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