Antidepressants Do Not Work by Numbing Emotions

Inna/AdobeStock

Recent evidence from randomized, placebo controlled trials (1979 to 2016) has shown that, in about 15% of patients with depression, antidepressant treatment is robustly superior to placebo—contrary to the often-repeated claim that antidepressants are “not much better than a sugar pill.”¹ It is not yet clear what clinical or biological features make this subgroup so antidepressant-responsive, although differences between drug and placebo increased significantly (P<0.001) with greater baseline severity of depression.

Perhaps if we had a better understanding of antidepressants’ mechanisms of action—and how these mechanisms interact with this drug-responsive subgroup—we would be better able to predict which patients are likely to do well on antidepressants. Unfortunately, the matter is further complicated by the marked heterogeneity of major depressive disorder (MDD), which almost certainly contains several biological subtypes.²

Critics of antidepressant treatment sometimes argue that antidepressants work—to the extent that critics acknowledge they work—by “numbing” or “blunting” emotions. Thus, Moncrieff has hypothesized that “Antidepressant-induced emotional numbness may directly reduce the intensity of people’s feelings of depression.”³ Similarly, Moncrieff and Horowitz have argued that⁴:

“…antidepressants appear to have a generalized emotion-numbing effect which may influence people’s moods, although we do not know how this effect is produced or much about it…[but] if antidepressants exert their effects as placebos, or by numbing emotions, then it is not clear that they do more good than harm.”

A recent review provided a much more nuanced picture, concluding that⁵:

“Emotional blunting has been reported by many patients diagnosed with MDD, but its neuropsychological basis remains indefinite. Most patients specifically attribute this symptom to their antidepressant medication; however, some psychologists believe that emotional blunting is also a residual symptom of depression due to incomplete treatment.”

In this article, we examine 3 independent studies of antidepressant treatment in major depression and its effects on emotional numbing or blunting. The key difference between 2 of these studies and much of the critical writing about antidepressants is their use of the Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQESA or OQuESA)—arguably the “gold standard” of assessment in this area.⁶ (This scale is now called the Oxford Depression Questionnaire, or ODQ.)

We shall see that none of the studies support the claim that antidepressants act to reduce depression through a process of emotional blunting or “numbing.” This is not to deny the clinical importance of assessing emotional blunting in the course of antidepressant treatment, nor is it to discount in any way the patient’s felt experience during treatment.

A Randomized-Controlled Study from France

Corruble and colleagues carried out a randomized, controlled, double-blind study comparing agomelatine (25-50 mg/d, n=164) and the SSRI, escitalopram (10-20 mg/d, n=160).⁷ Agomelatine is an atypical antidepressant that acts as an agonist to the melatonin receptors MT1 and MT2 and an antagonist of the serotonin receptors 5HT2B and 5HT2C. It is not approved for use in the United States. [https://www.psychiatryadvisor.com/home/depression-advisor/unique-attributes-of-agomelatine-might-renew-interest/]

The trial involved 12 weeks of active treatment, then a 12-week double-blind extension. The effects of these drugs on emotional experiences were compared in patients who completed the OQESA (agomelatine: n= 25; escitalopram: n= 20). Agomelatine and escitalopram similarly improved depressive symptoms, but emotional blunting was reported by 60% of patients taking escitalopram, versus 28% of those taking agomelatine.

At baseline before antidepressant treatment, the emotional experiences probed were extremely common and the same in both treatment groups. Of 20 OQESA items, 8 were more common in the escitalopram group and 12 in the agomelatine group. The occurrence of blunting items was associated with the depressed state measured by the Hamilton Depression Scale (HAMD) and Clinical Global Impression (CGI). Emotional blunting was significantly less prominent after 2 weeks, 12 weeks, and 24 weeks of treatment. At 24 weeks, emotional blunting was endorsed more frequently in the escitalopram group than in the agomelatine group, despite similar depression ratings in the 2 groups.

The authors concluded that “emotional blunting is prominent among patients with MDD at baseline” and hypothesized that emotional blunting “…behaves overall like a correlate of depressive symptoms.”⁷ Specifically, they opined that⁷:

“The simplest explanation for our present findings is that emotional blunting is a symptom of depression not measured in conventional scales, which is incompletely treated with SSRIs as compared with agomelatine.”

In short, the study findings provide no support for the claim that antidepressants act by a generalized emotion-numbing effect.

Two More Studies Reach Similar Conclusions

In a 16-week study of 98 patients diagnosed with MDD, Aşçibaşi et al analyzed the effects of antidepressant treatment (SSRI, n = 41; SNRI, n=40, other, n=13) on Montgomery-Åsberg Depression Rating Scale (MADRS) and OQESA scores.⁸ The OQESA scale was used at the 8- and 16-week visits. In brief, the study found that as the rate of remitted patients is increased, OQESA scores get decreased; and furthermore, the OQESA score of the remitted group was statistically low when compared with that of the nonremitted group at the 8- and 16-week visits. OQESA and MADRS scores were significantly correlated in all assessments. The authors opined that “…during the treatment of depression, depression-related emotional blunting symptoms and antidepressant-related emotional adverse effects may coexist”; however, “…as the severity of [the] depressive syndrome decreases, the severity of emotional adverse effects due to the antidepressants also decreases.”⁸

These findings are not consistent with the claim that antidepressants reduce depressive symptoms via an emotion-numbing effect.

Finally, Peters et al analyzed data from adult outpatients with acute MDD who participated in 3 8-week randomized controlled trials.⁹ Trials 1 and 2 were pooled (venlafaxine, n = 378; bupropion, n = 389; placebo, n = 383), and Trial 3 (escitalopram, n = 254; bupropion, n = 260) was analyzed separately. Emotional blunting was measured with the “inability to feel” item from the MADRS. The study found that emotional responsiveness improved, on average, in all treatment groups, and that fewer than 6% of participants experienced more emotional blunting after antidepressant treatment. The authors acknowledged that this was a short-term study that cannot speak to the long-term effects of antidepressant treatment. Nonetheless, they concluded that, “The study medications did not significantly decrease emotional responsiveness, and there was no evidence that emotional blunting mediated treatment response.” Rather—and consistent with the previous 2 studies—the authors hypothesized that “In acute treatment, emotional blunting may be better conceptualized as a residual symptom than as an adverse drug effect.”

Some Important Caveats and Study Limitations

Table 1. Emotional Blunting By Antidepressants or Persistent Depression Research

Tables 1 and 2 highlight the methodological advantages and limitations of the research discussed in this article. The Peters et al study has the highest-quality evidence, using completed controlled clinical trials, with a substantial number of research participants in each arm, including the placebo group.⁹ The study also uses the most neutral screen for emotional blunting, in that there is no suggestion of what might be the cause.

Table 2. Emotional Blunting Screening items

The studies by Corruble et al⁷ and Aşçibaşi et al⁸ both use the OQESA/ODQ, which was designed to measure more than emotional blunting and has a separate section to determine if the patient endorses emotional blunting to be caused by antidepressant treatment. The wording of the questions—and the fact that no other possible etiology for emotional blunting is suggested in the remainder of the questionnaire—is a potential source of bias. In this case, the participants are forced to choose antidepressants as an etiology. In effect, this is a “leading question,” and research participants may be able to guess that antidepressant induced emotional blunting is a focus of the research.¹⁰ In contrast, MADRS Item 8 captures emotional blunting but does not suggest a specific cause.

Concluding Thoughts

Emotional numbing or blunting is a fairly common complaint among patients taking serotonergic antidepressants and appears less common with noradrenergic/dopaminergic agents like bupropion.¹¹ It is important to inform and educate patients about this problem and to inquire about it periodically, since emotional blunting is both distressing and associated with poor adherence to antidepressant treatment.⁵ However, it should not be assumed that the patient’s antidepressant is necessarily the cause of the patient’s complaint, since emotional blunting or numbing is frequently reported at baseline (prior to treatment).

Indeed, the studies reviewed here show that antidepressants did not significantly decrease emotional responsiveness, and that treatment response was not mediated by emotional blunting. More likely, emotional numbing, in most cases, is a residuum of the original depression.

How, then, do antidepressants work? Their precise mechanism of action is not fully understood, although recent studies point to the role of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which is now regarded as “… a key player in antidepressant action.”¹² Antidepressants may also have anti-inflammatory effects—potentially important, since major depression is associated with elevated biomarkers of inflammation.¹³ During the past 4 years, 2 antidepressants modulating the glutamate system have been approved by the US Food and Drug Administration (FDA) for the treatment of major depression.¹⁴ Evidence supporting a role for stress, GABAergic dysfunction, altered neurosteroid signaling, and HPA axis dysregulation in major depression may suggest a role, in the near future, for neuroactive steroids in the treatment of depression.¹⁵

In summary, there is no credible, scientific basis for telling patients that antidepressants are acting by means of generalized emotional numbing. On the contrary, our review shows that several antidepressants are actually associated with reduced levels of emotional numbing during the course of treatment. That said, if emotional blunting is convincingly related to use of a serotonergic antidepressant, changing to a noradrenergic/dopaminergic agent is a viable option for many patients.

Dr Dawson is recently retired from clinical practice and is a freelance writer and researcher on psychiatric topics. He writes the Real Psychiatry Blog. Dr Pies is professor emeritus of psychiatry and a lecturer on bioethics and humanities at SUNY Upstate Medical University in Syracuse, New York; a clinical professor of psychiatry at Tufts University School of Medicine in Boston, Massachusetts; and editor in chief emeritus of Psychiatric Times™ (2007-2010). He is the author of several books. A collection of his works can be found on Amazon.

Acknowledgment: Dr Pies would like to thank Dr Marc Stone, Dr Randall Moore, and Prof Cathryn Lewis for their helpful email comments on aspects of this article. Thanks to Dr John J. Miller for suggestions re: mechanism of action. The views presented here are solely those of the authors.

References

1. Stone MB, Yaseen ZS, Miller BJ, et al. Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ. 2022;378:e067606.

2. Kennedy SH, Ceniti AK. Unpacking major depressive disorder: from classification to treatment selection. Can J Psychiatry. 2018;63(5):308-313.

3. Moncrieff J. Against the stream: antidepressants are not antidepressants – an alternative approach to drug action and implications for the use of antidepressants. BJPsych Bull. 2018;42(1):42-44.

4. Moncrieff J, Horowitz M. Depression is probably not caused by a chemical imbalance in the brain – new study. The Conversation. July 20, 2022. Accessed September 22, 2022. https://theconversation.com/depression-is-probably-not-caused-by-a-chemical-imbalance-in-the-brain-new-study-186672

5. Ma H, Cai M, Wang H. Emotional blunting in patients with major depressive disorder: a brief non-systematic review of current research. Front Psychiatry. 2021;12:792960.

6. Price J, Cole V, Doll H, Goodwin GM. The Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQuESA): development, validity, reliability and sensitivity to change. J Affect Disord. 2012;140(1):66-74.

7. Corruble E, de Bodinat C, Belaïdi C, Goodwin GM; agomelatine study group. Efficacy of agomelatine and escitalopram on depression, subjective sleep and emotional experiences in patients with major depressive disorder: a 24-wk randomized, controlled, double-blind trial. Int J Neuropsychopharmacol. 2013;16(10):2219-2234.

8. Aşçibaşi K, Çökmüş FP, Dikici DS, et al. Evaluation of emotional adverse effects of antidepressants: a follow-up study. J Clin Psychopharmacol. 2020;40(6):594-598.

9. 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;318:29-32.

10. Choi BC, Pak AW. A catalog of biases in questionnaires. Prev Chronic Dis. 2005;2(1):A13.

11. Goodwin GM, Price J, De Bodinat C, Laredo J. Emotional blunting with antidepressant treatments: a survey among depressed patients. J Affect Disord. 2017;221:31-35.

12. Björkholm C, Monteggia LM. BDNF - a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72-79.

13. Tynan RJ, Weidenhofer J, Hinwood M, et al. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun. 2012;26(3):469-479.

14. Frizzo ME. The effect of glutamatergic modulators on extracellular glutamate: how does this information contribute to the discovery of novel antidepressants? Curr Ther Res Clin Exp. 2019;91:25-32.

15. Gunay A, Pinna G. The novel rapid-acting neurosteroid-based antidepressant generation. Curr Opin Endocr Metab Res. 2022;24:100340.

16. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.