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

Spare The Venlafaxine.....

Venlafaxine is a commonly prescribed second-generation antidepressant. It is well-known to psychiatrists because it is a second line medication if SSRIs fail and for many psychiatrists it is another first-line antidepressant. In some head-to-head comparisons with SSRIs venlafaxine has a more favorable side effect profile. It does have the risk of discontinuation symptoms and typical antidepressant side effects. I have noticed that the dose escalation with venlafaxine seems to be out of proportion with SSRIs, bupropion, and third-generation antidepressants.

Consider the following venlafaxine related scenarios:

1. A colleague comes into my office late in the day and asks me: “Have you ever heard of venlafaxine causing sedation at higher doses?” The patient in question was just increased from 187.5 mg to 225 mg - the suggested max dose according to the FDA approved package insert. 

2. I am asked to consult on patient who had extensive pharmacogenomic testing in a different facility where she was told that she may need to take 350 to 450 mg of venlafaxine per day based on that genetic profile. She wants to make sure that she gets an adequate dose of the antidepressant and is currently on 225 mg.  I reviewed the limitations of that approach with the patient and potential side effects and I let her know that the commonest side effect I see in people taking high-dose venlafaxine is excessive sedation or low energy in the daytime. As we start to follow the recommended dose increase she discloses that she has had sedation even at the 225 mg level. We decreased the dose to 150 mg and that side effect is gone.  Her depression is also gone.

3. I see a significant number of patients taking more than 300 mg per day of venlafaxine from the same geographic location in the United States. They all tell me that the target dose in that location is 350 mg per day and they are all experiencing numerous side effects. Many had dose escalations into that range in a week or two - much faster than any increase I have done.

What is wrong with this picture? Why are there a significant number of people taking more than the recommended dose of venlafaxine in some cases much more and appearing to have side effects? The roots of this prescribing behavior can be traced back to old-school psychopharmacology. Proponents of that approach suggests that there may always be a group of outliers that need to take higher-than-expected doses of medications - typically antidepressants but there has also been a history of excessive dosing of antipsychotic medications. People were generally more cautious with more toxic medications like tricyclic antidepressants, monoamine oxidase inhibitors, lithium, and various addictive compounds. They also seem to be more cautious with SSRI type medications at least initially. It took over a decade for me to see a dose of sertraline in excess of the maximum recommended dose.  While it is true that there are always outliers in terms of dose-response what is the best way to approach that problem.

I have attended medical education courses where the lecturer suggested titrating the medication to the point of toxicity and then reducing it back down to the next lowest dose. That particular lecture was focused on treating anxiety disorders with SSRIs. I don’t think that is the best approach. The best approach to me is one where the patient recovers from anxiety or depression and the process does not experience a single side effect. I know that can be done because I have been doing it for decades.

That also brings me to what I think is a good research article that looks at optimal dosage ranges. It is a very large meta-analysis of fixed dose randomized clinical trials that utilize the specific antidepressants - citalopram, escitalopram, fluoxetine, paroxetine, sertraline, venlafaxine, and mirtazapine.  The trials were identified by searching the literature and looking for unpublished studies specifically by searching national drug licensing agencies and requests directly to pharmaceutical manufacturers. Outcomes were noted at eight weeks of treatment and defined as a 50% reduction on an observer rated scale for depression.  Dose equivalence among medications was determined from previous studies and the recommendations of the manufacturer. The article is written by researchers that I consider to be world experts in meta-analyses and the analysis of large data sets in psychiatry.

77 studies were identified from a total of 24,524 published references and 4030 unpublished records.  27 were published, 21 or unpublished, and 29 were both published and unpublished. The study showed too hard when treatment groups across all of the medications of interest between the years 1986 and 2013.

The authors calculated dose response, dropouts due to adverse effects, and dropouts for any reason. Relative risks (RRs) were calculated for specific doses. The dose outcome relationships for venlafaxine are included in the figures below from the original article.  The Response figure shows the significant increase of up to about 150 mg and then a much more modest increase beyond that. The Dropout figure shows a similar increase up to the 150 mg range. The Dropout for any reason was less remarkable. The authors calculated that the 75-150 mg dose of venlafaxine was equivalent to 20 to 40 mg of fluoxetine (click to enlarge graphic)

The authors conclude that optimal acceptability of SSRIs and venlafaxine and and mirtazapine occurs within the lower end of the licensed dose range. They reconcile this with serotonin transporter (SERT) studies that show that 80% SERT occupancy occurs at the minimum doses of SSRIs or venlafaxine with further dose increases showing small increase in SERT occupancy.

In the case of venlafaxine they suggest that noradrenalin reuptake transporter (NET) may require higher doses of venlafaxine in the 225 mg to 375 mg per day range. Given the lack of efficacy of atomoxetine, a logical question might be whether NET blockade adds much to the antidepressant effect.

The authors review other dose-efficacy studies of antidepressants and point out that they are variable. The variability ranges from optimal doses of fluoxetine in the 21-40 mg per day range to doses at the recommended lower end of the range being superior. Response to doses in the higher range were variable in some studies. One study found a significant greater response for high-dose antidepressants but the dose of 40-50 mg fluoxetine equivalents showed the greatest efficacy.

The authors considered strengths and limitations their study. They thought that their state-of-the-art meta-analysis was a strength as well as the size of the data set. They also examined dose dependency for both efficacy and tolerability and acceptability. The limitations they discussed included patient selection and dosing not reflecting clinical practice. They also discussed the calculation of dose equivalency among antidepressants and how that might be problematic.

Another obvious strength of this study is the calculation of relative risks for response across SSRIs, venlafaxine, and mirtazapine. The figures are modest but favor antidepressants across all dosage ranges with the exception of mirtazapine at the 60 mg dose.  The authors don’t seem to mention it but it would seem that the optimal dosage ranges could be predicted from the regulatory information since that is based on dose ranging studies and tolerability studies. In that regard, the conclusion about dose ranges don’t seem to be that surprising but they may be needed given what is happening clinically.

Getting back to the issue with venlafaxine I see people respond to dosing within the lower and of the range from 37.5 to 75 mg in many cases. That same response rate continues up to the 150 mg dose and then starts to diminish between two or 25 and 375 mg. Over that same range there is a significant increase in dropout rates due to adverse effects.

How clinicians approach this new information will be interesting. There will still be people like me and the conservative camp looking for the first signs of side effects and toxicity and deciding at that point whether to stop dose escalation. I explicitly tell people that the goal is not to experience any side effects and that I doubt that people “get used to” side effects. There are clearly clinicians out there who are doing exactly the opposite and that is increasing the dose of venlafaxine and advising people to either tolerate the side effects or expect that they will go away.

The balance between therapeutic effect and side effects is a central issue in all branches of medicine. In many cases, the severity of adverse effects like an allergic reaction determines the decision. In the case of the medication like venlafaxine making that decision can be complex. Some of the side effects like sedation and lethargy at high doses can mimic symptoms of depression. At this point in time neither pharmacogenomics or most plasma level determinations guarantees either tolerability or efficacy.  

Detailed analysis of the situation by an expert with a bias toward preventing side effects is required as the first step in any dose increase.

George Dawson, MD, DFAPA

References:

1:  Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G.  Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis.  Published:June 06, 2019DOI:  https://doi.org/10.1016/S2215-0366(19)30217-2.

Attribution:

Above figure of the venlafaxine dose response and drop outs are directly from the paper in reference 1 and used per the Creative Commons Attribution 4.0 International Public License.

Attribution 4.0 International (CC BY 4.0)

Attribution 4.0 International (CC BY 4.0)