Emotional Blunting By Antidepressants - Does It Occur?

 

Ron Pies and I reviewed three recent papers on emotional blunting in this paper called Antidepressants Do Not Work by Numbing Emotions. It is a very self-explanatory essay that I encourage anyone to read if they have an interest in that topic specifically or in the general repetitive criticism that only our field seems to enjoy. I have previously commented on the rhetorical aspects to a previous paper and recent publications allow us to address specific scientific issues. The main argument that emotional blunting is the mechanism by which antidepressants work - has no scientific merit as explained in the essay. The basic argument is that if emotional blunting is rated at baseline before any antidepressants are started it is present and as treatment begins and starts to work – emotional blunting decreases as the depression remits. That led the authors we reviewed to conclude it was more likely a symptom of depression than either a mechanism of action or a side effect.

 1:  Measurement – is a better measurement needed?

In the reviewed studies we made some specific comments on the methodologies used to detect emotional blunting specifically Item 8 of the Montgomery Åsberg Depression Rating Scale (MADRS) or the Oxford Depression Questionnaire (ODQ). The ODQ was previously the Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQESA or OQuESA).

The single item on the MADRS provides the most unbiased assessment of emotional blunting and is a single question worded very much like a clinician might ask to assess the problem. The ODQ has more questions and a specific question where the subject is asked to estimate whether or not the antidepressant is contributing to antidepressant side effects.  Since no other potential etiologies (like depression) were considered we thought that these were questions that might lead to predictable biases like choosing antidepressants as the cause of decreased emotional range rather than the depression.

Are there better questionnaire designs to eliminate bias and allow for quantification.  Two good examples include the Attributional Style Questionnaire (ASQ) (1) and the Cognitive Style Questionnaire (CSQ) (2). In both of these questionnaires - subjects are asked in an open format to write down what they consider to be the cause of a hypothetical situation, answer a question about that situation, and then rate the important of the cause. The questions are all focused on perceived internal and external causes of depression consistent with the cognitive theory of depression. There is no reason why a similar questionnaire could not be designed to find cognitive and emotional side effects of medications.  It could be validated by including questions about the known physical side effects of medication.    

2:  Normal subjects taking antidepressants:

In thinking about unbiased opinions about the emotional effects of antidepressants my mind wandered back to a paper I read in the American Journal of Psychiatry many years ago.  It was easy to remember because it involved giving fluoxetine to research subjects who had no known psychiatric diagnoses. In that study – 15 subjects were enrolled and took placebo for two weeks followed by fluoxetine 10 mg x 1 week then fluoxetine 20 mg/day x 5 weeks and then placebo daily for two weeks.  There were assessed weekly on standard scales for anxiety and depression.  They were also assessed weekly on the General Well Being Schedule and the Quality of Life Enjoyment and Satisfaction Questionnaire.  Subjects were also assessed weekly for side effects and only three of the 15 subjects reported side effects and they were nausea, dyspepsia, and dizziness – all typical SSRI side effects.  The authors conclude:

“No significant effects attributable to fluoxetine were observed on any of the psychological variables examined. Minimal adverse effects were reported. … Significant mood elevating and other psychological effects of fluoxetine would appear to be induced only when symptomatic targets exist.”

Interestingly these authors contrast their work with that of Peter Kramer (4) and suggest that: “….mood-enhancing and other psychoactive effects of SSRIs are not a general property of these agents but are manifest in the context of target symptoms.”  A similar argument has been made about emotional blunting and why it may not occur in normal subjects.

In a second study of fluoxetine and dothiepin in subjects without mental illness a 5 week placebo controlled, double blind crossover study was used (4).  Each subject received each treatment and placebo.  The active treatment lasted for 35 days. Subjects received fluoxetine 20 mg/day or dothiepin (a tricyclic antidepressant) titrated to 150 mg/day. They were tested at day 10 and day 36.  Eleven mood ratings using an analogue scale were done three times a day. The subjects were also asked is they had any “problems with your health”.  Some increased irritability (3 subjects), anxiety (one subject), and “mood lowering” (2 subjects) was noted.  There were no reports of emotional blunting. The researchers generally reported:

“Throughout the study period, all subjects remained well, including during the drug-free periods between treatments.”

In looking for a third study, I found one by David Healy – a well-known pharmaceutical business critic (6).  This study involved 20 subjects randomized to receive 2 weeks of either reboxetine or sertraline in a cross over design.  There was an option to increase either drug to the next expected level on day 5 of active drug treatment.  Three scales were done on a daily basis including the Profile Of Mood States (POMS), Positive and Negative Affect Scale (PANAS), and the Social Adaptation Self Evaluation Scale (SASS).  A side effects questionnaire was administered. Subjects were also asked if they could distinguish the “behavioral effects” of the drugs and to rate their preferences on an 11 point Likert scale ranging from “worse than normal (-5) to better than normal (+5).  A relevant excerpt from this paper:

“In focus group settings, while still under the blind, half of the subjects volunteered that sertraline made them mellow, or less emotionally reactive and that these effects were either appreciated or not, while yet others described agitation. Effects consistent with a reduction in emotional reactivity were not described with reboxetine.”

This focus group observation was not observed in any of the data collected from the mood rating scales.  The authors point out studies suggesting that normal volunteers do not tolerate medications well and suggest that their study shows that tolerance of the antidepressant may depend on whether it is a preferred agent of the subject.  Side effects listed but not quantitated include chilblains, sweats, insomnia, nausea, sexual dysfunction, and “jaw or throat dyskinesias or dystonias on sertraline.”

In summary, my main additional concerns about the emotional blunting issue and whether it occurs to any extent with antidepressants is one of accuracy of measurement and why it has been conspicuously absent in clinical trials until recently – including trials where antidepressants are given to normal controls (defined as volunteers screened for the presence of any current or lifetime psychiatric disorders).  Although I suggested a way to get to a much less biased measurement of emotional blunting, I have a question about whether it can be accurately measured at all in an era where psychiatric research is often presented as political debate in social media and the popular press. There have been many examples of how biased press coverage has misrepresented the effects of psychiatric medications and you only have to look as far as the Peter Kramer reference and the appendix on “Violence”.  A study to look at a better questionnaire to see if this is ever spontaneously mentioned when it is not cued would be useful - but it is probably not any more possible today than asking if the last election was stolen. 

On the issue of emotional blunting in clinical practice – I have seen the equivalent in some patients over the years. I typically discuss it with people as restricted affective range that either they notice or other people notice. It typically occurs during reassessments of people who have partially remitted depressions. At that point in time, it makes sense to discuss the time course of that phenomenon and try to determine the time course and whether it is improving or getting worse. After making it explicit at that point – the options in clinical care include continued observation or an immediate change to a different medication. That aspect of clinical care would be an interesting study in itself – because in my experience the majority of people do not want to change the medication at that initial discussion. I think it is also an element of ongoing informed consent at that point.

At a practical level, I think that the study by Peters, Balbuena, and Lodhi (7) that we referenced has paved the way for many more replication studies for any RCTs of antidepressants that used the Montgomery-Åsberg Depression Rating Scale (MADRS) and that is a very significant number.

It also requires a degree of biological sophistication to realize that brain systems are so complex and individualized that you cannot expect a medication to affect everyone in the exact same way – either positively or negatively. In fact, you cannot have that expectation in attempting to treat far less complex organ systems. Responses to treatment and side effects in medicine are always probability statements.

George Dawson, MD, DFAPA

 

References:

1. Peterson C, Semmel A, Von Baeyer C, Abramson LY, Metalsky GI, Seligman ME. The attributional style questionnaire. Cognitive therapy and research. 1982 Sep;6(3):287-99.

2.  Haeffel GJ, Gibb BE, Metalsky GI, Alloy LB, Abramson LY, Hankin BL, Joiner Jr TE, Swendsen JD. Measuring cognitive vulnerability to depression: Development and validation of the cognitive style questionnaire. Clinical Psychology Review. 2008 Jun 1;28(5):824-36

3.  Gelfin Y, Gorfine M, Lerer B. Effect of clinical doses of fluoxetine on psychological variables in healthy volunteers. Am J Psychiatry. 1998 Feb;155(2):290-2. doi: 10.1176/ajp.155.2.290. PMID: 9464215.

4. Kramer PD: Listening to Prozac. New York, Penguin, 1993

5.  Wilson SJ, Bailey JE, Alford C, Weinstein A, Nutt DJ. Effects of 5 weeks of administration of fluoxetine and dothiepin in normal volunteers on sleep, daytime sedation, psychomotor performance and mood. J Psychopharmacol. 2002 Dec;16(4):321-31. doi: 10.1177/026988110201600406. PMID: 12503831.

6.  Tranter R, Healy H, Cattell D, Healy D. Functional effects of agents differentially selective to noradrenergic or serotonergic systems. Psychol Med. 2002 Apr;32(3):517-24. doi: 10.1017/s0033291701005086. PMID: 11989996.

7.  Peters EM, Balbuena L, Lodhi RJ. Emotional blunting with bupropion and serotonin reuptake inhibitors in three randomized controlled trials for acute major depressive disorder. J Affect Disord. 2022 Dec 1;318:29-32. doi: 10.1016/j.jad.2022.08.066. Epub 2022 Aug 24. PMID: 36029876.

8.  Hieronymus F, Lisinski A, Østergaard SD, Eriksson E. The response pattern to SSRIs as assessed by the Montgomery-Åsberg Depression Rating Scale: a patient-level meta-analysis. World Psychiatry. 2022 Oct;21(3):472-473. doi: 10.1002/wps.21029. PMID: 36073711; PMCID: PMC9453909.

Supplementary:

I was made aware of a new analysis of MADRS data (8) today after writing the above essay.  Those authors analyzed MADRS ratings from 4,243 subjects participating in twelve acute phase placebo‐controlled trials of an SSRI in major depression and looked at emotional blunting on Item 8 of the scale. They found that treatment reduced emotional blunting with the same effect size as other items on the scale.  They agree with the opinion that emotional blunting should not be ignored but in the case of these antidepressant trials the ratings moved in a favorable direction.

Updated Table including this new analysis (click to see a clearer version):

Graphic Credit:

Nasa surface of Europa per their media guidelines

Old Men Throwing a Football…

 

Three days ago – I drove up to my hometown on Lake Superior to visit relatives and some friends that I have had since childhood.  From about 1963 to 1973 we played football primarily but also several other sports in and around the only park we had as kids.  For a few months in the winter, it was a skating rink.  The rest of the time it was an abandoned field.  For about half of those years, the field was next to a ravine with a small swamp at the bottom of it.  Eventually the ravine was filled in and it was an even rougher field to play one.  We stuck to the rink surface, an abandoned lot across the street and in the wintertime the streets lined by snowbanks.  Of course, in the fall and winter we typically played in the dark after school.

And we played every night – in the rain, snow, and subzero weather.  There was no formal start time. Sometimes I would hear a pebble bouncing off my bedroom window and look out and the boys were all there waiting.  Other times I would step out into the alley and two blocks away see one of my friends waving his arms in a crossing motion over his head.  I would reply with the same motion, and we would head to the field. People would filter in when they saw us there warming up.  Quitting time, was highly dependent on when the neighborhood store closed (usually 8:30 PM).  The winner was often determined by that quitting time: “Whoever gets to this score or 8:15 PM”.  Our post game ritual was consuming 16 oz RC Colas at the store, and we couldn’t miss it.  

Most of these games were 2 on 2 or 2 on 3 passing games.  As a result we could all throw well and learned to catch a football very well. What was remembered three days ago was learning how to catch a ball that disappeared above the streetlights in the extreme dark cold of winter when it suddenly reappeared under the lights.  We would say “it came out of nowhere” – but we would catch it. On this day we did not do any kicking or punting, but I also remembered the guy in our group who taught himself to punt a perfect spiral.  It was amazing to see and that disappeared above the streetlights for a very long time before it came into view.

Today we were focused on short passes of 10-30 yards and throwing flat minimal arc spirals. I still recall my high school coach showing us how to throw a spiral with the nose of the ball slightly elevated for more distance and that was what I was going for.  I wondered if we were going to throw for distance like we used to do but that never happened.  The focus was on these short passes and catching the ball in the hands.  The fall detection on my watch was set off by catching a few of these passes. These passes still had a little heat on them. One of my friends talked about having "$1,000 hands" based on what he caught at work and telling the story of how he developed that ability. 

Only a couple of us played organized sports.  I wrote about that in another post. But the caliber of play was high.  Playing a sport every day for 10 years brings with it a high degree of athleticism both in terms of conditioning and coordination.  And it seems hard to believe these days but the only diversions available to us was very mediocre black and white television transmitted through the air and reading. Technical problems were common with the TV and to see a show you had to be there. It seems hard to believe now - but there was no on-demand viewing or recording.  Reading was limited by what you could buy or borrow from the library. At the same store where we drank the RC Colas – a bookmobile showed up every Saturday.  I remember borrowing and reading When Worlds Collide - a novel written in 1933 - and being fascinated by it.  Toward the end of my football period I worked for the library and mailed books out to other bookmobile locations.

That lack of diversions – technical and otherwise may have kept us focused on our game.  Several people commented to me that nobody ever plays in that field anymore.  On some days we had 10 or 20 additional players.  But these days nobody ever shows up and plays every day.  The city baseball and softball leagues have also been decimated far beyond what could be accounted for by a population decrease. It seems that in small town America not many people are playing sports anymore.

As we were throwing the ball around. One of my friends reminded me of a time when I threw him a pass and he dropped the ball.  I told him to take his gloves off so he could catch it the next time and it was 17 degrees below zero at the time. I am certainly not the same guy I was back then – you become a better person with age.  I asked him what he made of that today and he summed it up: “That’s just the way it was back then.”  There were definite periods where we were unnecessarily rough and angry. But I don’t recall any out and out fights.  The roughness of the game when you are a kid is a source of pride.  We were all from the East End and we had a shared "wrong side of the tracks" blue collar mentality. To this day – one of my friends in the photo gives West Enders a rough time.  He told me that he recently asked one of them: “Did you even play outside when you were kids?”  Trash talking is not a new invention.

The shared experience is something I never thought about at the time. I heard a recent piece on This American Life about the importance of camping to some people and how there were campers and non-campers and the non-campers would never understand the emotional importance of camping.  The same thing was true of our football games.  It gave us all meaning at a time in our lives where there wasn’t much. It gave us a chance for intense emotional expression and eventually being able to control that expression.  It helped us through some pretty bad times. I still remember hearing the pebble bounce off my window and telling the guys: “I can’t play today – my Dad died last night.”  I remember the expression on their faces when they heard that news. I remember it as clearly as if it happened yesterday.  All of the homilies that I heard at various sports banquets about the importance of teamwork - rings hollow. It is more important just to be there and share the experience.  Nobody ever tells you that when you are a kid beating yourself up for losing a game. It really doesn't matter who wins or loses.  It doesn't matter how you play either. It just matters that you show up and keep showing up.

This day - it was happier times.  We had all just finished working - as in retired.  School, work, and in some cases military service were all necessary distractions from our game. One of my friends has just completed 41 years of work without missing a day and for some of those days he was working 7 days a week. We had all dodged severe medical problems of one form or another.  We had all survived COVID so far and had the vaccinations. It was a good day to be alive on our childhood playing field.   

We may have lost a step or two but old men can still throw and throw quite well.  But there were no diving catches.

 

George Dawson, MD, DFAPA

Happy Labor Day

 

Happy Labor Day

 

“It should be evident to all students, residents, and practicing physicians that the enormous investment in time, money, and commitment typically necessary to become a physician makes no sense if practicing medicine frequently fails to be interesting and enjoyable.”  Samuel B. Guze, MD 1992 (1)

 

Every year I try to post something about my impression of the physician work environment. That has been a progression of depressing posts as the work environment deteriorates every year largely due to micromanagement by managed care companies and various governments that has resulted in a trillion dollar overhead, quality as an advertising meme rather than a clinical reality, poorer reimbursement for physicians, massive numbers of wasted hours for the bureaucracy and its documentation requirements, and the negative feedback loop of using the healthcare system as a jobs program for business administrators.  Each of those iterations moves use farther and farther from Dr. Guze’s reality of an enjoyable and intellectually stimulating career in medicine.  Interestingly – enjoyability is not an obvious factor in the most frequently used scale to detect burnout in medical staff.  Those scales tend to be focused on a learned helplessness/loss of personal efficacy model.  Lack or loss of enjoyability is probably the first step toward that extreme conclusion.

It is equally frustrating for patients who have seen access get markedly worse.  Just this month I tried to assist a friend in finding a therapist either inside or outside of her insurance plan. And there were none. I am not talking about a waiting list and an appointment 2 or 3 months out.  I am talking about no access at all.  The clinics would not even place her on a waiting list.  I saw a consultant myself back in January who told me he was referring me to another specialist to be seen this August.  When that did not happen, I called and my calls were not returned. Eventually by sending enough messages to my primary care MD they called me and set up an appointment on September 2.  I was called yesterday and told that appointment was cancelled.  They gave me another appointment in mid-November with the qualifier: “We have you penciled in but there is no guarantee that this won’t change again”.

I am very aware of the strain the pandemic and its mismanagement has put on the system.  Also aware of physicians and nurses resigning in droves (2). In the case of primary care specialties and psychiatry there was a serious shortage before the pandemic hit.  The pandemic itself is an insufficient explanation for what has happened over the past three years. The lack of an adequate pre-existing public health infrastructure had a lot to do with it (4).  Inadequate protection for front line workers and an inability to scale as the morbidity and mortality increased in some cases exponentially. In the case where public health officials were doing what they could they often found themselves threatened and attacked by pandemic deniers, anti-vaxxers, and let’s face it various elements of the right wing (3). The same people basically responsible for building out America’s immense for-profit and inefficient health care system. What could be more depressing than to try to treat a pandemic while a political party is basically denigrating standard public health measures and either verbally attacking or threatening public health officials to the point that many had to get security personnel for protection. When you have a big enough platform – I consider acts of omission-like not taking a stand firmly against political violence as bad as the people making the threats. I also don’t make any distinction between threats from the average man or woman on the street and members of Congress making clear threats.  Many seem to act like they have immunity in those situations.

The politically designed medical systems of care that is basically run by unqualified business people was ramped up to even worse performance by the associated political anarchy. That anarchy continues. Who could blame physicians for bailing out in those circumstances?  I think there is a legitimate concern about whether the system will every get back to its baseline prepandemic inefficiency.

Some have considered the increased use of telemedicine and telepsychiatry to be a positive correlate of the pandemic. I gave a continuing medical education presentation on it in November of 2021. For various reasons – I think the eventual outcome of telemedicine is uncertain. The main reasons have to do with businesses taking over and managing the visits for profit and to the detriment of any therapists or physicians involved. A review of what can happen was published in the New York magazine (5). I see television ads all the time for rapid access to all kinds of prescriptions just by calling a business running a specialty telemedicine site. Some of these sites are already controversial and there appears to be very little transparency when it comes to comparing these sites to the even meager quality of care offered by in-person managed care.  Payer gaming at all levels is another possibility. During the pandemic reimbursement for care delivered was at the standard rate.  We are just starting to see decreased reimbursement or no reimbursement for televisits. I have also seen very disadvantageous contracts for physicians and therapists attempting to do televisit work at the levels of reimbursement, risk, and required access. That is consistent with the decade’s old observation that medical practice environments deteriorate in quality with increasing business involvement.

On a positive note this year – the main alternative to maintenance of certification by  American Board of Medical Specialties (ABMS) is the National Board of Physicians and Surgeons (NBPAS). This year the NBPAS was given recertification status by the Joint Commission and hospital accrediting agencies. The NBPAS model is the original “life long learning” model proposed for all physicians since the Flexner era. I have personally been recertified every two years by the NBPAS, but until this year realized that most younger physicians were not in a position where they could abandon much more costly and some would say overly involved ABMS recertification procedures.  The change this year apparently makes it easier to make that transition, but a lot will depend on hospital committees and local accreditation procedures. ABMS recertification is onerous enough to tip the balance in favor of leaving the field for retirement of a different occupation so that this change may also lead to physician retention.  But a lot will depend on how all of this unfolds.

I can still recall reading about why Paul Tierstein, MD came up with the original idea for NBPAS. He noticed a colleague who was an electrophysiologist cramming for a recertification examination and learning details he would never use in his day-to day practice.  Most physicians – even within their own specialty or subspecialty develop a knowledge base for that practice.  That knowledge base is not consistent with a preparatory based knowledge learned in medical school or as a resident. Relearning irrelevant material for the sake of taking an examination is another unnecessary drain on a physician’s time and finances. Life long learning is a better way to acknowledge that physician’s highest level of certification and ongoing efforts to maintain that specialized knowledge.

All things considered it has been another very stressful year for physicians. There is a glimmer of hope on the recertification front that will hopefully alleviate a lot of unnecessary stress.      

We still have a very long way to go to reach Dr. Guze’s suggested practice environment that is both fun and intellectually stimulating.  Like he says in his book – I was taught about that is medical school and experienced it only in the very first years of practice. We need to make medicine interesting and enjoyable again and that’s a very tall order.

 

George Dawson, MD, DFAPA

Supplementary:

 Explanation of the graphic: sometime ago I posted that heavy lifting is a metaphor for what has happened to medical practice in the US. This is another example. 

References:

1:  Guze SB. Why Psychiatry Is a Branch of Medicine. New York; Oxford University Press: 1992: p. 118.

2:  Abbasi J. Pushed to Their Limits, 1 in 5 Physicians Intends to Leave Practice. JAMA. 2022;327(15):1435–1437. doi:10.1001/jama.2022.5074

3:  Ward JA, Stone EM, Mui P, and Resnick B, 2022:Pandemic-Related Workplace Violence and Its Impact on Public Health Officials, March 2020‒January 2021.American Journal of Public Health 112, 736_746, https://doi.org/10.2105/AJPH.2021.306649

4:  Bishai DM, Resnick B, Lamba S, Cardona C, Leider JP, McCullough JM, Gemmill A. . Being Accountable for Capability—Getting Public Health Reform Right This Time. American Journal of Public Health 0, e1_e5, https://doi.org/10.2105/AJPH.2022.306975

5: Fischer M.  The Lunacy of Text Based Therapy (And other technological solutions for a nation in trauma).  New York Magazine March 29-April 11, 2021.

Image Credit:

National Archives and Records Administration, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Girls_deliver_ice._Heavy_work_that_formerly_belonged_to_men_only_is_being_done_by_girls.

Heavy work that formerly belonged to men only is being done by girls. The ice girls are delivering ice on a route and their work requires brawn as well as the patriotic ambition to help. - NARA - 533758. https://upload.wikimedia.org/wikipedia/commons/0/0a/Girls_deliver_ice._Heavy_work_that_formerly_belonged_to_men_only_is_being_done_by_girls._The_ice_girls_are_delivering_ice_on_a_route_and_their_work_requires_brawn_as_well_as_the_partriotic_ambition_to_help._-_NARA_-_533758.gif

Has The Mechanism of General Anesthesia Finally Been Discovered?

 

General anesthesia is one of the greatest innovations of modern medicine.  Even within  the history of that innovation there have been tremendous improvements ranging from the administration of ether in the 1960s to very closely monitored combinations of opioids, benzodiazepines, and inhaled anesthetics in more modern times. The mechanism of action of opioids and benzodiazepines at the receptor level are known, but the effects of inhaled anesthetics have been more of a source of speculation.  I first became aware of this as an undergraduate taking physical chemistry (1) when I read about Linus Pauling’s hypothesis (2).  He suggested that microcrystalline hydrates form from the reaction of anesthetic gases and water molecules at the membrane surface. Those microcrystalline hydrates then interfere with synaptic transmission leading to loss of consciousness. Pauling was a physical chemist who was awarded the Nobel Prize for his work on the hydrogen bond and wrote about many general anesthetics as not working through hydrogen bond mechanisms.  He was also very optimistic about the role of physical chemistry in biological systems. Interestingly he briefly discusses how general anesthesia and the mechanism are important for psychobiology (2):

“The progress that has been made in the field of molecular biology during this period has related in the main to somatic and genetic aspects of physiology, rather than to psychic. We may now have reached the time when a successful molecular attack on psychobiology, including the nature of encephalonic mechanisms, consciousness, memory, narcosis, sedation, and similar phenomena, can be initiated. As one of the steps in this attack I have formulated a rather detailed theory of general anesthesia, which is described in the following paragraphs.” (p. 15)

He provides an elaborate physical chemistry rationale for the hydrate-microcrystal theory of anesthesia in this paper.  Pauling’s work comes on the cusp of the era of molecular biology – a field that he is credited with creating.  In his original explanation he discussed x-ray crystallography of crystals and new biologically active protein structures continue to undergo this analysis when they are isolated and purified.

Fast forward to a paper I just read in Current Biology a few days ago (3). It is written in the context of no clear mechanism of action for volatile inhaled anesthetics since their first observed effects noted over a century ago despite numbers speculative papers including papers from the past decade in this same journal.  The authors suggest that a disruption in electron transport in the mitochondria specifically Complex I  of 4 transport proteins is the area responsible for the effects of general anesthesia. Before getting to their experiment, a few words about this system.

Electron transport, oxidative phosphorylation, and ATP synthesis are all tightly coupled processes occurring over 5 proteins known as mitochondrial complexes (Complexes I-V).  Before the era of molecular and structural biology, these processes were partially deduced using in vitro methods looking at chemical reactions in mitochondrial preparations and specific reactions that affect each step. The cofactors were determined along with the overall stoichiometry of the process. With greater emphasis on structural and molecular biology there have been additional hypotheses about the specifics of electron transfer across the complexes and how ATP synthesis occurs.  Although there is much evidence to support various hypotheses about how all of these processes occur – in all of my reading it does not appear to be settled science.  In fact, some authors talk about emergent properties of this system that cannot be defined by what is known about the current components (10).  The discussion of emergent properties is interesting on at least a couple of levels. First, that kind of discussion is routine in consciousness research. There are no clear-cut biological mechanisms that generate a conscious state and it is discussed as an emergent property of the brain. Second, the minimum requirements of a biological system to create emergent properties is never really discussed. Does the mitochondrial system of electron transport, generating a proton gradient, ATP synthesis, and tightly couple oxidation and phosphorylation qualify?

This mechanism may have implications for the science of consciousness. In humans who are in good health and have no known brain diseases - general anesthesia and non-REM (NREM) sleep are considered to the the only states of unconsciousness. During that time the thalamus appears to be inactivated (13).  There have been several studies showing that some people dream during NREM sleep so that is not a clear boundary. But in the case of this mechanism questions would include considering the synaptic mechanisms as well as the global neuroanatomical mechanisms as well as the issue of emerging properties of biological systems of varying complexity.  What does it mean if a smaller system with emergent properties can turn off a larger system with emergent properties? What is the relationship of the emergent properties between systems?  

Moving on to the paper – the authors start by pointing out that neurotransmitter recycling in neurons is dependent on ATP and endocytosis.  Further - that Complex I of the mitochondrial electron transport chain (ETC) is the rate limiting step in this process and that disrupting it causes sensitivity to volatile anesthetics (VA). Knockout mice (for a protein in Complex I) were physiologically normal but much more sensitive to VA. The authors hypothesized that VAs decrease presynaptic ATP production by the ETC (oxidative phosphorylation) leading to decreased endocytosis and neurotransmitter cycling, and that the inhibition of Complex I was the primary mechanism.  They conduct a number of experiments to illustrate the effects of VA (isoflurane) on the ETC chain looking at perturbations would increase the effect and decrease the effect and conclude that their hypotheses are supported by the data.  They conclude that Complex I inhibition may be the mechanism of action of isoflurane. If supported by other studies the mystery of the mechanism of action of VA may be solved after 170 years.

I continue to be astonished at the trajectory of brain science and all of the factors that are needed for these advancements.  Even at the level in this paper the suggestion is that the proposed hypothesis will require additional work.  This research occurs at the intersection of a series of historical hypotheses about the mitochondrial ETC and parallel hypotheses about the mechanism of action of volatile anesthetic gases. The scientific work and hypothesizing was built both on previous discovery and advances in technology.  In this area advancement was slow and is still not completely settled in either research area. A lot of science discussed in the press seems to suggest that there are arbitrary time frames or amounts of investment for advances and that is obviously not true.

George Dawson, MD, DFAPA

 

References:

1:  Moore WJ.  Physical Chemistry, Fourth Edition. Englewood Cliffs: Prentice-Hall, Inc; 1972: p. 241-243.

2:  Pauling L. A molecular theory of general anesthesia. Science. 1961 Jul 7;134(3471):15-21. doi: 10.1126/science.134.3471.15. PMID: 13733483.

3:  Jung S, Zimin PI, Woods CB, Kayser EB, Haddad D, Reczek CR, Nakamura K, Ramirez JM, Sedensky MM, Morgan PG. Isoflurane inhibition of endocytosis is an anesthetic mechanism of action. Curr Biol. 2022 Jul 25;32(14):3016-3032.e3. doi: 10.1016/j.cub.2022.05.037. Epub 2022 Jun 9. PMID: 35688155; PMCID: PMC9329204.

4:  Sharma LK, Lu J, Bai Y. Mitochondrial respiratory complex I: structure, function and implication in human diseases. Curr Med Chem. 2009;16(10):1266-77. doi: 10.2174/092986709787846578. PMID: 19355884; PMCID: PMC4706149.

5:  Wikström M, Hummer G. Stoichiometry of proton translocation by respiratory complex I and its mechanistic implications. Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4431-6. doi: 10.1073/pnas.1120949109. Epub 2012 Mar 5. PMID: 22392981; PMCID: PMC3311377.

5:  Jones AJ, Blaza JN, Varghese F, Hirst J. Respiratory Complex I in Bos taurus and Paracoccus denitrificans Pumps Four Protons across the Membrane for Every NADH Oxidized. J Biol Chem. 2017 Mar 24;292(12):4987-4995. doi: 10.1074/jbc.M116.771899. Epub 2017 Feb 7. PMID: 28174301; PMCID: PMC5377811.

7:  Toda C, Diano S. Mitochondrial UCP2 in the central regulation of metabolism. Best Pract Res Clin Endocrinol Metab. 2014 Oct;28(5):757-64. doi: 10.1016/j.beem.2014.02.006. Epub 2014 Mar 7. PMID: 25256770.

8:  Giorgio V, Fogolari F, Lippe G, Bernardi P. OSCP subunit of mitochondrial ATP synthase: role in regulation of enzyme function and of its transition to a pore. Br J Pharmacol. 2019 Nov;176(22):4247-4257. doi: 10.1111/bph.14513. Epub 2018 Nov 28. PMID: 30291799; PMCID: PMC6887684.

9:  DiMauro S, Garone C. Historical perspective on mitochondrial medicine. Dev Disabil Res Rev. 2010;16(2):106-13. doi: 10.1002/ddrr.102. PMID: 20818724; PMCID: PMC3839238.

10:  Voet D, Voet JG. Electron Transport and Oxidative Phosphorylation. In: Biochemistry, 2^nd Edition. New York: John Wiley & Sons, Inc;1995: 563-598.

11:  Kurz FT, Aon MA, O'Rourke B, Armoundas AA. Functional Implications of Cardiac Mitochondria Clustering. Adv Exp Med Biol. 2017;982:1-24. doi: 10.1007/978-3-319-55330-6_1. PMID: 28551779; PMCID: PMC7003720.

12:  Deshpande OA, Mohiuddin SS. Biochemistry, Oxidative Phosphorylation. [Updated 2021 Aug 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK553192/

13:  12:  Vacas S, Kurien P, Maze M. Sleep and Anesthesia - Common mechanisms of action. Sleep Med Clin. 2013 Mar;8(1):1-9. doi: 10.1016/j.jsmc.2012.11.009. PMID: 28747855; PMCID: PMC5524381.

Graphics Credit:

 Mitochondria graphic is my modification of a VisiScience slide per their user agreement for non-commercial use.

Supplementary:

1:  The Krebs cycle, citric acid cycle, or tricarboxylic acid cycle occurs only in the mitochondrial matrix basically converting chemical energy into the reducing power of NADH for ATP synthesis from electron transport.

2:  Additional review on mitochondrial dysfunction and Alzheimer's Disease:

Misrani A, Tabassum S, Yang L Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease.  Front. Aging Neurosci. 2021; 13:617588. doi: 10.3389/fnagi.2021.617588

Rosacea Is A Complex Illness – And Here Is Why That Is Important

 

Pathophysiology of Rosacea from Ref 2 via-Noncommercial 4.0 International (CC BY-NC 4) 0)

    (click to enlarge)

 

This post is part of my apparent never-ending quest to get complex illnesses and blog about them.  About 15 years ago, I saw my primary care physician and described some dermatology problems that I was having.  I won’t get too deep into the weeds about my symptoms, but somewhere along the line I also recalled that my father had similar symptoms. In those days back in the 1950s and 1960s he really did not get any formal diagnosis.  He was told instead that the somewhat matted lesions he had on his face should be “drained” and his physician cut into them with a scalpel.  Eventually they cleared up on their own. In my case I was given some topical metronidazole that seemed to work for local outbreaks and have been using it ever since. It seems good for focal lesions but it does not seem to do much for more global symptoms such as a burning and stinging sensation of the more recently discovered ocular symptoms of rosacea. 

I first started to diagnose it and refer it for treatment when I was seeing patients in acute care psychiatric units.  I acquired a text that was considered state-of-the art in the late 20^th century (1) to assist me in describing rashes and diagnosing dermatology diseases.  The definition of rosacea was: “Papules and papulopustules occur in the center of the face against livid erythematous background with telangiectasias. There is also quite often diffuse connective tissue and sebaceous gland hyperplasia and sometimes hypertrophy of the nose (rhinophyma)” (p. 730).  The disease was described as progressive stages rather than discrete phenotypes and the pathology of each stage was described and as a chronic inflammatory condition.

Little was known about the pathophysiology at the time but the usual suspects of genetic predisposition and relationships to diet and other potential irritants. The mite Demodex folliculorum was suspected.  Various irritants like sun, mechanical irritation, heat, cold, hot drinks, alcohol, and caffeine increased the erythema (redness).  The authors described progressive stages rather than distinct phenotypes. Eye involvement was known at the time including complications like blepharitis, conjunctivitis, iritis, and in some cases keratitis of the cornea leading to blindness.  Associated symptoms were eye pain and photophobia.  The main treatment described was systemic and topical antibiotics, sunscreen and avoiding other irritants.

Today like many diseases there are clearer diagnostic criteria and there is also accumulated knowledge on possible pathophysiology. The American Rosacea Society proposed the criteria listed in the following table. Currently 2 or more major features are diagnostic.  The criteria are controversial because they include a number of features with low predictive value.  A subsequent update by the Global ROSacea COnsensus Panel (ROSCO) modified the criteria and expanded to 6 phenotypes. Note that there are no formal biomarkers for the phenotypes just very approximate clinical descriptions.

 

Primary Features	Central distribution of:   Transient erythema (flushing) Permanent erythema Papules/pustules Telangiectasia
Secondary Features	Burning or stinging sensation Ocular involvement Edema Dryness Plaque formation Peripheral location Phymatous changes
Phenotypes	Subtypes:   Erythematotelangiectatic Papulopustular Phymatous Ocular   Variant: Granulomatous

 

 

ROSCO Phenotypes

Flushing

Persistent Erythema

Telangiectasia

Papules/pustules

Phymatous changes

Ocular manifestations

 

This post is not about how to make the diagnosis or treat this disorder, although every physician including psychiatrists should be able to recognize the condition. I am hoping to convey some diagnostic imperatives and discuss disease complexity that underlies fairly basic diagnostic categories. It will also be apparent that basic science research has added quite a lot in terms of the treatment or this disorder, but that a lot of uncertainty remains.

Let me start with pathophysiology. There is always plenty of controversy about pathophysiology despite the fact that not much is known about it – even in common complex diseases.  That includes psychiatric diseases and yet people seem to suspend their critical thinking when it comes to psychiatry – and claim that the lack of pathophysiological mechanisms and medications specific for that pathophysiology represents something unique. In the case of rosacea since it is considered a complex inflammatory disease there are a couple of approaches to looking at pathophysiology. The first is to consider the two main types of immunity and how they are modified.  The first general type in innate immunity basically comprised of various barriers to pathogens like skin and mucous membranes, non-specific immune cells, and inflammatory proteins like interferons.  Local chemical environments can also produce a number of physical and chemical conditions that can kill potential pathogens.  Adaptive immunity is more specific and it depends on recognitions on antigens on pathogens and the resulting reactions with antibodies and immune cells. In the case of rosacea there are different theories involving both types of immunity.

One theory suggests that there is increased production of cathelicidin antimicrobial peptide (CAMP) – a component of innate immunity that leads to the inflammatory process associated with rosacea.  CAMP gene expression is regulated by VDR (a Vitamin D dependent transcription factor) and C/EBPα (a Vitamin D independent transcription factor). During winter months there is not enough UV light to produce CAMP by the Vitamin D dependent process. This theory suggests there is a mutation that allows for C/EBPα activation leading to toll-like (TLR) receptor mediated immune responses and upregulation of endoplasmic reticulum (ER) stress responses.  Although this sequence of events leads to increased inflammation due to a number of end products [sphingosine-1-phosphate (S1P), LL-37 the active cleavage product of CAMP, interleukin-1β (IL-1β), IL-17, IL-18, as well as associated T-helper (Th) cells and chemokines.  This process is depicted in the graphic at the top of this post (click on it to enlarge).  The activation of this inflammatory reaction can be verified by measuring end products in both the epithelium and the ocular surface.  Dry eye clinics have the capacity to check for tear osmolarity and inflammatory markers like matrix metalloproteinase-9 (MMP-9) – an enzyme.  MMP-9 can be done as a point-of-care test so that the results are available within minutes.

A logical question to ask is whether widespread activation of the inflammatory response associated with rosacea can affect organ systems other than skin. The degree of inflammation is also a factor. It is common to see patients with diverse findings ranging from mild erythema on the cheeks to intense erythema of the eyelids and central facial areas. The question of other organ systems has been examined with interesting findings. Cardiac, neurological, and psychiatric conditions are all more likely in patients with rosacea (6-15).  In terms of cardiac conditions that includes a modest increased risk for atherosclerotic heart disease.  There is less evidence of increased risk for arrhythmias but that increased risk has been demonstrated for other inflammatory dermatological conditions like atopic dermatitis and psoriasis (14). In the papers where the authors comment on possible pathophysiology the suggested mechanisms are innate immunity, adaptive immunity, or both.

Rosacea is a complex inflammatory disease that can lead to significant ocular and dermatological complications. According to one theory the pathophysiology of the illness may have been caused by an adaptive mutation in Nordic populations that preserved innate immunity when Vitamin D dependent factors were not available due to decreased photoperiod and UV light. The general consensus is that there is no agreed up theory to explain the underlying pathophysiology and like the immunological literature in psychiatry different authors have differing hypotheses.

Psychiatrists need to be aware of the condition because about 5% of the population has it, it is readily diagnosed based on visual inspection but the ocular phenotype may require referral to a specialized dry eye clinic. The dry eye disease untreated can lead to significant eye complications. From a theoretical perspective there are direct parallels with the psychiatric process including the categorial diagnoses, theoretical pathophysiology, and a number of treatments that may or may not address that pathophysiology.  Current clinical and future research questions include:

1:  Are there immunological mechanisms common to both rosacea and common psychiatric disorders?  Immune etiopathophysiological hypotheses for psychiatric disorders have been proposed since 1985 (16) and their complexity and the number of disorders covered have only increased since that time.  Over the same time frame much more has been discovered about the basic science of immunology. Do the proposed immune mechanisms of rosacea affect other organ systems in the same way that the skin is affected?  Are these mechanisms responsible for some of the early observations about PET imaging of the brain (15) in rosacea?

2:  What about the immunological products of rosacea?  Is it possible that they are contributing to what are considered symptoms of general disorders like anxiety and depression?  Cytokines like IL-17 can lead to flu-like symptoms and a general feeling of malaise – could this lead to the appearance of a treatment resistant anxiety or depressive disorder?  Could it lead to the misdiagnosis of a psychiatric disorder?

3:  Even if there is no direct physiological connection between rosacea and anxiety and depression can pathophysiological processes lead to psychiatric complications especially with pre-existing anxiety and depression. For example- rosacea leads to neurovascular hyperactivity in the form of facial flushing and skin sensitivity to a variety of physical and chemical irritants. If you have a pre-existing concern about embarrassment, humiliation, and obvious physical signs of anxiety rosacea compounds that.  It also can lead to sleep problems due to skin sensitivity that will compound any associated psychiatric disorder.

4:  Dealing with the stress of a chronic disorder activates additional processes that can either exacerbate or precipitate anxiety or depression. There is an inherent bias to see conditions like rosacea as a minor problem rather than a potentially very stressful problem with considerable morbidity that can actually lead to physical disability.

That is what I have found to be interesting about rosacea and dealing with it at an individual level.  I hope there is more research focused on it in the future from the combined perspectives of psychiatry, dermatology, and immunology.  There is much more to be learned.

 

George Dawson, MD, DFAPA

 

References:

1:  Braun-Flaco O, Plewig G. Wolff HH, Winkelmann RK.  Dermatology.  Springer-Verlag, Berlin 1991: 730-731.

2:  Melnik BC.  Rosacea: the blessing of the Celts – an approach to pathogenesis through translational research.  ACTA Derm Venerol 2016; 96: 147-156.

3:  Ratajczak MZ, Pedziwiatr D, Cymer M, Kucia M, Kucharska-Mazur J, Samochowiec J. Sterile inflammation of brain, due to activation of innate immunity, as a culprit in psychiatric disorders. Frontiers in psychiatry. 2018 Feb 28;9:60.

4:  Salam AP, Borsini A, Zunszain PA. Trained innate immunity: A salient factor in the pathogenesis of neuroimmune psychiatric disorders. Molecular Psychiatry. 2018 Feb;23(2):170-6.

5:  Zengeler KE, Lukens JR. Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders. Nature Reviews Immunology. 2021 Jul;21(7):454-68.

6:  Garrett ME, Qin XJ, Mehta D, Dennis MF, Marx CE, Grant GA, VA Mid-Atlantic MIRECC Workgroup, PTSD Initiative, Injury and Traumatic Stress (INTRuST) Clinical Consortium, Psychiatric Genomics Consortium PTSD Group, Stein MB. Gene expression analysis in three posttraumatic stress disorder cohorts implicates inflammation and innate immunity pathways and uncovers shared genetic risk with major depressive disorder. Frontiers in Neuroscience. 2021 Jul 29;15:678548.

7:  Pape K, Tamouza R, Leboyer M, Zipp F. Immunoneuropsychiatry—novel perspectives on brain disorders. Nature Reviews Neurology. 2019 Jun;15(6):317-28.

8:  Bekkering S, Domínguez-Andrés J, Joosten LA, Riksen NP, Netea MG. Trained immunity: reprogramming innate immunity in health and disease. Annual review of immunology. 2021 Apr 26;39:667-93.

9:  Dounousi E, Duni A, Naka KK, Vartholomatos G, Zoccali C. The innate immune system and cardiovascular disease in ESKD: monocytes and natural killer cells. Current Vascular Pharmacology. 2021 Jan 1;19(1):63-76.

10:  Scott Jr L, Li N, Dobrev D. Role of inflammatory signaling in atrial fibrillation. International journal of cardiology. 2019 Jul 15;287:195-200.

11:  Zhou X, Dudley Jr SC. Evidence for inflammation as a driver of atrial fibrillation. Frontiers in cardiovascular medicine. 2020 Apr 29;7:62.

12:  Bellocchi C, Carandina A, Montinaro B, Targetti E, Furlan L, Rodrigues GD, Tobaldini E, Montano N. The Interplay between Autonomic Nervous System and Inflammation across Systemic Autoimmune Diseases. International Journal of Molecular Sciences. 2022 Feb 23;23(5):2449.

13:  Choi D, Choi S, Choi S, Park SM, Yoon HS. Association of Rosacea With Cardiovascular Disease: A Retrospective Cohort Study. J Am Heart Assoc. 2021 Oct 5;10(19):e020671. doi: 10.1161/JAHA.120.020671. Epub 2021 Sep 24. PMID: 34558290; PMCID: PMC8649155.

14:  Schmidt SAJ, Olsen M, Schmidt M, Vestergaard C, Langan SM, Deleuran MS, Riis JL. Atopic dermatitis and risk of atrial fibrillation or flutter: A 35-year follow-up study. J Am Acad Dermatol. 2020 Dec;83(6):1616-1624. doi: 10.1016/j.jaad.2019.08.039. Epub 2019 Aug 20. PMID: 31442537; PMCID: PMC7704103.

15:  Liu Y, Xu Y, Guo Z, Wang X, Xu Y, Tang L. Identifying the neural basis for rosacea using positron emission tomography-computed tomography cerebral functional imaging analysis: A cross-sectional study. Skin Res Technol. 2022 May 29. doi: 10.1111/srt.13171. Epub ahead of print. PMID: 35644027.

16:  Knight JG.  Possible autoimmune mechanisms in schizophrenia.  Integrative Psychiatry 1985; 3: 134-143.