b y J . P r i c e a n d G . M . G o o d w i n , U n i t e d K i n g d o m
|Jonathan PRICE, MD
Guy M. GOODWIN, MD PhD
Department of Psychiatry
University of Oxford
The Warneford Hospital
Oxford, UNITED KINGDOM
Antidepressants such as the selective serotonin reuptake inhibitors are used widely to treat major depression. While they have reasonable efficacy, they also produce adverse effects. The best known of these relate to physical effects like nausea and the impact on sexual function. However, anecdotally there appears to be a broader impact on emotional experience. This is usually described as a reduction in sensitivity or a sense of numbing or blunting, which may emerge as depression remits. While it may be confounded by the residual effects of depression, patients often attribute it to their medication. We propose that this phenomenon of emotional side effects of antidepressants requires further study. There is laboratory evidence to relate it under experimental conditions to the processing of emotion. Reduced detection of negative emotion in the faces of others can be demonstrated in healthy volunteers who have taken citalopram or reboxetine for just 1 week. This effect may predict the clinical problems that we see. We have now also developed an assessment scale expressly for use in clinical studies. The future will be to look at antidepressants whose profile appears to be less emotionally blunting—like agomelatine and other medications now in development with novel mechanisms of action—in well-designed clinical studies that can illustrate the absolute and relative frequency of what is an increasingly troublesome side effect of current treatments.
Medicographia. 2009;31:152-156. (see French abstract on page 156)
Keywords: depression; emotional processing; sexual function; clinical trial; outcome assessment; SSRI; side effect; pharmacotherapy; antidepressant
An emerging body of evidence indicates that antidepressants have adverse effects on emotional experience in some people. It is now well known among health care professionals that antidepressants such as selective serotonin reuptake inhibitors (SSRIs) may cause anxiety and agitation, especially in the early days of administration. However, it is much less well known that antidepressants are associated with a syndrome of emotional numbing or blunting, often emerging as depression remits, which can be troublesome enough to lead to noncompliance. We call this phenomenon “emotional side effects of antidepressants” rather than “emotional blunting,” because of the broad range of impacts on emotional functioning that are seen.
The phenomenon of emotional side effects
Some patients taking antidepressants report that while they feel less emotional pain than before commencing their antidepressant medication, they also experience a restricted range of emotions and, in particular, cannot get a “normal” emotional response to everyday events that would usually be associated with, for example, joy or sadness. This complaint is prominent on Web sites where patients may post their views about their medicines, such as Cybercity and Rxlist. Box 1 provides several examples derived from such Web sites.
The reduced level of positive emotion in patients taking SSRIs may be linked both physiologically, and in the minds of patients who complain about the experience, to reduced sexual interest. This has been widely described. There is a reduction both in desire and arousal. As always in studies in depressed subjects, there is the potential for confounding the effects (and after-effects) of depression itself with the drugs employed to treat it.1 However, in the case of sexual side effects, there is clear evidence from effects in healthy male volunteers that the SSRI paroxetine has an important and immediate effect on sexual function.2 Moreover, a comparison between the sexual function of patients recovering from depression but treated with venlafaxine (serotonin and norepinephrine reuptake inhibitor; SNRI) in one group and the non-SNRI/non-SSRI, agomelatine, in the other, clearly demonstrates an adverse effect of venlafaxine.3
The situation for emotional side effects as we have defined them is much less clear. A review of the wider medical literature re- veals that little formal research has been done on antidepressant-associated emotional blunting. However, there has been a steady trickle of reports since 1990, when Hoehn-Saric and colleagues reported dose-dependent apathy, indifference, loss of initiative, and disinhibition in patients on fluvoxamine or fluoxetine.4 There have, for example, been further reports of SSRI-induced apathy, indifference, and reduced motivation in children, adolescents, adults, and older adults5-9; of inability to cry10; of reduction in irritability, aggression, and negative affect11; and of reduced emotional lability resulting from cerebrovascular accident12-14 or other brain injury.15,16 Opbroek and colleagues17 moved the field conceptually by linking the rating of a wider impact of SSRIs on emotion to effects specifically on sexual function. The Laukes Emotional Intensity Scale (LEIS) was used in 15 participants meeting criteria for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition) major depression who reported SSRI-induced sexual dysfunction, and in a control group of 16 hospital employees. Compared with controls, the SSRI group reported significant reductions in 12 of the 18 LEIS items, including ability to cry, irritation, care about others’ feelings, sadness, erotic dreaming, creativity, surprise, anger, expression of their feelings, worry, sexual pleasure, and interest in sex.
However, the way in which emotional side effects should be understood, measured, and so definitively investigated has remained uncertain. We have recently investigated the nature of this phenomenon by conducting interviews with people who attribute emotional symptoms to their SSRI.18 This study provided evidence that some patients taking SSRIs experienced significant emotional symptoms that they strongly attributed to their antidepressant, and that had a demonstrable impact on their functioning and played a role in their decision making about ongoing antidepressant adherence. These emotional symptoms could be described within six key themes—general effects on all emotions, reduction in positive emotions, reduction in negative emotions, emotional detachment, just not caring, and a changed personality. These themes are expanded, and examples given, in Box 2.
There are no good data to indicate the frequency of emotional side effects, when they are most frequent and most problematic, and whether they are more common with some currently available antidepressants than others. However, it is clear from Internet reports, our clinical experience, and our experience of recruiting patients to research studies, that emotional side effects are not uncommon, and that there is a spectrum of experience from mild side effects through to severe side effects that is the source of bitter complaint. Some patients report that they suffered emotional side effects only as they experienced remission, while others report that they experienced them throughout the period of antidepressant administration. While SSRIs appear to be most closely associated with emotional side effects, other classes of antidepressant such as SNRIs and mood stabilizers such as lithium salts have also been described as doing the same thing.
Box 1. Patient descriptions of emotional blunting taken from the Internet.
All rights reserved.
Box 2. Emotional side effects of selective serotonin reuptake inhibitors: key themes. Based on data from reference 18.
Impact on quality of life
Little is known about the impact of emotional side effects on quality of life in remission. However, our recent qualitative study investigated this in a sample of patients with chronic antidepressant use (median duration 23 months) and modest levels of depression (median Beck Depression Inventory–II score 12.5).18 The impact of emotional side effects on participants’ daily lives varied widely, both in extent and in perceived helpfulness. Some participants described emotional side effects as being helpful. For example, the reduction of certain emotional responses, such as anger, aggression, or worry might benefit personal relationships. Furthermore, emotional detachment and reduced anxiety might enable a person to think more clearly and objectively about their life situation.
However, some participants were concerned that blunting of their emotions and, thereby, of their day to day concerns, might mask or hide problems. This might prevent them resolving their own emotional issues, prevent them engaging with other problems or issues requiring their attention, and “cover up” who they really were. “Just not caring” had an unhelpful effect on everyday responsibilities, resulting in financial problems and problems at work or college. Emotional detachment from family and reduced emotional responsiveness had an unhelpful impact on family life, and on perceived quality of parenting. Reduced inspiration, reduced imagination, reduced motivation, and reduced passion for and enjoyment of creative activities, had adversely affected some participants’ creativity. In some participants, emotional side effects had led to reduced sociability. Finally, emotional flattening, emotional detachment from other people, and reduced concern for other people’s needs and feelings had unhelpful effects on relationships within families, with a significant other, and at work.
It is likely that emotional side effects are under-reported in clinical populations due to the lack of systematic enquiry by health care professionals. We recommend that clinicians ask routinely about emotional side effects when they are assessing progress with antidepressants. This might comprise asking a broad screening question, and then, if necessary, following up with more specific questions to characterize the nature and extent of the problem, the extent to which the patient attributes the problems to their antidepressant, and its contribution to their decision-making regarding ongoing adherence. An effective screening question might be: “Have you experienced any emotional side effects from your antidepressant? (prompt if required…) Emotional side effects are varied, but might include, for example, feeling emotionally ‘numbed’ or ‘blunted’ in some way, lacking some positive emotions or negative emotions, feeling detached from the world around you, or ‘just not caring’ about things that you used to care about.”
Scientific assessment: in the laboratory
Changes in emotional processing can also be shown to accompany the administration of SSRI and SNRI drugs to healthy volunteers.19 By emotional processing, one means the capacity of subjects to identify either the emotional expression in the faces of others (a perceptual expression of emotional sensibility) or to remember emotionally charged self-referent words. The SSRI citalopram given to healthy volunteers for 7 days and the selective noradrenergic drug reboxetine given for the same period of time both reduced the capacity of volunteers to accurately detect negative emotion in faces presented to them in an experimental paradigm. There was even a reduced signal in the amygdala in response to the same faces presented subliminally.20 This could imply that these individuals might be less sensitive socially to the expression of negative emotions by others. While this could be a helpful change in emotional processing with regard to both anxiety and depression, it could also, when patients have recovered, lead to a changed sense of the immediacy of experience.
Changes could also be demonstrated in the domain of emotional memory following the administration of antidepressants to healthy volunteers. In this case, subjects were more able to recall positive than negative adjectives that could refer to them. This effect may be interpreted as reflecting a potentially therapeutic change in how emotion is processed. However, in potential contrast with the perception of emotion in faces, it would not itself lead to a predictable change in emotional experience that would be likely to be negative. Therefore it is possible that one way to screen for the presence or absence of emotional blunting from any medication would be to compare the impact on a patient’s immediate judgment of emotional valence with the impact on how emotionally charged adjectives are recalled from memory. It is a strong hypothesis of the Oxford group that emotional blunting may be associated with the former, while antidepressant efficacy per se will be associated with the latter. Findings with the new antidepressant agomelatine, whose novel mechanism of action comprises melatonergic agonist activity at MT1 and MT2 receptors and antagonist activity at serotonergic 5-HT2C receptors, when given for 1 week to healthy volunteers, will be an important test: the further question will be whether these properties of agomelatine translate as we would predict into antidepressant efficacy without emotional blunting. However, to know if this occurs we will require a better measure of the clinical as opposed to the laboratory experience.
Scientific assessment: in the clinic
A sensitive and valid questionnaire measure of this phenomenon is needed. This would enable research into the prevalence of the emotional side effects of antidepressants, and comparison of the extent to which individual antidepressants are associated with them. It could be an important outcome measure in clinical trials designed to compare different products. Such a measure needs to be carefully designed and validated. Unfortunately, the two existing measures that attempt to address this issue appear to lack either careful design or validation.
The first is LEIS,17 a self-report instrument comprising 18 questions asking patients to rate an aspect of their emotional life compared with their “usual” state according to a 5-point scale (a lot less/ somewhat less/same as usual/somewhat more/a lot more). This scale is unvalidated, and the single published report of its use in an observational study gives few details about its development, stating only that “we systematically questioned patients treated with SSRIs about their subjective emotional experience before and after treatment,” and that “these unstructured interviews led to the development of a rating scale for SSRI-induced emotional blunting.”
The second is the Bell-Shipman Apathy/Emotional Blunting Questionnaire,21 which is described in the study report as “under development.” This self-completion questionnaire comprises five questions, each rated on a six point scale from “strongly disagree” to “strongly agree,” which relate to aspects of four of the themes we identified—reduction in positive emotions, reduction in negative emotions, emotional detachment, and not caring. However, there are no published details of the development and selection of these questions, and no validation work appears to have been carried out.
We have used the results of the careful observational work in our recent study to develop the Oxford Questionnaire of Emotional Side effects of Antidepressants (OQESA), which we have now piloted, refined, and validated in a sample of over 200 people taking antidepressants. The OQESA comprises 26 questions/statements in three sections. The respondent rates the extent of their agreement with each statement along a 5-point scale ranging from disagree to agree, according to their experience during the past week. Section 1 includes 12 statements relating to the respondent’s experience of emotional side effects during the past week (eg, “All my emotions, both ‘pleasant’ and ‘unpleasant,’ are ‘toned down’”). Section 2 includes 8 statements relating to experience of emotional side effects during the past week compared with the respondent’s experiences before they developed their illness/problem (eg, “Day to day life just doesn’t have the same emotional impact on me that it did before my illness/ problem”). Within the 20 statements in Sections 1 and 2, the 4 dimensions, general reduction in emotions (GR), reduction in positive emotions (RP), emotional detachment from others (ED), and not caring (NC) are each represented by 5 statements. Finally, Section 3 comprises 5 statements regarding the extent to which respondents believe their antidepressant is responsible for their emotional symptoms (eg, “The antidepressant is preventing me from feeling my emotions in some way”), and a final statement regarding actual or contemplated non-adherence due to emotional side effects. A total score can be calculated, being the sum of the scores of the four dimensions, and represents the extent to which the respondent is affected by emotional side effects. If required, the further attributional dimension can be scored.
An important and, as yet, unanswered question is the extent to which emotional symptoms attributed to antidepressants are actually manifestations of residual depression, rather than being emotional side effects. Our validation data suggest that two of the four dimensions of the OQESA (RP and NC) may be closely related to depression as well as antidepressant- associated emotional blunting, whereas the other two dimensions (GR and ED) are less closely related to depression. We therefore recommend that, in high quality experimental work investigating emotional side effects of antidepressants, two subtotals are calculated—RP plus NC, and GR plus ED.
In summary, there is emerging evidence that one important adverse effect of SSRIs and related medicines is a negative impact on the processing of emotional experience. This was first described by patients themselves, and investigators are now catching up with the complaint by devising improved ways of measuring it, both experimentally and, perhaps most critically, clinically, by the use of an innovative scale. There is an appropriate and increasing emphasis upon the patient experience in judging the outcome of treatment with any intervention for mood disorder. In the case of antidepressants, the potentially negative effect on emotional experience is easily confounded with the symptoms of depression itself, but is a cause for concern and further research. It remains to be seen as to whether it proves to be an easy task to first devise the means to better measure the experience and second to develop treatments that will be effective in treating depression without producing the problem. The test of this will come from antidepressants with novel mechanisms of action, one of the first examples of which will be agomelatine.
_ Acknowledgements. Some of the work described here was supported by a grant from Servier to G. M. Goodwin.
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ÉMOUSSEMENT ÉMOTIONNEL OU RÉACTIVITÉ RÉDUITE
APRÈS RÉMISSION D’UNE DÉPRESSION SÉVÈRE
Les inhibiteurs sélectifs de la recapture de la sérotonine sont des antidépresseurs largement utilisés dans le traitement de la dépression sévère. D’une efficacité satisfaisante, ils ont aussi des effets indésirables dont les plus connus sont des effets physiques comme la nausée et la dysfonction sexuelle. De façon anecdotique, ces effets semblent également avoir un impact touchant plus largement le plan émotionnel. Cet impact est généralement décrit comme une réduction de la sensibilité ou une sensation d’engourdissement ou d’émoussement qui apparaît lorsque la dépression diminue. Bien que parfois confondus avec les effets résiduels de la dépression, les patients attribuent souvent ces signes à leur traitement. Nous considérons que ces effets secondaires des antidépresseurs sur l’émotion nécessitent d’être plus amplement étudiés. Des données expérimentales permettent sous certaines conditions, de les relier au processus de traitement de l’émotion. Des volontaires sains qui avaient reçu pendant juste 1 semaine du citalopram ou de la réboxétine ont montré qu’ils détectaient moins les émotions négatives sur les visages d’autrui. Un tel effet pourrait être prédictif des problèmes cliniques que nous observons. Nous avons développé une échelle d’évaluation expressément pour l’usage clinique. L’avenir est donc aux antidépresseurs entraînant moins d’émoussement émotionnel, possédant de nouveaux mécanismes d’action, comme l’agomélatine et d’autres médicaments actuellement en développement. Ces médicaments devront faire l’objet d’études cliniques bien construites capables de mettre en évidence les fréquences absolues et relatives d’un effet secondaire de plus en plus gênant liés aux thérapeutiques actuelles.