Saturday, September 12, 2020

Existential Psychopharmacology And Much More

 

 


I offered an opinion on existential psychopharmacology recently and after completing those three tweets - decided that a more comprehensive look at this issue was in order. Psychiatrists have been debating the extent of what can be done in time-limited sessions for at least 25 years now. Those debates basically come down to what the government and businesses allow psychiatrists to do. About 25 years ago there was a billing and coding scheme that suggested that psychiatrists could do a few things including a comprehensive evaluation, follow-up visits, follow-up visits with psychotherapy, and family therapy.  Eventually the follow-up visits without psychotherapy are broken down into “medication management” visits and very brief medication management visits. If you happen to work as an employee that might mean you had to see four or five people an hour and do the necessary documentation and billing. There were bitter debates about whether that was a long enough period of time to see someone. Because these designations all trickled down from the government and the business world they had very little to do with whether or not a psychiatrist could provide services that they thought were needed in those time frames. There some articles about how psychiatrists are just focused on medications and “no longer did psychotherapy”. There were counter arguments by psychiatrists and community mental health centers saying that they could provide adequate services in those time frames for a lot of people. The politics escalated the point that psychiatrists were being stereotyped as specialists who are only interested in prescribing medications.

Any critical thinker could question the idea of “prescription only” psychiatry. Looking at a few common scenarios illustrates why that is not possible or defensible irrespective of the fact that psychiatrists are trained to provide comprehensive mental health services. A common example encountered in clinical practice is the crisis situation.  The psychiatrist is treating a patient who they have been seeing for any length of time who suddenly experiences a crisis in their life usually due to an overwhelming loss or stressor. The appointment is no longer focused on the long-term treatment and needs to refocus acutely on the crisis. The crisis generally affects the evaluation and treatment of the long-term problem and I have had many patients state that explicitly at the beginning of those appointments. Medications can be prescribed for crises but in general the best approach is psychotherapy.  Staying with a rigid approach to the original problem is not only ineffective but it harms the therapeutic alliance between the psychiatrist and the patient. That alliance is built on the patient knowing that they are being heard and understood by the psychiatrist. Ignoring a new crisis fails that test.

Another common example about why “prescription only” psychiatry fails is problems that need to be discussed rather than treated medically. These vary from comprehensive analyses of various medical problems and how they fit into the psychiatric formulation to stressors and social problems. In many cases the approach is educational.  Common examples there would include recommendations on sleep, diet, and exercise where they apply. But the examples include supportive psychotherapy for interpersonal conflicts, maladaptive problem-solving, and any clear sequence of behavior that the patient has questions about that can benefit from additional discussion.

It doesn’t take too much consideration to understand that psychiatrists need to talk with their patients in great depth in order to establish a treatment relationship that works.  That is not to say that there are suboptimal practices at either end.  I have certainly talked with people who told me that their last doctor always seemed poised over a prescription pad and would only talk about medications. There are some mass prescribing practices in primary care that depend on checklist descriptions of symptoms for a diagnosis and then that diagnosis for a well-defined list of prescriptions. There are also patients who tell me that they were seeing a psychiatrist who was psychotherapy focused and very reluctant to consider a medication.  Eventually they did get someone to prescribe a medication that worked and they decided to terminate with that psychiatrist for not presenting medication alternatives to them.  Psychiatric practice is all about a balanced presentation of the diagnostic formulation and ways to address it and that always includes a dialogue with the patient that communicated both information and understanding.

 

Case Example:

I am working in a large trauma center on weekend call and have seen a number of admissions to the acute care unit.  I get a call to the Coronary Care Unit about a recent admission who is tearful and depressed. She was admitted to rule out a myocardial infarction and that was done but the fellow is concerned about discharging her without treatment for depression.

I interview the patient and she is definitely depressed and tearful. I learn that she has recently retired and is having some difficulty finding meaning in her life.  She was previously the CEO of a large company and her day was scheduled for years.  It was so scheduled that she needed an assistant and was in constant contact with her.  She has never seen a psychiatrist or psychotherapist before and never been treated for depression. She has two adult children and did not have postpartum depression associated with either pregnancy.  She is generally healthy and physically active.  Her husband has noticed that she is less interested in some of their mutual activities – tennis and travelling.

 A stereotypical approach to this problem of going down the diagnostic criteria for depression may not be the best one. When I am talking to a patient in this situation, I ask them to join me in a conference room for the interview and not in their CCU bed.  I introduce myself, explain why I was consulted and then ask the patient for their take on the situation.  The questions are always open-ended since I am interested in their unique experience of the problem. That is a technique I learned as a first year medical student and it was greatly expanded in psychiatry. Learning medicine involves trying to recognize certain patterns in what the patient is saying and then honing in for more specific details. Psychiatry is a little more complicated.  It involves recognizing the typical disease patterns (eg. stroke), the patterns specific to psychiatry (eg. aphasia versus formal thought disorder), and the best therapeutic way to talk with the patient (loss, role transition, problems associated with stroke, aphasia). The initial two elements of that pattern recognition are fairly straightforward but intense aspects of medical and psychiatric training. The third is not and it has been a topic that has been politicized over the years to the point that it has become confusing for both psychiatric residents and practicing psychiatrists.

The best way to conceptualize therapeutic discussions is to see it as an extension of interviewing and psychotherapy training. There is always plenty of hostility associated with the idea that psychiatrists might be doing psychotherapy with patients while they are discussing medications and medical treatment.  There should not be.  I have already illustrated in this post why it is impossible to function as a psychiatrist without psychotherapeutic discussions. The psychiatrists who I know who were highly regarded by patients approached all patient encounters this way.  They expected there was going to be a discussion with the patient that had nothing to do with their medications, but that was essential in some way to the patient’s wellbeing.  How exactly does that happen?

The basics start with those initial interviewing skills.  In psychiatry, an emphasis on empathy, boundaries, and therapeutic neutrality adds a lot to those skills.  Talking to hundreds of patients and discussing those experiences with supervisors adds even more.  I can recall for example, listening to a supervisor talk about how to directly express caring for the patient (“I am really concerned about your ability to take care of yourself”) and operationalizing that for the patient to assure their survival.  I recall seeing another one of my supervisors telling a patient who was sobbing uncontrollably to “snap out of it” (in a nice way) in order to proceed with identifying the patient’s problems. When I saw that happen it was shocking for a trainee, but watching the interview it was clear that was a necessary skill.

An additional level of skill building occurs with one-to-one psychotherapy with patients and the corresponding 1:1 supervision by staff clinicians. In my case, I was supervised based on direct observation, audio tapes, video tapes, and process notes – 3 ongoing cases/week for three years. Those supervisors were also a rich source of texts and papers on psychotherapy technique. As I was starting psychotherapy training I read texts by Grinker, Arieti, Sullivan, Yalom, Beck, Klerman and Weismann, Basch, Werman, Dewald and others.  I attended an APA seminar by Kernberg and read his research.  I attended an APA seminar by David Burns and read his book.  I read the competing approach by Kohut and read the “Two Analyses of Mr. Z” and several other papers.  I was exposed to Lorna Smith Benjamin’s Structural Analysis of Social Behavior (SASB) and Viederman’s  psychodynamic life narrative.  I remember thinking of Viederman’s paradigm as I interviewed a young patient and realizing that she was describing neuropsychiatric symptoms consistent with complex partial seizures and having to change the paradigm and refocus the interview.  The ability to do that is all part of the complexity of psychiatric treatment.

Getting back to my clinical example, we discussed the patient’s transition into retirement as being the most significant factor that eventually led to more depression, panic attacks, and admission to a coronary care unit.  With that as a major focus of the interview the cardiologist’s questions about acute suicide risk, transfer to a psychiatry unit and medical treatment could all be addressed. The recommended treatment was psychotherapy rather than a medication.  The Cardiology fellow was still making rounds when I finished.  I talked with her about the existential aspects of the patient’s crisis.  Luckily the fellow was a creative writing and philosophy major and knew where I was coming from. The discharge proceeded without a hitch and the patient was clearly improved when she left.

What I am describing is essentially a supportive psychotherapy approach.  I notice the themes that various psychotherapies were designed to address and test them out with the assistance of the patient.  Do they seem to be relevant to the patient or not? Most importantly what can be said in that context that will be the most useful to the patient? That can vary from education about the therapy and the theory, to a clarification tying various events and reactions together, to an interpretation based on the developmental history discussed over the course of the interview.  Once that has been done and documented in an initial assessment it continues to evolve over the course of treatment and sometimes beyond.  I have had people come back years later to discuss additional developments – all in the 30-minute interview.  When you have 30 minutes to provide comprehensive psychiatric treatment – it can be done.   

For the person interested in existential psychopharmacology, Ghamei, Glick and Ellison have written about it as a “humanistic approach to the med check” (1).  In this article the authors emphasize the need for human connectedness and how it is necessary for psychopharmacology.  It basically emphasizes recognition of the individual and personalized treatment rather than seeing people as cross sections of symptoms.  I could not agree with the authors more and have outlined common areas of discussion that I try to cover in psychiatric visits. They discuss pejoratives of the 15 minute “med check” that focus almost exclusively on target symptoms and medications for this target symptoms.  I agree that it is suboptimal care but I also cannot forget where it came from.  It is a product of the government and the health care business community. Historically, there is no psychiatrist who stood out for saying: “From now on let’s see all of our patients for 10-15 minutes and pretend that only changing their medications is effective psychiatric care”.  There were definitely business administrators who said: “If you want to get paid, we want you to see this clinic full of patients every 15 minutes.”  Purely medication-based treatment is not really psychiatric treatment and it continues today as collaborative care. In some of the original collaborative care models – the unique experience of the patient is completely ignored.  All patients complete the same rating forms for anxiety and depression and decisions are made on that basis.  The patient’s conscious experience is collapsed into an aggregate number and a rating on the subscale of suicidal thinking. The models are at the opposite end of the spectrum from personalized care and are heavily promoted by managed care companies and governments who consider some of these aggregate measures to be “quality measures”.  I attended a meeting two years ago, where people were trying to use tens of thousands of these rating scale reports to develop an artificial intelligence approach to predicting suicide for these numbers. Human consciousness is not that simple.  

I know that many will see a 30 minutes appointment with a psychiatrist as a luxury or “too much expense”. In fact, it is a starting point. Once treatment proceeds, every aspect of treatment including frequency and intensity can be discussed in sessions.  One of the most well-liked psychiatrists (by his patients) that I have known, had several large clinics where he typically saw most people for 20 minutes, but 30 minutes when he needed to. Over the years he knew the several hundred people in these clinics very well and his patients did very well.

This method is the outline of what I do in clinic every day, what I did on acute care inpatient units for 22 years, and what I did in a community mental health center for the first three years of my career.  One of the reasons for writing this blog is not to suggest that I am the standard to measure everyone else by.  I write this blog because I know that almost every psychiatrist including my supervisors and professors and my colleagues practice this way. 

I just figured out a way to describe it.


George Dawson, MD, DFAPA

 

References:

1:  Ghaemi SN, Glick ID, Ellison JM. A Commentary on Existential Psychopharmacologic Clinical Practice: Advocating a Humanistic Approach to the "Med Check". J Clin Psychiatry. 2018;79(4):18ac12177. Published 2018 Apr 24. doi:10.4088/JCP.18ac12177 (free full text)

 

Addendum 1:

I was tempted to come up with a catchy name to encompass my approach to medical treatment and psychotherapy. I can see why the authors like the term existential.   

Addendum 2:

I don’t want to give the impression that my psychotherapy education ended in residency.  It is an ongoing process and I am always open to new techniques to help my patients.  The same way I study the medical conditions of my patients and make sure I completely understand the potential complications for psychiatric care.

Addendum 3:

I hope to come up with an additional post of the supportive psychotherapy techniques that I have found useful over the years and how I see that field evolving.

Monday, September 7, 2020

Happy Labor Day 2020




Over the years that I have been writing this blog - I have written a Labor Day greeting to my physician colleagues generally documenting the lack of progress on the work environment. This posts range from discussions about the importance of knowledge workers and their characteristics to how physicians are treated. The most important one of those characteristics is that they cannot be treated like production workers. That is of course the way most physicians are treated these days and it is not a new development. Another important dimension has been the intrusion of business interests on the physician-patient relationship. Those business interests rationed the level of care in order to make corporate profits and prevented physicians from providing the best possible care. All of these intrusions happen across the board but my particular specialty is affected more than others. I learned just this year that when managed-care companies decided to target psychiatry 30 years ago, their goal was double their stock price. No access or quality goal - just more money in the pockets of shareholders and company officials. The end result has been a seriously eroded practice environment, decreased access, County jails being used as psychiatric hospitals, lack of availability of substance use treatment and detoxification, and very brief hospital stays where hardly any treatment is provided or the patient ends up being committed and staying far too long on a short stay unit that almost resembles a jail. None of this is good news for laboring physicians and none of it is changing. 

There was one recent bright spot. The headline in Psychiatric News on August 21 announced that the APA Presidential Task Force on Assessment of Psychiatric Bed Needs in the United States had been created by Jeffrey Geller, MD, MPH the president of the APA. Dr. Geller correctly identified a current “public mental health crisis” but he failed to describe its chronicity. There are apparently 30 members on this task force and they will be delivering a white paper in December that “includes a workable model for determining hospital bed needs within a community that can be refined and updated over time”. There are six subgroups including a modeling subgroup. There is a panel describing “how we got here” and stating “inpatient care falls prey to economic forces, ideology”. Nowhere in the article did I see the words “managed-care”. Instead - I see a number of managed-care friendly quotes especially from the panel. The APA has a long history of task forces and boards with so many conflicts of interest that either nothing gets done or something gets done that is in direct opposition to the needs of clinical psychiatrists who go to work every day and typically have to tolerate a very difficult work environment. 

I have written about how other groups have assessed the bed problem. An obvious but innovative way is to look at the beds necessary to prevent committed patients from staying long periods of time in acute care hospitals, the beds necessary to prevent emergency department bottlenecks, and beds necessary to prevent patients with obvious severe mental illness from being incarcerated for minor offenses. Another obvious deficiency in practically all cities is treatment for substance use problems. We need acute detox and people are often sent to a nonmedical detox unit until they develop medical complications. Adequate environments to accomplish all these tasks are needed and support the physicians doing it are critical. I will be interested in the eventual white paper but considering the APA track record against 30 years of managed-care, utilization review, and prior authorization I am not optimistic at all. 

I can’t let this catastrophic year slide without commenting on telepsychiatry. As readers can tell from my previous posts I am fairly enthusiastic about it even though I do prefer talking to people in person. I also take my own vital signs and do brief examinations as necessary and that just can’t happen over a computer network. I suppose there are people who have much better integration with the EHR, clinical systems, and electronic prescribing than my current system and I think that is where hope lies. I have three state-of-the-art computers that are much faster than medical software I am using. There are still plenty of glitches and communication problems that need to be solved but I am hopeful that they eventually will be. There is an associated regulatory burden and that is a wildcard when the pandemic recedes. Specifically will there be a rollback and telemedicine and less development. I am hopeful that better systems and more integrated systems will evolve to the point that there are no delays and the physician work environment is much more seamless. Like most things that physicians deal with we still have to dedicate our time to support software that is supposed to be supporting us. 

The tide has turned on the burnout industry. I am seeing more and more colleagues not accepting blame for their burnout. Burnout is not a yoga or meditation deficiency. It is a direct product of an inadequate and at times hostile work environment. The pandemic highlighted many deficiencies and many questionable administrative decisions. Maintenance of Certification (MOC) and Maintenance of Licensure (MOL) - still loom largely in the background. Dr. Geller has apparently stated one of his goals is to get rid of MOC but I will believe it when I see it. I recently read a document that the APA gets to million-dollar year payment from the American Board of Psychiatry and Neurology (ABPN) - the MOC body. That is a significant conflict of interest from the membership perspective. The ABPN is currently collecting $500/yr from all of its certification holders in additional to fees necessary to access required reading. If 30,000 psychiatrists are paying these fees every year, that exercise generates $150M for the ABPN very ten years. There is no evidence anywhere that investing this significant time and effort produces a superior psychiatrist. The ABPN response is” “The public demands it!” In fact, the public still doesn’t know the difference between a psychiatrist, psychologist, or nurse practitioner. Burnout will end when physicians can stop doing the work of billing and coding specialists, typists and other clerical workers, IT workers, and surrogate employees of pharmaceutical benefit managers and managed care companies. No physician can be expected to do all of that additional work and work a full time stressful job. That is the real unstated problem of burnout. 




 Is there a high ground left for psychiatrists? I have often closed a post with the statement that: “Psychiatry needs to be focused on innovation and the future. The best position to be in is looking at everyone else in the rearview mirror?” Is there still a way to do that? I think that there is. A survey of many of my posts on this blog focus on what is really irrelevant criticism from the past. I have lived through the era of the biological psychiatrists versus the psychotherapists. I have lived through the era of brainless versus mindless psychiatry. I have survived the Decade of the Brain. It seems that both our detractors and internal critics tend to focus on false dichotomies or irrelevant history from the past. The way forward is to stay focused on modern theories and forget about the rest. 

 What will that take? I would suggest – a firm shift to an all-encompassing view of the field that makes us more resistance to petty criticism but at the same time more focused. When I say focused -  on clinical care, research, and theory. We have at least two models of that as elaborated by S. Nassir Ghaemi (1) and others. The most modern all-encompassing theory comes from Kandel as interpreted by Ghaemi (1). In his book, Ghaemi makes a compelling argument for pluralism as the defining approach in psychiatry over eclecticism and the biopsychosocial model of Engel. Pluralism essentially means that multiple methods are necessary to treat mental illness and that there are no single methods that will work. He cites several traditional theories in psychiatry about how to diagnose and treat mental illness as well as the theorist who suggest more than one approach is necessary. He provides a checklist (p. 308) to determine if you might be a pluralist. It contains questions like: “Can you accept the absence of a single overarching theory in psychiatry, yet also reject relativism and eclecticism?” Thinking about that question I don’t know why psychiatry would be different from the rest of medicine. Is there a single overarching theory in medicine? Why would we expect to see it in the most complex organ in the body? He is clear that he sees psychiatry stuck at the point of dogmatism and eclecticism.

He describes integrationism as an approach that removes the barrier between the mind and the brain as opposed to pluralists believing that there may be some differences between the mind and the brain. Integrationists believe that the brain is required for mental phenomenon but not sufficient. The brain can affect mental phenomena and mental phenomena can affect the brain. It is reminiscent of emergent properties that consciousness theorists tend to talk about. Stochastic factors or genetic factors in the brain that randomize expected behavioral outcomes may also prove to be important at some point. Ghaemi outlines a 5 principle integrationist model of psychiatry that looks at all mental processes/mental disorders being derived from the brain, the effect of genetic and environmental factors on the brain and these processes, and the effect of both biological and psychological treatment affecting the brain through mechanisms of brain change. 

 Although this all sounds fairly basic at this time – it is not. The discovery of brain plasticity or experience dependent changes in the brain was a major revolution in seeing the brain as a dynamic organ that could be altered easily by practicing the violin or lifting weights or talking to a therapist. There are ways to measure these changes. Everyone trained as a physician and a psychiatrist – sees the effects of structural changes in the brain from observing the effects of trauma, various brain diseases, and global brain dysfunction. An integrationist approach is practically intuitive but the model is not widely taught as the basis for clinical work. With that model there would be more uniformity in clinical approaches to the patient and standardization of clinical care. Patients could expect more than just a discussion of medication for example. They could expect psychotherapeutic discussions along with the medication and possibly more time and more visits with their psychiatrist. Instead of the rare research paper discussing this type of session – exchanges about it and innovation would be commonplace. It would also help to establish the necessary environment (physical, administrative support) for this kind of work to be done. 

Labor Day is a reminder for me that where we labor and what we can do for our patients is meaningful. A better work model might help that irrespective of political success in changing the system or not. The work model itself can also be invigorating if it includes elements of clinical work and basic science and helps us to make continuous sense of what we are seeing and expected to treat. 

George Dawson, MD, DFAPA

References: 

1.  S. Nassir Ghaemi. Concepts of Psychiatry – A Pluralistic Approach to the Mind and Mental Illness. The Johns Hopkins University Press. Baltimore; 2003. 

Graphic Reference: 

Carpenter, F. G. (ca. 1920) Paris, France. France Paris, ca. 1920. [Photograph] Retrieved from the Library of Congress, https://www.loc.gov/item/2001705736/. No known copyright restrictions.


Friday, July 31, 2020

The Memory of Places Long Gone




I had a dream last night about my old inpatient psychiatric unit. I was moving up and down the hallways like I used to do looking for people to interview. It always seemed like I had to track people down in order to talk with them. In my dream, I was in and out of familiar rooms and talking with familiar staff. I have known some of the staff people for over 20 years. The place was congested, noisy, and malodorous. There were the associated tensions and anxiety. Everything was in the exact spatial order that I remember it being in - including all of the disarray in my old office. I eventually woke up from that dream somewhat anxious and decided that I was done sleeping.

As I drank a first cup of coffee, I thought about the various meanings in the dream and developed three or four different threads. I am used to analyzing my own dreams and the dreams of others so I had all my theories finalized by my 2nd cup of coffee. At that point I started to think about the visuospatial memory necessary to create that dream. Dreams are certainly fascinating if you just pay attention to the content and the emotional tone but to be they are more fascinating when you consider how much computational power it takes to create a Technicolor dream of your real life experience. I have asked neuroscientists to speculate about this for years now and nobody has come up with any ideas.  I came up with a few of my own based on very simplistic extrapolations of the bandwidth of single neurons and simplistic bundles of neurons. One of the problems is that bandwidth and information calculations are valid only for typical electronic devices. Bandwidth and biological systems has been talked about for 20 years but there are no straightforward or consistent calculations.

A first approximation might be a two-dimensional photograph. Everyone these days is used to seeing photographs and an estimate of how much information is in that picture. But when you are walking through a building, you are essentially walking through an infinite number of two-dimensional photographs with multiple soundtracks and additional sources of information. Even if a measure of the information it takes to portray that data in real time and space was possible the next question is - what happens when it is represented in the brain?

I pulled up Facebook and noticed that someone had posted a photo of my old high school. As I looked at the front of the school I located all the windows where my classes were held. I was in that building for the last six years of school because in our town it contained grades seven through 12. It took me a few minutes to look at the windows and think about significant events that occurred in those classes. When I think about those years, there is a lot of confusion and anxiety. I did not have a very positive experience in middle school or high school. I was one of the most obedient kids in the history of the world and yet I managed to have contentious relationships with teachers. Back in those days if you were on the wrong side of the teachers – you were basically on the wrong side.  Parents didn’t question teacher authority and I knew better than to bring that information back home. But just like my dream I was focused on the structure this building. I still remember the creaky wooden floors and stairwells. I remember the bad acoustics and echoes. I remember where my locker was on the first floor. I remember what the place smelled like. I remembered how to go to the ground floor and take the tunnel to a connected building where I had some regular classes but also mechanical drawing and technical graphics. In other words, I still had the memory of the three dimensional space - long after that space had ceased to exist. I made a short list of other structures where that was also true including my old inpatient unit. That building was demolished about three years ago.

If you think about it visuospatial memory is a fascinating area of study. It takes more than remembering a list of words or calculation or how to play a musical instrument. The data have to be stored and retrieved in a way that makes spatial sense. When I think about the way we assess this memory clinically, the tests are generally crude and two-dimensional. Real live visuospatial memory is much different. As an example I can visualize being in an English class at the northwest corner of my high school. I know the exit I would have to take and the stairwell to get out of the building. I know the directions to get to my locker and I can run through all of this traveling in my head. At some level that is a declarative memory function because I know the information I want, I can retrieve it, and I can do an operation on it and in this case imagine myself traveling according to that information. Why my brain elects to access visuospatial information while I am dreaming is not clear and I don’t think anyone knows the answer to that question.

Early information from lesion studies of parietal cortex was involved in visuospatial memories especially the right parietal cortex.  That was largely because patients with lesions in this area could not complete the basic construction tasks on bedside cognitive screening. Parietal cortex is important in the subjective experience of memory.  For example patient with bilateral parietal cortex lesions have similar recall as controls but they have less confidence in their recall (2).  One of the most well-known studies of visuospatial recall and brain structural changes was a study of London cab drivers.  They are required to acquire a significant amount of visuospatial information about London geography and be tested on it. In the initial study (3) the authors showed that acquiring this information was associated with greater cross sectional area of the right posterior hippocampus on MRI scan.  They suggested: “These data are in accordance with the idea that the posterior hippocampus stores a spatial representation of the environment and can expand regionally to accommodate elaboration of this representation in people with a high dependence on navigational skills.”  In a recent study of typical (non-expert) taxi drivers navigational skills did not seem to correlate with right posterior hippocampal volume (5).  One of the explanations that the authors had for this issue is that the posterior hippocampus is only one part of the structures necessary for the navigational map.

Since this thread of research on the hippocampus, the area of spatial learning has become a lot more complex.  As an example, there are now three different types of spatial learning (6).  Landmark knowledge is specific for objects encountered in the environment.  Route knowledge involves environmentally dependent decisions that have to occur at specific times to move through the environment.  Survey knowledge is a detailed representation of the relationship between all objects in the environment. In reference 6, the authors look at testing all of these types of spatial learning in a large group of people who are navigating a nuclear facility and looking at the impact that maps of varying complexity have on their learning that environment.

As a psychiatrist, one of my concerns is what the neural substrate of spatial learning is for both my own thought experiments but also the patients I see with known brain lesions or who have clear deficits in spatial navigation.  One of the most useful reviews I could find (7) looked at a summary of the available data and proposed a navigational network that is really a rough sketch.  In a fairly complex paper the authors suggest that the occipital place area (OPA), retrosplenial complex (RSA) and parahippocampal place area (PPA) may function for landmark recognition in the context of a larger network involving the hippocampus, parahippocampus, retrosplenial cortex, and entorhinal cortex.  From a clinical standpoint many of these structures are compromised in dementias like Alzheimer Disease with severe associated problems in spatial maps and orientation.   

The story of spatial mapping and memory is an incomplete one at this time, but the details are building. At some point in the near future we will have a better idea of what the brain substrate is for this memory and the various kinds of real or imagined navigation. How it is activated and placed in dreams will probably take additional research effort.  And at some point, I really would like to see a practical approach to estimating the information content and flow necessary to accomplish these tasks. 

The most important aspect of spatial representations may be the emergent properties of the system.  Consciousness scientist Christof Koch (11) has stated that there are an "uncountable" number of spatial relationships associated with any human experience.  Integrated into those spatial relationships are also sensory and affective dimensions. That results in a powerful system for recall of real physical systems or building new ones in your dreams. 

 

George Dawson, MD, DFAPA

 

References:

 

1:  Rosen ML, Stern CE, Devaney KJ, Somers DC. Cortical and Subcortical Contributions to Long-Term Memory-Guided Visuospatial Attention. Cerebral Cortex (New York, N.Y. : 1991). 2018 Aug;28(8):2935-2947. DOI: 10.1093/cercor/bhx172.

2:  Simons JS, Peers PV, Mazuz YS, Berryhill ME, Olson IR. Dissociation between memory accuracy and memory confidence following bilateral parietal lesions. Cereb Cortex. 2010;20(2):479-485. doi:10.1093/cercor/bhp116

3:  Maguire EA, Gadian DG, Johnsrude IS, et al. Navigation-related structural change in the hippocampi of taxi drivers. Proc Natl Acad Sci U S A. 2000;97(8):4398-4403. doi:10.1073/pnas.070039597

4:  Maguire EA, Woollett K, Spiers HJ. London taxi drivers and bus drivers: a structural MRI and neuropsychological analysis. Hippocampus. 2006;16(12):1091-1101. doi:10.1002/hipo.20233

5:  Weisberg SM, Newcombe NS, Chatterjee A. Everyday taxi drivers: Do better navigators have larger hippocampi?. Cortex. 2019;115:280-293. doi:10.1016/j.cortex.2018.12.024

 6: Stites MC, Matzen LE, Gastelum ZN. Where are we going and where have we been? Examining the effects of maps on spatial learning in an indoor guided navigation task. Cogn Res Princ Implic. 2020 Mar 20;5(1):13. doi: 10.1186/s41235-020-00213-w. PMID: 32198712; PMCID: PMC7083990.

 7: Epstein RA, Patai EZ, Julian JB, Spiers HJ. The cognitive map in humans: spatial navigation and beyond. Nat Neurosci. 2017 Oct 26;20(11):1504-1513. doi: 10.1038/nn.4656. PMID: 29073650; PMCID: PMC6028313.

 8:  Bellmund JLS, Gärdenfors P, Moser EI, Doeller CF. Navigating cognition: Spatial codes for human thinking. Science. 2018;362(6415):eaat6766. doi:10.1126/science.aat6766

 9:  He Q, Brown TI. Environmental Barriers Disrupt Grid-like Representations in Humans during Navigation. Curr Biol. 2019;29(16):2718-2722.e3. doi:10.1016/j.cub.2019.06.072

10:  Eichenbaum H. The role of the hippocampus in navigation is memory. J Neurophysiol. 2017;117(4):1785-1796. doi:10.1152/jn.00005.2017

11:  Christof Koch. The Feeling of Life Itself.  MIT Press. Cambridge, MA, 2019. p. 7-8.

 

 


Friday, July 17, 2020

Toward A Better Sedative Hypnotic Medication



(Click to enlarge the above graphic)


I made the mistake of suggesting that we need a better version of quetiapine for insomnia on Twitter.  That triggered the usual comments that basically suggested that I did not know anything about quetiapine or what I was doing in general.  This post is for cooler heads. Let me start out by saying quetiapine came out early in my career.  The early concern was ocular side effects and of course cardiac conduction problems (prolonged QTc). Since that time the ocular side effects are not a primary concern (both retinal hyperpigmentation and cataracts were a concern with phenothiazines).  Since I was in acute care psychiatry, the main concern was that this medication did not work fast enough for acute mania or psychosis.  There was a time lag of days to weeks relative to more potent atypical antipsychotics (AAP). And not too long after they were released the metabolic problems were noted including dyslipidemia, insulin resistance and overt diabetes mellitus, metabolic syndrome, and weight gain.  Since most Americans are overweight and have a moderate risk of diabetes mellitus Type 2 in middle age – this is the primary reason to avoid using most medications in this class. Theoretical considerations suggest that the newer AAPs – aripiprazole, lurasidone, and brexpiprazole have less risk, but I have certainly seen people who gained substantial amounts of weight on these agents.  I have also seen several people develop diabetes without gaining a pound. That risk is clearly there and it is significant.

Indications for both olanzapine and quetiapine include schizophrenia and mood disorders typically bipolar variants or psychotic depression. Ideally the medication will also work for any associated sleep disturbance but that is not always the case. Sleep is important in primary psychiatric disorders because the person with the disorder generally does better if they are sleeping well. In the real world that ideal solution is not always there. As an example, the patient may be responding well to a non-sedating AAP like aripiprazole but continuing to not sleep. They do not want to take the chance of significant weight gain, but at the same time practically all the other medications in the above table have been tried and are ineffective. In that case low doses of quetiapine are often added to the primary AAP, not for additional treatment of psychotic or mood symptoms, but in the hope of normalizing sleep. That can make a significant difference even though the risk of metabolic problems remains.

The above table was constructed to look at non-benzodiazepine drugs for sleep. I plan to revisit the benzodiazepine issue again this year and am working on a table. For the purpose of this post, I am referring to all high potency and low potency benzodiazepines as well as the z-drugs (zolpidem, eszopiclone, and zaleplon). As I wrote about a few years ago, this class of medications poses a significant risk of the term the side effects and also dose escalation and uncontrolled use. Since they were invented to replace barbiturates and were clearly safer than that class of medications, there was a lag time before physicians found that they also posed unique risks.  Benzodiazepines are also extremely risky for patients with diagnosed substance use problems and should generally be avoided in that population. The population also has very significant sleep problems as well as problems with anxiety and depression.

In treating this population, insomnia can be related to intoxication and withdrawal states, the chronic sleep effects of intoxicants, circadian rhythm disturbances due to patterns of substance use, secondary to a substance induced psychiatric disorders, as well as an ongoing primary insomnia that has never been addressed. Some withdrawal states most notably opioids, benzodiazepines, and alcohol can produce long-standing severe insomnia that can last for weeks or more. That insomnia can be considered life-threatening if it perpetuates the cycle of ongoing substance use. I often hear: “If you can't give me something that will help me sleep, I know what will do it.” That discussion invariably comes back to using heroin or alprazolam or alcohol or possibly a combination of all three in order to get to sleep. The sleep does not have to be “normal” in any way. It might only involve 3 to 4 hours of interrupted sleep but that is considered better than nothing or one or two hours.  This is typically referred to as "self-medication" and it illustrates that this concept has very little to do with normalization of function.  Self medication with addictive compounds is a semi-rational process that only partially addresses the problem.

With the exception of the above orexin receptor antagonists, amitriptyline, and trimipramine,  I use all of the compounds in the above table for the treatment of insomnia. The most commonly used medication is trazodone. It is generally well tolerated and effective. Like all medications it is not 100% effective and most common reasons people request changes are excessive morning sedation, daytime drowsiness, excessive dreaming, and nasal congestion.  The remaining sedating antidepressants all depend heavily on anti-histaminergic effects enter probably as well tolerated but have unique side effects that need to be monitored. The only antidepressant that has an FDA indication for sleep is doxepin and that is in a proprietary dosage form of 3 and 6 mg.  According to the Ki values, doxepin is the highest affinity for H1 receptors. Insurance company constraints usually result in people getting low-dose generic doxepin rather than the FDA approved proprietary version Silenor.  Silenor comes in 3 mg and 6 mg tabs and the smallest generic dose of doxepin that I can typically prescribe is 10 mg.

Antihistamines are typically over-the-counter sleep medications - usually diphenhydramine or doxylamine.  In the table, hydroxyzine seems to have a comparative advantage due to the lower Ki value, but the metabolism of this compound is extensive and one of the metabolites cetirizine has a high affinity for H1 receptors but also no brain penetration – so it is ineffective for sleep.  There is also a concern about prolonged QTc interval with hydroxyzine that has led European regulators to limit the total daily dose of hydroxyzine to 100 mg.  I typically see hydroxyzine prescribed for anxiety and insomnia in patients with substance use problems.  It is generally not very effective for either anxiety or sleep.

In the clinical population I see practically everyone has access to melatonin. It appears to be much less effective than trazodone but has the appeal that it is a “natural” supplement. That also means it is not monitored by the FDA in terms of bioequivalence. The dose of melatonin that most people take is many times the amount that is produce physiologically. I was told by one of the top sleep experts in the country several years ago that the appropriate way to take it is taking 1 or 2 mg at five or 6 PM to mimic the physiological release of melatonin. I often make that suggestion people who tell me they feel like they are taking too much with a 5 to 10 mg dose at bedtime. Ramelteon is available as melatonin receptor agonist and seems to be effective for sleep onset in about 30% of the people I see.

Gabapentin and pregabalin are unique compounds in that their primary action is through N-Type Voltage Gated Calcium Channels (VGCC).  A small segment of the population will experience these medications as very sedating.  Most people do not.  In addiction psychiatry, there was a trial of gabapentin in alcohol use disorder that showed that the treatment group (600 mg TID) had less insomnia, less anxiety, fewer cravings, and were less likely to relapse to alcohol use.  In the sleep literature, both are used for restless leg syndrome (RLS) and I have seen patients who experienced significant relief from these compounds when nothing else seemed to work.  These medications are currently controversial because of some concern of overuse in the context of limited efficacy.  In addiction, they are prescribed mostly for off label indications and sleep is one of those indications.  Even though I work in one of the strictest prescribing environments with regard to controlled substances, I do prescribe gabapentin for sleep, anxiety, chronic pain, and protracted benzodiazepine withdrawal (all off-label) but generally to patients with alcohol use disorders (per the clinical trial).  I generally avoid prescribing gabapentinoids for people with opioid use disorders because there is some evidence that they may escalate the dose and try to enhance the euphorigenic effects of opioids.  I also advise people ahead of time about these potential effects and encourage them to self-monitor for either euphorigenic effects or a tendency to escalate the dose.  Gabapentinoids should be discontinued in those circumstances.

I have not started using the orexin receptor antagonists yet.  Based on my previous review they look like very interesting compounds, but their clinical effects do not seem to match the theoretical effects at this point.  I think a clinical trial is needed to see if they can be safely used in populations with substance use disorders.  I hope to be of assistance designing and working on that trial.

 That brings me to the issue of quetiapine for sleep.  It is quite an emotional topic for some.  Some people will fly into a rage over the very mention of quetiapine being used off label for sleep.  As I mentioned AAPs present unique risks that other medications do not and if those risks are present they are basically cardiovascular risk factors. A significant proportion of the population being treated by psychiatrists already has cardiovascular risk factors like tobacco smoking that effectively reduces their life span by about 25 years. The addition of quetiapine of any AAP is a serious matter. 

In my capacity as a tertiary consultant, I am in the position of seeing large numbers of people for evaluations who are already taking quetiapine for sleep.  There is a selection bias in place because 100% of the people I see have a substance use disorder.  A substantial number overuse benzodiazepines and in some cases have been using very high doses for years before I see them.  If I am discussing treatment with a person at the end of my initial assessment and they are taking quetiapine, my first order of business is to inform them that according to Minnesota State Statutes – they need to sign a written consent form to take it and I review the sections on general side effects, metabolic effects (increased appetite, weight gain, diabetes, dyslipidemia) and the neurological effects – some of which may be irreversible (tardive syndromes).  That point is typically a defining point in the interview and I hear one of two things:

“Nobody ever told me about that before.”

“I have tried everything else for sleep and it doesn’t work.  And you know I can’t take benzodiazepines.”

In the case of the first response, additional details will depend on whether or not the patient has gained weight.  In some of those cases they will be irate.  Some will respond on the basis of a family history of diabetes and tell me there is no way they want to get it.  The majority of these patients will want to stop the quetiapine and in many cases they have never tried medications from the above table and one of them will work.  Those responses indicate to me that quetiapine was probably prescribed prematurely - before some of the other alternatives were tried.

In the case of the second response, I get very interesting histories of severe treatment refractory insomnia associated with substance use.  Most people take 25-150 mg of quetiapine for sleep but some take doses that are typically used for the stabilization of bipolar disorder (300-800 mg at night).  And they have been taking it for years. My basic job is to make sure they do not have tardive dyskinesia, diabetes mellitus, or cardiac conduction problems but things can get even more complicated than that.  For example, what about the person who already has diabetes mellitus Type II, hypertension, dyslipidemia, heart disease and a severe alcohol use problem?  What if they tell you: “Look doc – if I can’t use quetiapine for sleep my go to is alcohol and I know that alcohol is killing me.  You have to let me use that quetiapine or I will end up drinking myself to death”.

An equally compelling situation occurs in the person with opioid use disorder who refuses agonist treatment with buprenorphine of methadone.  After years of opioid use, severe insomnia generally does not resolve very easily and it can last for weeks or months.  Can a physician not prescribe a medication that can typically work for this insomnia based on the idea that some people consider the medication to be “bad”?  I think the answer is that the physician cannot.  If an assessment has been made that none of the other medications in the table are suitable, and the patient has a potentially life-threatening illness associated with insomnia and they have given adequate informed consent, then the medication must be prescribed.  Not sleeping and risking relapse to alcohol and drug use is a life threatening problem for most of the people I see.  In short, quetiapine should not be used casually for insomnia but there are situations where it may be required.

These are a couple of things I am working on with regard to sleep right now.  The Kis in the above table are only part of the story.  Coming up with better theories about quetiapine will hopefully lead to better ideas about sleep medications.

George Dawson, MD, DFAPA


Supplementary:

Table added to clarify the muscarinic acetylcholine receptor (mAChR) functions and the subtype most implicated in delirium. (click to enlarge).





References:


1.  Fukasawa H, Muratake H, Ito A, et al. Silicon-containing GABA derivatives, silagaba compounds, as orally effective agents for treating neuropathic pain without central-nervous-system-related side effects. ACS Chem Neurosci. 2014;5(7):525-532. doi:10.1021/cn500053d

2.  Kroeze WK, Hufeisen SJ, Popadak BA, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003;28(3):519-526. doi:10.1038/sj.npp.1300027

3. Nishiyama K, Shintani Y, Hirai K, Yoshikubo S. Molecular cloning and pharmacological characterization of monkey MT1 and MT2 melatonin receptors showing high affinity for the agonist ramelteon. J Pharmacol Exp Ther. 2009;330(3):855-863. doi:10.1124/jpet.109.155283  (monkey receptors)

4. Ancizu S, Castrillo N, Pérez-Silanes S, et al. New quinoxaline derivatives as potential MT and MT receptor ligands. Molecules. 2012;17(7):7737-7757. Published 2012 Jun 25. doi:10.3390/molecules17077737

5.  Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007;73(2):137-150. doi:10.1016/j.eplepsyres.2006.09.008 (human recombinant n 2— Type 1 subunit proteins)

6.  Salvi V, Mencacci C, Barone-
Adesi F. H1-histamine receptor affinity predicts weight gain with antidepressants. Eur Neuropsychopharmacol. 2016;26(10):1673-1677. doi:10.1016/j.euroneuro.2016.08.012

7.  Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P. Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194). Mol Pharmacol2002;61(2):391-399. doi:10.1124/mol.61.2.391

8.   Roth, BL; Driscol, J. "PDSP Ki Database"Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved July 5, 2020.

9.   Hshieh TT, Fong TG, Marcantonio ER, Inouye SK. Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci. 2008;63(7):764-772. doi:10.1093/gerona/63.7.764



Monday, July 13, 2020

Airborne Transmission Denial Dies Hard ........




I started this post as I left a staff meeting today on containing the coronoavirus. We had a similar meeting 2 months ago and at that point I added that there was airborne transmission of the virus.  The only comment I got was a condescending remark about how we don't know much about airborne transmission and we need to wait and see and blah, bah, blah. It was "as if" I did not know what I was talking about or any of the surrounding controversy.  To my surprise the same people today were sold on airborne transmission. They were even interested in HVAC issues and negative pressure rooms – all of the stuff I have been studying for 20 years.  Nobody mentioned UVC or air filtration.  I decided just to keep my mouth shut. Just like I usually do when politics seems to be the priority rather than science.  But the good news was undeniable.  Airborne transmission has much greater acceptance than it did prior to the current pandemic and there are clear reasons for it.

That staff meeting is a small part of a larger landscape of what airborne transmission advocates like me have been talking about for decades or longer.  Back in the days when I was working in an outdated building that had an HVAC system that was designed to contain heat rather than provide fresh air to dilute and remove airborne pathogens – I routinely observed the effects of this approach on myself and my coworkers.  Upper respiratory infections were endemic.  If one person came into that building with a severe form of a respiratory virus – most people got it. I can recall coming down with an acute flu-like illness one morning at work and getting ill so quickly and severely that I was barely able to make it home due to the cognitive effects.  I was close to delirium.

When you are in medical facilities, the party line is always “wash your hands”. I got the respiratory infections if I washed my hands 20 times a day or a hundred times a day.  The pandemic equivalent of that advice has been “don’t touch your face”.  But it is apparently safe to eat food that has been contaminated with SARS-CoV-2 because the virus is not infectious via gastrointestinal pathways.  The expert opinion is really based on the lack of evidence that eating food or touching food packaging is associated with SARS-CoV-2 infections.  We hear about the virus being infectious through the eyes and nose. It could be rubbed into the eyes from the face or into the nose by nose picking – but how common is that?  Certainly, washing your hands and not touching your face along with physical distancing at 6 feet seem like common sense rules.  But is that going to protect you?

I have never felt like any of those measures was enough and this week a letter came out pointing out the evidence for airborne transmission of respiratory viruses in general and for SARS-CoV-2 in particular.  I was pleased to see Dr. Milton as a co-author of this statement.  I have been reading his work for 20 years on airborne viruses in buildings of different design including the viruses that have been detected both in the air and the occupants of the building. This paper is a brief commentary specific to SARS-CoV-2 with a couple of generalities about airborne viruses and it is signed by 239 scientists who support it. 
   
The commentary starts out as an appeal to the medical community to recognize the potential for airborne spread of COVID-19.  Airborne transmission is defined as the release of droplets containing viral particles during breathing, coughing, sneezing, and any type of vocalization.  There is no doubt this happens. A distribution of droplet particle sizes occurs.  The larger droplets at a typical velocity settle out of the air in shorter distances typically in about 2 meters or 6 feet. The smaller droplets can travel much longer distances.  The authors cite an example of a 5 µm droplet at an original height of 1.5 meters and expelled at a typical indoor velocity travelling for “tens of meters” before it falls to the floor. This is typical airborne transmission and it will obviously not be contained by hand washing or physical distancing.

The authors on to describe some of the well-known scenarios where COVID-19 was transmitted despite no observed direct or indirect contact among the parties where the transmission occurred by video recordings.  They go on to cite other experiments demonstrating that several viruses (influenza, Middle East Respiratory Syndrome coronavirus (MERS-CoV), and respiratory syncytial virus (RSV) can all be spread by airborne routes. Although they don’t go into a lot of technical detail in the commentary, respiratory viruses are exhaled in normal tidal breathing.  The distribution and velocity of exhaled droplets will vary based on the way they are generated.  Infective viral RNA in small (5 µm) droplets from COVID-19 has been detected.

The critical sentence from this document follows:

“Hand washing and social distancing are appropriate, but in our view, insufficient to provide protection from virus carrying respiratory microdroplets released into the air by infected people.”

The is really a landmark statement from this group of experts. In my opinion it revolutionizes the approach not only to this virus but all respiratory viruses.  They all have access to the same type of spread and many have already been shown to have permeated heating and ventilation systems.  One of the main differences is virulence of the virus.  For example, smallpox or variola virus can cause an infection from the inhalation of a single viral particle (6).  Adenovirus, a much more common respiratory virus can cause an infection by the inhalation of as little as 6 viral particles (3).  Although adenovirus is potentially a flu-like respiratory virus, the main initiative at preventing the associated morbidity and mortality occurs in the military where a vaccination is used. The SARS-CoV-2 infections dose has been estimated to be about 280 particles – but the authors of one study suggest it is in the same ballpark of influenza virus and in that paper suggest that the amount of virus leading to infection in volunteers may be twice the amount of the aerosolized virus (5).

The main implication of airborne spread is that sustained inhalation of COVID-19 in poorly ventilated spaces of just being indoors increases risk of transmission. People who are coughing, sneezing, singing or engaged in any activity that results in forceful exhalation will expel small droplets at higher rates of speed and they will remain airborne for a longer period of time and travel much greater distances than the current suggested social distancing of 6 feet. 

To reduce the airborne transmission risk they have straightforward recommendations to avoid overcrowding (every additional person in the room is generating airborne droplets), have adequate ventilation, and supplement these measure with additions like HEPA filtration, germicidal UVC light, and exhausting room air rather than recirculating it. I can recall getting into an argument at one of my Avian Influenza Task Force meetings about a fast way to change the hospital ventilation system in the event of an influx of avian influenza patients.  Recall that the hospital was designed to retain heat by recirculating room air rather than exhausting it – like modern hospital rooms.  At the time, the counterargument was that it was just too expensive to build negative airflow rooms to prevent the flu virus from leaving the room with medical staff caring for the patients.  Most hospital rooms, even the ones I worked in that were built in the 1960s, had windows to the outside.  How difficult would it be to fit these windows with exhaust fans to the exterior of the hospital? 

This consideration is important now that there are political initiatives to reopen schools and other public places.  The ventilation systems of all of these places should be looked at and that assessment incorporated into the overall decision about how safe they are to open.  Further, there should be a systematic approach to how safe buildings are in general from the perspective of transmission of respiratory viruses.  A prospective approach that looks at how buildings in temperate climates need to be designed to minimize the spread of respiratory viruses needs to be a long term goal.  

It took a virus with heightened mortality and morbidity to raise awareness that physical measures rather than any available medication may be the best way to contain respiratory viruses.  Airborne transmission of respiratory virus denial dies hard - but hopefully it is being put to rest once and for all.  That should be a continued priority for everyone and momentum we cannot afford to lose.


George Dawson, MD, DFAPA

References:

1:  Lidia Morawska, Donald K Milton, It is Time to Address Airborne Transmission of COVID-19, Clinical Infectious Diseases, , ciaa939, https://doi.org/10.1093/cid/ciaa939

2:  Erin Bromage.  The Risks - Know Them - Avoid Them.  Erin Bromage COVID-19 Musings.  May 16, 2020.  Link

3:  Yezli S, Otter JA. Minimum Infective Dose of the Major Human Respiratory and Enteric Viruses Transmitted Through Food and the Environment. Food Environ Virol. 2011;3(1):1–30. doi: 10.1007/s12560-011-9056-7. Epub 2011 Mar 16. PMCID: PMC7090536.

4:    Nicas, M., Hubbard, A. E., Jones, R. M., & Reingold, A. L. (2004). The Infectious Dose of Variola (Smallpox) Virus. Applied Biosafety, 9(3), 118–127. https://doi.org/10.1177/153567600400900302

5:  Schröder I. COVID-19: A Risk Assessment Perspective. J Chem Health Saf. 2020;acs.chas.0c00035. Published 2020 May 11. doi:10.1021/acs.chas.0c00035


Previous Airborne Transmission Posts from this Blog:

SARS-CoV-2 Is An Airborne Virus?

Viruses Are In The Air - Protection From Airborne Viruses

Hand Washing

New Twist On An Old Method To Kill The Flu Virus


Is It Time To Quarantine Air Travelers?


Supplementary:

This statement from a recent Nature article:

"But this conclusion is not popular with some experts because it goes against decades of thinking about respiratory infections. Since the 1930s, public-health researchers and officials have generally discounted the importance of aerosols — droplets less than 5 micrometres in diameter — in respiratory diseases such as influenza."

from:  Dyani Lewis.  Mounting evidence suggests coronavirus is airborne — but health advice has not caught up.  Link.



Graphics Credit:

Graphic at the top is from Reference 1 based on the following CC License.  This is an Open Access article distributed under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/),