In this study, we aimed at overcoming limitations of previous behavioral and neuroimaging work on empathy in MDD. By measuring an untreated sample at baseline and follow-up after 3 months of antidepressant therapy, we aimed to disentangle the effects of MDD and antidepressant treatment on empathy. By controlling for neural responses in an electrical pain task, we are also able to draw conclusions regarding the specificity of the observed effects for empathy versus affective responding to aversive stimuli in general.

Contrary to previously reported evidence, neither behavioral nor neural differences between patients with MDD and HC were observed in the first fMRI session, indicating a “normal” empathic response in patients with acute MDD before they underwent antidepressant treatment. After 3 months of therapy, patients showed decreased neural responses in a priori selected brain areas that are reliably activated by empathic pain (bilateral AI and aMCC), and reported reduced self-experienced unpleasant affect in response to the pain of others. This reduction is significant both when compared to their own pre-treatment responses and when compared to those of the HC in the post-treatment session. Here, it needs to be noted that the complimentary whole-brain analysis revealed similar decreases within the MDD group. Anyhow, no differences appeared in the interaction contrasts (e.g., HC > MDD: S1 > S2). Decreases of self-experienced unpleasantness were correlated with symptom severity reduction (HAMD scores). At first sight, these results contradict previous findings in terms of both behavioral (see review6) and neural responses12. However, taking into consideration that previous findings were mainly derived from medicated samples, they are well in line with the present post-treatment results. Insufficient inclusion of nonmedicated participants and lack of follow-up analyses on medication effects in previous studies restrained their authors from drawing reliable conclusions on the “pure” effects of MDD on empathy. To our knowledge, the present study is the first to show the behavioral and neural effects of (a) untreated MDD and (b) antidepressant treatment on empathy.

Special attention should be dedicated to the comparison of our results with those reported by Fujino et al.12, the only previous systematic fMRI investigation of empathy in patients with MDD. Comparability is strongly enhanced because both studies used video clips as stimuli (faces of patients showing pain in the present study, hands being harmed in Fujino et al.). The present post-treatment results of lowered empathy ratings as well as reduced activation in the aMCC parallel similar findings in the medicated sample of Fujino et al.12. Opposed to the findings of this previous study, patients did not show reduced, but enhanced activity in the SII compared to HC in both sessions. However, there was no significant change in SII activity in the MDD group between sessions. SII has been reported to play an important role in encoding vicarious pain perception35. It is specifically recruited in people who experience localized sensations of vicarious pain36,37. Thereby, enhanced activity in comparison to HC may stem from a more vivid or self-referential representation of others’ pain in MDD. Future studies might explore a possible relationship of vicarious sensory pain experience and MDD.

Differentiation between the two distinct behavioral ratings used in this study is another important aspect of our results: the target unpleasantness rating, which is a rather cognitive-evaluative measure of others’ pain, was unaffected by both MDD and antidepressant treatment. On the contrary, the self-related unpleasantness ratings, which reflect vicarious distress (for detailed views on this differentiation, see23,24), were significantly reduced over time in the MDD group. On top, these reductions were highly correlated to symptom severity improvement. Thus, antidepressant treatment seems to have a protective function for the affective processing of negative events in a social context. Cognitively, patients were similarly aware of the extent of pain that the tinnitus patients expressed, but their own affective state was less affected. This differentiation of effects on cognitive versus affective empathy is in line with previously reviewed findings38, which were thought to be linked to MDD instead of antidepressant treatment. If the decrease in self-experienced unpleasantness was just a function of improved mood and resulting avoidance or reinterpretation of mood-incongruent events, an effect on the cognitive evaluation of others’ unpleasantness would be expected as well. We interpret these findings in terms of a recently proposed framework by Coll et al.39, who argued that specific manipulations could independently affect either the ability of an individual to accurately perceive another’s emotional state (emotion identification) or their degree of affective sharing of that state. We did not observe an effect of antidepressant treatment on emotion identification (target unpleasantness evaluation), but found an effect on empathy in terms of affectively sharing the other’s emotions (self-experienced unpleasantness). Usage of rating measures targeting different aspects of empathy should be considered in future clinical studies on empathy.

Self-reported improvements in ERQ and ECS, as demonstrated by partial normalization towards levels of HC in the post-treatment session, point to the known beneficial effects of antidepressant treatment on emotion regulation40. The fact that treatment led patients to (a) having a stronger tendency to reappraise situations for better emotion regulation and (b) being less likely to catch up others’ negative affect is in good accordance with less self-experienced unpleasantness in the empathy task. Similar to previous reports38,41,42, we observed significantly higher values of IRI personal distress (measuring feelings of discomfort that occur as a result of observing another’s negative experience27) in depressed patients, which was not changed by treatment. This discrepancy between trait and state distress might be explained by the relatively general nature of the items of the IRI (e.g., “I tend to lose control during emergencies”). Also, the personal distress trait appears to be rather stable even over long time periods43, while situation-specific distress (e.g., encountering someone in pain) is apparently more prone to interventions such as antidepressant treatment.

Contrary to behavioral findings (higher unpleasantness ratings in response to ineffective treatment condition) and previous evidence for the influence of appraisal on neural responses to empathy18, no effect of cognitive appraisal (effective versus ineffective condition) was found in the main imaging analysis. In the present study, only 12 trials per condition were used, while previously18, 20 trials per condition were shown. This relative lack of power represents a likely reason for absence of an effect. Nevertheless, analyses of psychophysiological interactions showed differentiation also on the neural level, with significantly reduced post-treatment connectivity between lAI and precuneus only in the ineffective condition. Admittedly, these results need to be interpreted with caution, because connectivity changes across sessions were only significant within the MDD group, not when contrasting them with HC. The AI has consistently been associated with affect sharing10, while the precuneus is involved in rather cognitive functions implicated in empathy, such as perspective taking or theory of mind44,45. Previous research demonstrated enhanced interplay between brain areas involved in affective versus cognitive empathy under conditions of high negative emotionality19,46. Restriction of the effect to the ineffective condition might therefore be explained by its higher negative emotionality (as reflected in subjective ratings). Interestingly, connectivity between insular ROIs and occipital regions decreased in the MDD group across sessions (compared to HC). As both visual occipital regions and insular cortices are implicated in facial emotion processing47, reduced interplay between these regions might be related to the decreased affective impact of others’ pain in the MDD group.

Interestingly, no relevant effects on pain processing (apart from an increase in no-pain brain activity in the HC group, which was probably driven by slightly, yet not significantly different calibration values between sessions in this group) were observed in the ROIs. This speaks against general blunting of affective responses, as well as against generally decreased neural reactions to negative stimuli, but rather for an effect that is specific to affective responding in a socioemotional context. Since we did not obtain self-report ratings in the pain task, however, changes in the subjective experience of pain cannot be evaluated. Slightly lowered sample size in the electrical pain task in comparison to the empathy task also represents an obvious limitation.

Our study was not a full randomized controlled trial, which restrains us from excluding second-order effects as an alternative explanation for the observed changes after treatment. Changes in empathic responding after treatment could be directly related to the influence of antidepressants on the serotonergic (but possibly also the noradrenergic48) system. An alternative explanation, which is in line with the cognitive neuropsychological theory of antidepressant drug action49, suggests reversal of depression-related negative affective bias by antidepressants. Usually, depressed patients show a bias towards negative stimuli in simple emotion processing tasks50,51. Antidepressants lead to normalization of such biases, demonstrated for example by reduced neural responses to negative facial expressions52,53. Such reduced responses to negative affective experiences might also come into play in more complex social situations involving empathy. Influences of SSRIs on the hemodynamic response (e.g., via changes in blood flow) could be seen as a potential limitation. However, in light of recent evidence that did not show effects of SSRIs on brain hemodynamic responses nor on vascular artifacts, this seems unlikely as an alternative explanation54,55.

While application of three different antidepressants may be considered disadvantageous in terms of homogeneity, this allowed maximization of treatment effectivity for the patients, and thus also reflects a more ethical and realistic scenario compared to a more controlled design. Importantly, change of medication did not have significant effects on behavioral or neural measures.

Our results should be taken into consideration by future studies investigating clinical samples. For example, recent studies in samples under treatment reported depression-related deficits in emotion recognition (see meta-analysis56) and reading of facial expressions57. This is not to say that such findings are solely related to antidepressant treatment (see contrary evidence58). Still, interactions may play a role in such cases, and care needs to be taken before ascribing specific deficits to groups of patients without sufficiently controlling for medication status.

The presented insights put a different complexion on depression-related changes of empathy. As demonstrated, antidepressant treatment might lead to effects that were previously attributed to MDD. Considering the observed relationship between reductions in affective empathy and improvements in symptom severity, this might be an advantageous side effect with protective function, which could possibly spread to other kinds of negative events in social contexts. It remains to be explored whether these treatment-induced changes also lead to changes in prosocial behavior (see reviews59,60,61 for discussion of the relationship between empathy and prosocial behavior; recent research showed unchanged moral judgements in medicated patients with MDD62, but increased cooperation in symptom-free patients with a history of MDD63): on the one hand, lowered empathic distress might enable medicated patients to assign more cognitive resources to helping another person in need (here, it has to be emphasized again that the cognitive evaluation of the others’ pain was left unchanged). On the other hand, it might substantially reduce the salience of the situation, and, consequently the motivation to help the other. Thus, this seems to be an important endeavor for future research.