessive morbidity and mortality from respiratory viruses.  The track record there is some wins and many losses.  Every year various populations around the world are subjected to significant effects from flu-like illness that are nowhere as lethal as SARS-CoV-2.  Remarkably – everyone accepts this state of affairs until a more lethal virus comes around and affects a larger group of people.  There is politics as usual leading to irrational attitudes about viruses and physical interventions.  The appropriate environmental interventions may make mask refusers irrelevant at some point in the future.

The bottom line of today’s release is good news for all of the airborne virus crowd and I definitely consider myself in that crowd. I would still like to see the CDC modify their position on transmission in respiratory droplets and I think that is coming.  But most of all, I would like to see us get serious about using environmental measures to limit the exposure and spread of all respiratory viruses including the current one that has killed far more Americans than any influenza epidemic since 1918.

 

George Dawson, MD, DFAPA

 

References:

1:  Lewis D. Why indoor spaces are still prime COVID hotspots. Nature. 2021 Apr;592(7852):22-25. doi: 10.1038/d41586-021-00810-9. PMID: 33785914.

2: Dietrich WL, Bennett JS, Jones BW, Hosni MH. Laboratory Modeling of SARS-CoV-2 Exposure Reduction Through Physically Distanced Seating in Aircraft Cabins Using Bacteriophage Aerosol — November 2020. MMWR Morb Mortal Wkly Rep. ePub: 14 April 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7016e1

3: Greenhalgh T, Jimenez JL, Prather KA, Tufekci Z, Fisman D, Schooley R. Ten scientific reasons in support of airborne transmission of SARS-CoV-2.  The Lancet (online).  Published 4/15/2021. https://doi.org/10.1016/S0140-6736(21)00869-2  Current link

4: Tang JW, Bahnfleth WP, Bluyssen PM, Buonanno G, Jimenez JL, Kurnitski J, Li Y, Miller S, Sekhar C, Morawska L, Marr LC, Melikov AK, Nazaroff WW, Nielsen PV, Tellier R, Wargocki P, Dancer SJ. Dismantling myths on the airborne transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Hosp Infect. 2021 Apr;110:89-96. doi: 10.1016/j.jhin.2020.12.022.  Current Link

Medical Library Access For Everyone

 

Medical library access is a critical issue for physicians because only a few physicians have access to all of the literature that they need.  For as long as I have practiced medicine and psychiatry life long learning has been a stated goal of the profession.  That forms not only professional behavior but it is also incorporated into the medical practice laws of each state.  In order to be relicensed each year, medical practitioners also have to fulfill the continuing medical education (CME) requirements in each state.  That typically requires a combination of self-study and CME courses sponsored by various medical education organizations typically departments of psychiatry or professional organizations.

When I first came to the Twin Cities in 1989, I worked for a large multi-disciplinary clinic in St. Paul, MN.  We were the second largest hospital-based practice in the Twin Cities and a Level 1 Trauma Center and Burn Unit.  We had the most psychiatry beds in the East Metro area. I did a rotating internship at this hospital and liked the practice and the attendings well enough to return there and stay for the next 22 years. We also were a teaching hospital and trained medical, surgical, and psychiatric trainees from the University of Minnesota.  As a result of that position, I was expected to train resident physicians and medical students. At some point we were given electronic access to the Biomedical Library at the University of Minnesota and could access a wide array of biomedical journals online at that facility.  Up to that point, I had to go to the library and make copies of articles that I wanted to study and keep for future reference.  I was also able to access interlibrary loan articles through my hospital library that I would get via mail or fax in 2-3 days.  All of this reference material was relevant to my clinical work, teaching, and research at the hospital.

In general, University training programs depend on their affiliated or adjunct staff and facilities for teaching residents.  These affiliations result in broader clinical exposure to both patients and practitioners as well as different work environments. Good examples of the necessity of these affiliations is the amount of individual and psychotherapy supervision residents require.  Much of that training is provided by practitioners in the community who are doing the work every day.  In some cases a University training program may lack a critical component like an addiction service or a community psychiatry service and these affiliations provide those resources.  In return for the services provided to the training program, the affiliated practitioners get University titles and electronic access to the library.  In todays work environment stressing excessive productivity, there is generally no break in the work of the day.  For example, the adjunct teachers are still required to put in a full day’s work in addition to their teaching and supervisory role.  All of the work for the training program is uncompensated with the exception of the access to the library perk.

In my case, the other physicians in my group had negotiated with the University so that we all had regular Assistant Professor titles. We understood our role was critical to the components of the educational program and that these titles had nothing to do with regular track university titles.  As time went by our group was acquired by a managed care company and the teaching role diminished.  There was some turmoil at the University and a non-psychiatrist was appointed temporary department head. He ended up sending out letters firing numerous adjunct faculty – myself included.  The letter stated that we were "costing the department too much" as the rationale for the “firing”.  Since I was curious about how much I could be costing, when I had not ever been compensated – I called the University and asked them that question.  The answer was a $1,000/year library access fee. When I got that figure I called the University library and asked them if I could retain library access by paying them $1,000/year and they declined giving no good reason other than "it is policy".

To establish how much an individual physician may expend on journal resources – I include my subscriptions below.  The total cost is $2,640/year for a very inefficient way to access articles of interest.  Some are more inefficient than others. For example, my APA membership includes 1 of a possible 5 journals.  Just a few years ago it included at least an additional journal, but now the other journals are all for addition fees.  By comparison – the AMA membership includes access to 11 journals for only slightly more money.  Getting all of these journals to read only a fraction of the articles is also very inefficient.  The educational and self-improvement goals of individual physicians depend a lot on medical specialty and current practice environment as well as how much interest they have in the biology relevant to that specialty. Early in my career I was in a research position where we all got a hard copy of Current Contents, checked off the articles of interest and got the reprints within a day or two.

Another level of inefficiency is introduced at the level of publishers.  If you think about it medical publishing is a relatively low-cost endeavor.  Publishers are not paying for content. All of the submissions to their journals are generated for free by scientists and physicians wanting them published.  The peer reviewers who expend significant amounts of time reviewing these articles are not reimbursed.  The costs are basically for a small editorial staff, maintaining an information technology (IT) infrastructure and Internet presence, and printing paper journals.  Ideally, paper journals could be eliminated and readers could access the electronic copies and read and print what they want. We are not in the ideal world at this point. Many if not most publishers do not provide access to electronic only journal copies.

Licensing agreements between publishers and services that aggregate publications is also a controversial area. Publishing has become a very high margin business, particularly if that publisher has a number of widely read journals. In some of these cases, the annual licensing fees are easily in the millions of dollars per year for large university facilities.  That has led some library facilities to refuse or threaten to refuse agreements with major publishers so that their journals cannot be accessed.

Given this landscape, is there a possible solution that resolves the physicians need for eclectic reading, the state’s interest in physicians with life long education, the library’s interest in providing a useful service to its patrons, and the publisher’s interest in being paid.  I think there is and that is to make the University medical library electronic services available to anyone willing to pay an agreed upon fee. I was willing to pay $1,000/year 12 years ago and I am clearly paying much more for limited individual access to the journals listed in the table below.  Basically, the state and the library’s ability to negotiate group access will makes it more widely available to more physicians or for that matter anyone in the state who wants the equivalent access to electronic journals.

There are alternatives to paid journals for access.  Some grant recipients need to provide a free copy of their paper that is posted as open access on the National Library of Medicine web site (in their PubMed search engine). There are open access journals, many of which charge the authors a publication fee.  I was an editor for one of these journals and came away from that experience with the perspective that it adds significant conflict of interest for the publisher and may encourage the publication of low-quality research for profit. There are many high-quality journals that have added a smattering of open access papers for one reason or another. During the current pandemic many high-quality journals have offered articles relevant to the pandemic as open access. There are also research sites where authors can be contacted to request papers and pre-print servers where you can read the unedited versions. All of these indirect measures assure some level of access to articles that might be behind a paywall, but it is no guarantee.  For example, my requests to researchers are successful about 50% of the time and in many cases, they tell me they are prohibited from sharing their research due to copyright constraints.  The only way that you can review the literature for writing or research purposes is with complete access to what is out there.

At some point I am hopeful that physicians and/or their professional organizations advocate for these services.  

George Dawson, MD, DFAPA

Graphic Credit - Shutterstock per their standard agreement.  Click on any graphic to expand.

The New Black Box Warnings On Benzodiazepines

 

 

The FDA started communicating that there was going to be a new black box warning in the package inserts of benzodiazepines starting last fall.  Black box warnings are defined as applying to potential problems with medications that can lead to serious or life-threatening complications.  These warnings have been around since 1979 and they are included in the package insert or detailed prescribing information included with every medication. They are also available on line by searching “[drug name] FDA package insert”.  The changes in the package insert for benzodiazepines (in this case diazepam and clonazepam) are shown in the graphic at the top of this page. In this case the old package insert is on the left and the new one that I received in the mail on March 18, 2021 is on the right.

Benzodiazepines are controversial medications and have been over most of their 60-year existence.  Current benzodiazepines and z-drugs that are primarily used for sleep and their release dates are listed in the graphic below:

At the time of their original release the primary indication for the medication was anxiety (although current diagnostic nomenclature was not in use at the time) and that continued to be the main indication until the advent of higher potency benzodiazepines like clonazepam, lorazepam, and alprazolam. Higher potency benzodiazepines were used for panic disorder and panic attacks. As clinical use expanded it became clear that these medications also reinforced their own use and that people could develop a substance use disorder with all medications in this class.  They were also noted to be cross tolerant with alcohol and other sedative hypnotics so that the use of benzodiazepines expanded to detoxification applications.

When it became apparent that some people were not able to stop using benzodiazepines, escalated the dose, or began acquitting them from non-medical sources strategies were developed to minimize their use as much as possible.  The following timeline looks at how the treatment guidelines for anxiety and panic changed over the years with the goal of minimizing benzodiazepine exposure.

The graphic illustrates that benzodiazepines have gone from a primary role (and in some case very high dose role) in the treatment of panic disorder to a secondary and time limited role.  Clinical prescribing typically expands on the original FDA approved indications. In the case of benzodiazepines, it is common to see them prescribed for various types of situational anxiety like public speaking or air travel.  It is also very common to see them prescribed for both transient emotional disorders (from a time limited stressor) and ongoing emotional disorders from chronic stressors.  In society today there is always a performance enhancement aspect. A common example is the person who consumes a lot of caffeine in the daytime to stay energetic and alert at work and in the gym who needs to take a benzodiazepine to treat the expected insomnia.  The main problem in prescribing the medication to a benzodiazepine naïve patient is that it is not possible to predict with certainty how they will respond.  With any medication that reinforces its own intake a substantial number of people will stop taking to due to side effects – typically excessive sedation or cognitive problems. Patients at risk with notice a euphorigenic effects that is very reinforcing.  A large number of people will take it as prescribed. In my experience, fewer people will take benzodiazepines if they receive informed consent that they are a potentially addictive medication.

The move to benzodiazepines by psychiatrists and primary care physicians came after decades of using medications with a much lower therapeutic index – primarily barbiturates but also meprobamate (Miltown) and ethchlorvynol (Placidyl). For the initial decades of use, it was taught that it was nearly impossible to ingest a lethal overdose of benzodiazepines unless they were combined with alcohol.  

Withdrawal effects with benzodiazepines can also be significant.  They depend on the duration of use, dose of medication, and pharmacological properties of the medication. In the most severe case, withdrawal delirium or withdrawal seizures can occur and both are potentially life-threatening situations compounded by the lack of effective treatment facilities.

From an epidemiological standpoint, one question is what is the current level of benzodiazepine use and is it changing over time?  Are there any direct measures of prescriptions rather than proxies like overdose deaths or benzodiazepine-based office visits?  There is a business that does collect prescriptions in retail pharmacies and has done that for the past 60 years. That data is proprietary and tends to be available only in glimpses where it is referenced by the purchaser.  In all of my searches on this subject, I located an FDA presentation on prescription patterns of controlled substances (3).  In the benzodiazepine section of that presentation there are a fairly consistent 20 million prescriptions per year between 2009 and 2015.  The commonest prescribed benzodiazepines were alprazolam (50-60%), lorazepam (25%), and diazepam (10-15%).  Further analysis shows that about 75-80% of all these prescriptions were from non-psychiatric physicians and 15% by psychiatrists and 15% by nurse practitioners and physician assistants.  67% of all benzodiazepine prescriptions were for women.  By age demographics 80% of all prescriptions were to people who were 40-59 (41.4%) and 60+ (38.2%).  This information is interesting because there is a life stage correlation with increased benzodiazepine use and use by the oldest demographic that has been flagged in the geriatric literature as being higher risk because of falls and cognitive impairment.

A global perspective on benzodiazepine use is available from INCB (International Narcotics Control Board) who estimates global supply and demand for controlled substances across the world.  According to that report, global production in 2018 was 199 tons and increase of 24% from 2017 (p. 36). The INCB also estimates the total benzodiazepine use by country for clinical and scientific use.

Additional resources in this area include this post that looks at a selective study of several states that agreed to disclose prescription levels for the purpose of this study.  There is significant variation in both opioids and benzodiazepine use from state to state.  My initial thoughts about pharmacosurveillance and pharmacovigilance still apply.  A robust system of following medication side effects and utilization can no longer depend on inadequate snapshots and voluntary reporting.

With regard to the specific change in black box warning the three main bullet points are all very reasonable and I would be shocked if any physician is not aware of these problems.  The first bullet point, highlights that the epidemiology of overdoses clearly shows a correlation of deaths with concurrent use of benzodiazepines and a shift to more potent fentanyl based illicit opioids.  A trend that has not received any comment yet is the use of fentanyl to produce counterfeit benzodiazepine tablets.  The second bullet point is necessary for the informed consent discussion with any patient.  Unless the addictive potential is openly discussed patient concerns about their past experience with addictive drugs and their family history is never mentioned.  The severity of addiction and withdrawal effects including the potential for protracted withdrawal also need to be openly discussed. The third bullet point is basically a necessary extension of the warning about tolerance and withdrawal. In clinical practice it is common to talk with patients who decided that they wanted to discontinue benzodiazepine on their own and experienced seizures and/or severe withdrawal after abrupt discontinuation.

The associated concern about the black box warning is whether it will change physician behavior or not. The experience with the black box warning on antidepressants and suicidality in patients less than 25 years of age had a significant effect on decreased prescriptions in that age group. The black box warning on benzodiazepines is really nothing new and it will be interesting to see if there are any effects. The lack of comprehensive prescription information restricts any study of that phenomena to local effects. A useful outcome may be a more comprehensive discussion of the risks and benefits before benzodiazepines are prescribed.        

 

George Dawson, MD, DFAPA

 

References:

1:  Silberman E, Balon R, Starcevic V, Shader R, Cosci F, Fava GA, Nardi AE, Salzman C, Sonino N. Benzodiazepines: it's time to return to the evidence. Br J Psychiatry. 2021 Mar;218(3):125-127. doi: 10.1192/bjp.2020.164. PMID: 33040746.

2:  Balon R, Starcevic V, Silberman E, Cosci F, Dubovsky S, Fava GA, Nardi AE, Rickels K, Salzman C, Shader RI, Sonino N. The rise and fall and rise of benzodiazepines: a return of the stigmatized and repressed. Braz J Psychiatry. 2020;42(3):243-244. doi: 10.1590/1516-4446-2019-0773. Epub 2020 Mar 9. PMID: 32159714; PMCID: PMC7236156.

3:  Jones CM.  The latest prescription trends for controlled prescription drugs. FDA presentation. September 1, 2015

4:  International Narcotics Control Board.  Psychotropics 2019 Statistics for 2018 Assessments of Annual Medical and Scientific Requirements.  Link.

Graphics:

All graphics made by me.  As far as I know package inserts are public information. Click on any graphic to enlarge.