A web‐based survey on the occurrence of emotional blunting in patients with major depressive disorder in Japan: Patient perceptions and attitudes

Abstract Aims To determine the prevalence and impact of emotional blunting (EB) in patients with major depressive disorder (MDD) in Japan, and identify treatment needs for EB using patients' perceptions and attitudes. Methods Eligible patients in Japan (aged 18–59 years) who reported a diagnosis of MDD and antidepressant medication use for >3 months were eligible to complete an online survey. The primary outcome was the prevalence of EB, self‐reported using a validated screening question. Secondary outcomes included the correlation between EB symptoms (measured by the Oxford Depression Questionnaire [ODQ]) and scores on the Patient Health Questionnaire 9‐item (PHQ‐9), Generalized Anxiety Disorder 7‐item (GAD‐7), Work and Social Adjustment Scale (WSAS), and the EuroQol 5‐Dimension 5‐Levels questionnaire (EQ‐5D‐5L). Descriptive questions were used to explore patients' perceptions and attitudes toward EB. Results In total, 3376 patients were included in the analysis (56% male; 48% aged 50–59 years). Overall, 67.1% of patients self‐reported symptoms of EB, with 10% rating these as severe. The mean (SD) ODQ total score was 78.2 (21.5), which increased with worsening EB symptoms. There were correlations between ODQ total scores and the PHQ‐9, GAD‐7, WSAS, and EQ‐5D‐5L scores (correlation coefficients: 0.67, 0.55, 0.56, −0.51, respectively; all p < 0.0001). Descriptive analyses showed that one‐third of patients reporting EB symptoms did not tell their physician, with two‐thirds finding these symptoms distressing and likely to affect recovery. Conclusion EB is an important clinical issue in Japan that needs to be considered alongside functional recovery when managing treatment of patients with MDD.


| INTRODUC TI ON
Major depressive disorder (MDD) is a common yet serious mental illness and a leading cause of disability.In 2019, global prevalence estimates suggested that 280 million people were affected by depressive disorders (defined as MDD and dysthymia); in East Asia (including Japan), the age-standardized prevalence was 2720.1 per 100 000 people. 1,2Therefore, MDD remains a significant global health burden.[5][6] Therefore, treatment of MDD should aim to not only improve clinical symptoms of the disease but also prevent relapse and support reintegration into society -a key part of functional recovery. 7,8cently, the concept of emotional blunting (EB) as a symptom of patients with MDD has been proposed.EB is defined as the 'numbing' or 'flattening' of emotions, as well as emotional indifference or reduced emotional responsiveness, such as not caring, being emotionally detached, or having a reduction in positive emotions or emotions generally. 9Unlike anhedonia, one of the core symptoms TA B L E 1 Descriptive questions to explore the patients' perception of and treatment needs for EB.

Q1
Did you tell your physician about your symptoms of EB? Self-rated on a 10-point scale (1 is "not painful" and 10 is "very painful") Q5 Do you believe that EB symptoms can harm your ability to regain your pre-depression daily life?
I don't think so at all I don't think so Somewhat I think so very much None of the above Q6

If you experience EB symptoms, how do you think it affects your recovery from depression?
I believe that the presence of EB symptoms will prevent recovery from depression I believe that the presence of EB symptoms delays recovery from depression I don't think EB symptoms delay recovery from depression I think EB symptoms accelerate recovery from depression I don't see any connection between EB symptoms and recovery from depression Q7 How did you describe your EB symptoms to your physician?(free text)

Q8
In what aspects of your daily life do you have trouble with feeling EB symptoms?(free text) Note: Unless otherwise specified, all respondents with EB symptoms were sampled (those patients who responded "mildly," "moderately," or "severely" to the question "To what extent have you had any of the following emotional experiences in the last 6 weeks?") (n = 2266).
of MDD that is defined as the inability to anticipate and experience pleasure, EB represents a toned-down state of both positive and negative emotions and an inability to experience expected emotional responses. 10 has a significant negative impact on the treatment of MDD.
Results from an online survey of 896 patients with unipolar and bipolar depression showed that EB was among the common reasons for medication discontinuation, as reported by over one-third of respondents in the study. 113][14] However, the effect of EB on the overall functional recovery in patients with MDD has not been fully examined, and although international reports on EB have increased, there are no published reports on the prevalence and impact of EB in patients with MDD in Japan.It is therefore important to know whether the detrimental effects of EB on functional recovery from MDD are universal, regardless of the medical environment and geography.
The aims of this study were to determine the prevalence of EB symptoms in patients with MDD in Japan, to measure the impact of EB symptoms on the daily lives of patients, and to identify treatment needs for EB using the patients' perceptions and attitudes toward EB.This study is the first to investigate the clinical relevance of EB in patients with MDD in Japan.Potential participants who met the inclusion criteria (described below) were identified from the patient panel and invited to participate.Respondents were then provided with information about the study before being screened for eligibility.Before completing the survey, participants were informed that they could refuse to answer any question and could withdraw at any point.Data were collected by means of a self-completed online survey comprised of a validated screening question, 9,13 followed by multiple validated questionnaires, namely the Oxford Depression Questionnaire (ODQ), 9,15 the Patient Health Questionnaire 9-item (PHQ-9), 16,17 the Generalized Anxiety Disorder 7-item (GAD-7), 18 the Work and Social Adjustment Scale (WSAS), 19 and the EuroQol 5-Dimension 5-Levels questionnaire (EQ-5D-5L). 20,21Respondents received Macromill points for their participation.This study was approved by the Research Institute of Healthcare Data Science Institutional Review Board (Tokyo, Japan) before initiation.

| Participants
Participants were eligible for the study if: they were aged 18-59 years (regardless of sex); had been diagnosed with MDD (self-reported by the participant); had been taking antidepressant medication for at least 3 months; had been visiting a hospital for more than 3 months; could use the internet with a personal computer, smartphone, or tablet; and could give informed consent after reading and understanding the study information provided in Japanese.Patients were excluded from the study if they had been diagnosed with bipolar disorder or were not currently taking antidepressants.

| Assessments
The primary outcome of this study was to measure the prevalence of EB in patients with MDD using a validated screening question. 9,13e question was: "To what extent have you had any of the following emotional experiences in the last 6 weeks?"This was qualified by the explanation: "Emotional effects and treatment vary, but may include, for example, feeling emotionally 'numbed' or 'blunted' in some way; lacking positive emotions or negative emotions; feeling detached from the world around you; or 'just not caring' about things that you used to care about."Patients who replied "mildly," "moderately," or "severely" were defined as having EB in our study.
Secondary outcomes included the ODQ, 9,15 the PHQ-9, 16,17 the GAD-7, 18 the WSAS 19 and the EQ-5D-5L, 20,21 which were used to investigate the correlation between the degree of EB symptoms (as measured by the ODQ) and the severity of depression/anxiety, social functioning, and health-related QoL.All translated Japanese versions of these screening measures are licensed for use.The ODQ is a validated instrument for assessing EB in patients with MDD (including those treated with antidepressants). 9,15The ODQ comprises 26 questions about emotional experiences during the past week, for which respondents are asked the extent to which they agree or disagree. 9,15Questions cover five domains of EB (general reduction in emotions; reduction in positive emotions; emotional detachment from others; not caring; antidepressant-as-cause).For each question, responses are indicated on a 5-point scale ranging from 1 (disagree) to 5 (agree).For the ODQ, an overall ODQ score is calculated, as well as scores for each ODQ subdomain.The ODQ total score ranges from 26 to 130 points, with higher scores indicating more severe EB. 9,15 The Japanese translated version (https:// innov ation.ox.ac. uk/ wp-conte nt/ uploa ds/ 2014/ 09/ Final_ ODQ _ Japan ese_ Japan_ SAMPLE.pdf) has been cross-culture validated in Japan. 22The PHQ-9 is a 9-item questionnaire that screens for the presence and severity of depression.Items are scored by the patient between 0 (not at all) to 3 (nearly every day).The total score ranges from 0 (absence of depression) to 27 (severe depression), and the total score is studied as a continuous outcome. 16,17The GAD-7 is a 7-item questionnaire that screens for the presence and severity of generalized anxiety disorder. 18Items are scored on a 4-point scale (0-3 points) with total scores ranging from 0 to 21.Total scores categorize anxiety as mild (≥5), moderate (≥10), or severe (≥15).The WSAS is a self-reported scale of functional impairment attributable to an identified problem. 19Five questions are rated on a scale from 0 (not at all) to 8 (very severely).The EQ-5D-5L consists of a descriptive system of five dimensions (mobility, selfcare, usual activities, pain/discomfort, anxiety/depression), 20,21 with response levels for each dimension from 1 (no problems) to 5 (extreme problems), giving a utility score ranging from 0 to 1 (the highest possible score).
The survey used in this study also included six descriptive questions to explore the patients' perception of and treatment needs for EB (Table 1, Q1-Q6).Unless otherwise specified, all respondents with self-reported EB symptoms (as per the validated screening question) were sampled.Exploratory outcomes included a linguistic analysis to investigate problems with daily life reported by patients with EB.Terms appearing in the free-text field of two questions (Table 1, Q7 and Q8) were analyzed using "KH coder," a free text-mining software for text-type materials. 23,24The top 60 words were extracted, and a co-occurrence network was generated for each question to show associations between frequently occurring words.Subgraphs composed of the drawn co-occurrence network were labeled based on the meaning of the co-occurring words, and each subgraph was assigned a number.The Jaccard coefficient (which measures the similarity between finite sample sets) 25 was defined as the size of the intersection divided by the size of the union of the sample sets, and was calculated using the formula (the terms "A" and "B" in the formula indicate the extracted words by the KH coder): Co-occurrence networks were considered significant when the Jaccard coefficient was ≥0.1.

| Statistical analysis
The population for this analysis comprised all patients who met the study inclusion criteria and completed the online survey.Data are presented descriptively using mean and standard deviation (SD) for continuous variables, and frequencies and percentages  1A).The increase in ODQ score with worsening EB symptoms was also seen for each ODQ subdomain (Figure 1B-F).When ODQ total scores were classified by patients' characteristics, there were numerically higher scores in patients in the following subgroups: 40-49 years old; male; unemployed; living alone; and those who told their physicians about their EB symptoms (Table 4; it should be noted that no statistical analysis was carried out on these subgroup comparisons).
The relationship between EB symptom severity and the severity of other depression/anxiety and functional measures was also as- correlations between ODQ total scores and the PHQ-9, GAD-7, and WSAS scores (correlation coefficients: 0.67, 0.55, and 0.56, respectively), and a negative correlation between ODQ total scores and EQ-5D-5L scores (correlation coefficient: −0.51).
Descriptive analyses on the communication of EB between patients and physicians showed that 68.3% (1548/2266) of patients with MDD who self-reported EB symptoms had told their physician about their symptoms.Overall, 49.2% of patients reported that they would like their physician to ask about their EB symptoms (Figure 3A).For those patients who did not inform their physician about their EB symptoms, the two most common reasons were the patient "did not know how to describe the symptoms" (42.8%) or "was not asked by their physician" (41.8%; Figure 3B).
Overall, 65.0% of patients self-reporting symptoms of EB responded with a distress level of 6 or higher when asked to rate how distressing they found their symptoms (on a scale of 1-10; Figure 4A),

TA B L E 5
Analysis of correlations between the total scores from patientreported outcome instruments (analysis set; N = 3376).
62.7% recognized EB as an obstacle to regaining their pre-depression daily life (Figure 4B), and 67.5% thought that EB had an unfavorable influence on their recovery from depression (Figure 4C).

| DISCUSS ION
This is the first study in patients with MDD in Japan that evaluated the prevalence of EB and showed an association between EB symptoms (as assessed by the ODQ) and depressive/anxiety symptoms, as well as measures of social functioning and QoL.We also assessed the distress caused by, and the burden of, EB in patients with MDD and the negative impact of EB on the treatment for MDD and functional recovery.
Our survey suggested that more than 60% of patients with MDD in Japan who are currently taking antidepressants have experienced symptoms of EB.Previous reports have indicated similar results, with incidence ranging from 46% to 71%. 10,26,27It is unclear whether EB is a residual symptom of MDD and/or a side effect of antidepressants. 26,28,29However, regardless of the cause, it is important that physicians are aware of symptoms of EB in their patients.
More severe symptoms of EB may be associated with more severe symptoms of depression/anxiety. 10In our study, the severity of EB symptoms (as measured by the ODQ) was positively correlated with measures of depression (PHQ-9) and anxiety (GAD-7).
Interestingly, ODQ scores in patients with depression have also been shown to correlate with other measures (such as the Hospital Anxiety and Depression Scale depression subscore and the Beck Depression Inventory), 9,10,30 with significantly more patients reporting extremely severe EB in the acute phase of the disease compared with the remission phase (72% vs. 25%, respectively; p < 0.01). 31garding social function and QoL in patients with MDD, the ODQ total score has been shown to have a positive correlation with the 2.9%; I don't like to be asked at all.I'd rather my physician ask.I don't like to be asked too much.
Neither.I'd like my physician to ask me somewhat.F I G U R E 5 Linguistic analysis of terms with high frequency in the free-text field of questions about EB symptoms.For patients with EB, a data show the co-occurrence network created by using the top 60 terms appearing in the free-text field of Q7 (How did you describe your EB symptoms to your physician?)(A) and Q8 (In what aspects of your daily life do you have trouble with feeling EB symptoms?)(B).The size of the circles indicates the frequency of occurrence of each word, and the strength of the connections between words (calculated by the Jaccard coefficient) are shown numerically and visually by the lines connecting the co-occurring words within the network.Dotted lines show co-occurrence between terms in different subgraphs.a Patients who responded "mildly," "moderately," or "severely" to the question "To what extent have you had any of the following emotional experiences in the last 6 weeks?" (n = 2266).
Functioning Assessment Short Test total score (a brief self-report instrument designed to assess problems in daily functioning), 32 and a negative correlation with the World Health Organization-Five Well-being Index score (a short self-reported measure of current mental well-being), suggesting that the ODQ may also be a predictor of patient functioning and QoL. 33In this study, the severity of EB as perceived by patients was confirmed using a validated screening question on a four-point scale (as described in the Methods), with 10% of respondents rating it as "severe."Patients with MDD who report the most severe symptoms of EB should be considered a In this study, we also investigated the patients' perception of EB.
Approximately 30% of the patients in our study who were aware of EB symptoms had not told their physician.Just over 40% reported that this was because "they did not know how to describe the symptoms," suggesting that it may be difficult for some patients to accurately communicate EB symptoms to their physician.Just over a quarter of patients did not inform their physician about EB symptoms because "they didn't think that EB symptoms relate to depressive symptoms or the side effects of antidepressants," perhaps reflecting a lack of awareness and understanding of EB in patients with MDD.Another potential reason why a patient may not report EB symptoms to their physician could be their diminished perception of negative emotions, meaning they do not recognize them as being particularly problematic.This lack of acknowledgment remains a significant barrier to recovery.Studies have shown that healthcare professionals may also underestimate the prevalence, severity, and impact of EB on patient functioning and treatment adherence when compared with the patients' own perspectives. 14Interestingly, about half of the patients with EB in our study reported that they would like their physician to ask about their EB symptoms, and nearly twothirds of the patients with EB symptoms found them distressing and likely to negatively impact recovery.Overall, this suggests that increasing awareness of EB symptoms in both patients and physicians is necessary to improve detection and reduce suffering in patients with MDD.
Currently, there is no established method for physicians to measure EB symptoms in daily clinical practice in Japan.In our study, the linguistic analyses identified key words and connections that are more frequently used when patients describe EB to their physician.The data suggest that EB symptoms interfere with workplace relationships and cause difficulties with aspects of a patient's social life.As mentioned above, some patients did not communicate EB symptoms to their physician because they did not know how to describe the symptoms.Further studies are required to develop linguistic methods to screen for patients who may be affected by EB.
A working knowledge of the vocabulary used to express symptoms and problems specific to patients with EB may help physicians identify such patients in clinical practice in Japan.
Limitations of this study include the fact that results were based on responses from patients who have self-reported a diagnosis of MDD; diagnoses of MDD or EB were not confirmed by a physician.Therefore, responses may have included patients without MDD, meaning results cannot be generalized to all patients with MDD.
As the focus of this study was to explore the prevalence of EB in patients with MDD on antidepressants, we did not analyze the effect of antidepressant class on EB, although this would be a valid relationship to explore in future studies.In addition, it would be interesting to clarify the relationship between a patient's social functioning and the subdomains of the ODQ.This would allow us to understand which symptoms of EB affect social communication and QoL in patients with MDD.Finally, because this was a crosssectional study, it is likely that patients' attitudes and responses regarding EB differed depending on the disease stage and treatment course.
In conclusion, this study showed for the first time in Japan that EB is a distressing symptom that can negatively affect recovery in patients undergoing treatment for MDD.This adds to the growing data set suggesting that EB is an important clinical issue that needs to be considered alongside functional recovery when managing the treatment of patients with MDD.

AUTH O R CO NTR I B UTI O N S
TK planned the analysis, gave medical interpretation of study results, and contributed to the discussion.JI reviewed the analysis plan, gave medical interpretation of study results, and contributed to the discussion.MO contributed to the analysis and discussion of study results.TH contributed to the study plan and the analysis and discussion of study results.YM and MI reviewed the analysis plans and study results.All authors took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

ACK N OWLED G M ENTS
The authors wish to thank the following for their contributions to planning, analysis of results, and advice regarding this study: Shinji Fujimoto, Tatsuro Marumoto, Keita Fujikawa (Japan Medical Office, Takeda, Japan), Hiromi Mizutani, and Keiko Uchida (Medical Affairs, Lundbeck Japan K.K.).The authors also acknowledge Tomoki Ohashi and Yoshikazu Kurita (Macromill Carenet, Inc.) for their contribution to the data acquisition and analysis in this study.Medical writing support was provided by Emily Manktelow PhD of Oxford PharmaGenesis, Melbourne, Australia, and funded by Takeda Pharmaceutical Company Limited and Lundbeck Japan K.K.

FU N D I N G I N FO R M ATI O N
This study was funded by Lundbeck Japan K.K. and Takeda Pharmaceutical Company Limited.

CO N FLI C T O F I NTER E S T S TATEM ENT
TK has received consultant fees and speaker's honoraria from Lundbeck Japan K.K and Takeda Pharmaceutical Company Limited, and speaker's honoraria from Mochida Pharmaceutical Company Limited, MSD K.K., Otsuka Pharmaceutical Company Limited, No Q2 Why didn't you tell your physician about your EB symptoms?(Only for those respondents who answered 'No' to Q1): Because I didn't know how to describe the symptoms Because my doctor didn't ask me I didn't think that EB symptoms relate to depressive symptoms or the side effects of antidepressants I didn't have time to tell them because of the short consultation I thought the EB symptoms would get better with time I had no specific reason Other Q3 Are you willing to be asked about your EB symptoms by your physician?I don't like to be asked at all I don't like to be asked too much I'd rather my physician ask I'd like my physician to ask me somewhat None of the above Q4 To what extent do you feel EB symptoms are distressing?
This web-based survey (UMIN Clinical Trials Registry ID UMIN000048497) was conducted by Macromill Carenet, Inc. (www.macro millc arenet.jp) via the monitored patient panel.The survey was conducted between July 29, 2022, and August 9, 2022.
sessed.Patients who responded "severely" to the validated screening question showed worse depression/anxiety, social functioning, and QoL scores than those patients with less severe EB symptoms (Figure2).Secondary outcomes measured the correlation between the ODQ and other measures of depression/anxiety, social functioning, and health-related QoL.As shown in Table5, there were positive F I G U R E 1 ODQ total and subdomain scores by EB severity.Data show the mean (SD) scores for (A) ODQ total score, a (B) ODQ general reduction, b (C) ODQ positive reduction, b (D) ODQ emotional detachment, b (E) ODQ not caring, b and (F) ODQ antidepressant-as-cause, b for each subset of EB symptom severity (self-reported in response to the validated screening question: "To what extent have you had any of the following emotional experiences in the last 6 weeks?"); the dotted line shows the mean for the whole analysis set (N = 3376).a ODQ total score ranges from 26 to 130 points; higher scores indicate more severe EB. b Responses range from 1 (disagree) to 5 (agree); higher scores indicate more severe EB.EB, emotional blunting; ODQ, Oxford Depression Questionnaire; SD, standard deviation.

F I G U R E 2
Patient-reported outcome scores by EB severity.Mean (SD) scores for (A) PHQ-9, a (B) GAD-7, b (C) WSAS, c and (D) EQ-5D-5L d for each subset of EB symptom severity (self-reported in response to the validated screening question: "To what extent have you had any of the following emotional experiences in the last 6 weeks?"); the dotted line shows the mean value for each PRO for the whole analysis set (N = 3376).a Total score ranges from 0 (absence of depression) to 27 (severe depression).b Total score ranges from 0 to 21 and is rated as mild (≥5), moderate (≥ 10), or severe (≥ 15).c Five questions are rated on a scale from 0 (no impairment at all) to 8 (very severe impairment); total score 40.d Descriptive system of five dimensions (range 0-1) where a higher score indicates a better QoL.EB, emotional blunting; EQ-5D-5L, EuroQol 5-Dimension 5-Levels questionnaire; GAD-7, Generalized Anxiety Disorder 7-item; PHQ-9, Patient Health Questionnaire 9-item; PRO, patient-reported outcome; QoL, quality of life; SD, standard deviation; WSAS, Work and Social Adjustment Scale.

F I G U R E 3 I
Communication between patients and physicians about EB. Results show percentage of patients responding to each option for two questions (A, B) about their communication with their physician regarding EB symptoms.Similar responses in (A) are grouped in red.a Patients who responded "mildly," "moderately," or "severely" to the question "To what extent have you had any of the following emotional experiences in the last 6 weeks?" were included in the sample.b Included patients who had reported any symptoms of EB but had not told their physician.EB, emotional blunting.'t know how to describe the symptoms Because my physician didn't ask me I didn't think that EB symptoms relate depressive symptoms or the side effects of antidepressants I didn't have time to tell them because of the short consultation I thought the EB symptoms would get better in time Are you willing to be asked by your physician about your EB symptoms?(n = 2266) a (B) Why didn't you tell your physician about your EB symptoms?Please choose all reasons why you did not tell your physician.(n = 718) b

F I G U R E 4
The burden of EB symptoms and the effects on treatment for MDD.Panel (A) shows the percentage of patients with EB a who reported distress levels between 1 (not painful) and 10 (very painful) in response to the question "To what extent do you feel EB symptoms are distressing?"Distress levels of 6 or higher are shown in red.Panels (B and C) show the percentage of patients with EB a responding to each question about their EB symptoms and treatment.Similar responses are grouped in red.a Patients who responded "mildly," "moderately," or "severely" to the question "To what extent have you had any of the following emotional experiences in the last 6 weeks?" (n = 2266).EB, emotional blunting; MDD, major depressive disorder.(A) To what extent do you feel symptoms of EB are distressing?Do you believe that EB symptoms can harm your ability to regain your pre-depression daily life?(B) priority in clinical practice, as our results show that they are likely to experience more severe symptoms of depression and anxiety with a greater impact on daily functionality and QoL.During the acute phase of MDD, physicians need to be aware of EB symptoms (both from observation and patient feedback), especially in patients who present with more severe depressive symptoms.For patients in remission, the physician should continue to use validated measures (such as the ODQ) to assess for residual EB symptoms, as well as symptoms that may occur as a side effect of treatment.

Analysis set (N = 3376), n (%) 95% CI Lower Upper
Prevalence of EB a in patients with MDD.
TA B L E 4 ODQ total scores classified by patients' characteristics.