Prevalence and clinical characteristics of major depressive disorder (MDD) without depressed mood in Koreans with MDD: results from the CRESCEND study

ABSTRACT Objective: We examined the prevalence and clinical characteristics of patients with major depressive disorder (MDD) without depressed mood, using data from the Clinical Research Center for Depression (CRESCEND) study in South Korea. Methods: Using analysis of covariance for continuous variables and binary logistic regression analysis for discrete variables, the clinical characteristics of MDD patients with and without depressed mood were compared after controlling for the potential effects of gender. To represent the extent of group differences, we computed Cohen’s d statistics. Results: Of 1009 MDD patients, only 2.2% were without depressed mood. Compared with those with depressed mood, these patients were characterized by a significantly lower rate of current suicidal ideation (adjust odds ratio = 5.258, p = .003; d = 0.193), fewer depressive symptom profiles (F = 8.731, p = .003; d = −0.543) and lower severity scores for overall depression (F = 16.027, p < .0001; d = −0.853), core depressive symptoms (F = 14.233, p < .0001; d = −0.810), insomnia (F = 6.967, p = .008; d = −0.579), anxiety (F = 14.235, p < .0001; d = −0.810), and suicidal ideation (F = 9.034, p = .003; d = 0.531), as well as a higher level of social functioning (F = 6.862, p = .009; d = 0.531). Conclusions: MDD without depressed mood is associated with a lower illness burden than MDD with depressed mood, and may have the distinctive clinical characteristics of MDD.


Introduction
Depressed mood and loss of interest or pleasure have been defined as core symptoms of major depressive disorder (MDD) in the Diagnostic and Statistical Manual of Mental Disorder, 4th edition (DSM-IV) and 5th edition (DSM-5) [1]. In addition, a strong association has been reported between depressed mood and MDD, and evidence has been presented that low socioeconomic status and social isolation contribute to depressed mood [2]. Also, an association between depressed mood and sleep disturbance has been reported based on a cohort of 3880 patients in Germany [3]. Moreover, depressed mood has been proposed as an independent risk factor for 22-month mortality in physically ill patients [4].
To overcome the non-specificity and/or heterogeneity of MDD in DSM-IV and DSM-5, a symptombased model of depression subtypes has been proposed. In this model, depressed mood is one of the defining symptoms of the distinct disorder of melancholia [5].
One study has indicated that depressed mood is not reported by a substantial proportion of currently depressed patients with co-morbid physical illness [6]. This raises the possibility that the absence of depressed mood might identify the distinctive clinical features of MDD. However, to our knowledge, the distinctive clinical features of MDD without depressed mood have rarely been reported. Hence, using the data from the Clinical Research Center for Depression (CRESCEND) study which is the largest clinical study of a nationwide sample of depressed patients in South Korea [7,8], we aimed to explore and present the prevalence and clinical characteristic of MDD patients without depressed mood in Koreans with MDD.

Study subjects
As reported previously [7,8], 1183 depressed patients, who were beginning psychiatric treatment, were recruited from 16 university-affiliated hospitals and 2 general hospitals in the CRESCEND study. The study protocols and informed consent forms were approved by all the institutional review boards of the survey centres. Before initiation of the study, written informed consent forms were completed by all study subjects. Under the supervision of clinical psychiatrists, certified clinical research coordinators collected demographic and clinical variables and determined assessment scales at regional centres. Formal consensus meetings to train the raters were held twice a year. Only MDD patients who were (i) aged 18-80 years and were (ii) diagnosed with the DSM-IV [9], were enrolled in our study, which was based on the data of the CRESCEND study. The diagnoses of the subjects were confirmed with the Structural Clinical Interview based on DSM-IV Axis I (SCID-I) [10]. Finally, 1009 MDD patients, 22 without depressed mood and 987 with depressed mood, were enrolled.

Depressed mood
Presence or absence of depressed mood and other depressive symptom profiles were determined with the DSM-IV [9] and confirmed with the SCID-I [10]. In addition, numbers of depressive symptom profiles were identified.

Statistical analysis
The Kolmogorov-Smirnov test was used to examine the normality of the distributions of continuous variables. The demographic and clinical characteristics of MDD patients without and with depressed mood were compared using the independent t-test for continuous variables and the χ 2 test for discrete variables. To adjust for the potential effects of non-relevant variables, the analyses of covariance (ANCOVA) for continuous variables and binary logistic regression analyses for discrete variables were used. Significance was set at p < .01 (two-tailed) for all tests to reduce the familywise error rate caused by multiple comparisons. In addition, to assess the effect sizes of group differences, Cohen's d statistics (0.2 = small, 0.5 = medium, and 0.8 = large) were computed. All statistical analyses were performed using SPSS 21 for Windows (SPSS Inc., Chicago, IL, USA).

Results
As shown in Table 1, only 2.2% (n = 22) of MDD patients were without depressed mood. Those without depressed mood tended to include a lower proportion of females (χ 2 = 4.673, p = .031) than those with depressed mood, although the differences were not significant. After controlling for the effects of gender, patients without depressed mood had a significantly lower rate of current suicidal ideation (adjusted odds ratio

Discussion
In summary, out of 1009 MDD patients, only 2.2% did not suffer from depressed mood. The latter had a lower rate of current suicidal ideation, fewer depressive symptom profiles, less severe depressive symptoms (in terms of core and insomnia symptoms), anxiety symptoms and suicidal ideation, and higher social functioning than those with depressed mood.
To our knowledge, the prevalence of MDD without depressed mood has been little reported. Since depressed mood is a core symptom of MDD, it has been regarded as a sensitive symptom for identifying drug-placebo responses and optimal antidepressant doses in clinical trials [25]. We have presented evidence above that MDD without depressed mood is associated with a lower illness burden than MDD with depressed mood, and may have the distinctive clinical characteristics of MDD. Our findings also indicate that MDD without depressed mood is rare in MDD patients and may be somewhat differentiated form MDD with depressed mood. It is however possible that depressed mood in these patients is masked by being replaced by other presentations. Moreover, Asians have a tendency to present somatic complaints, suicidal ideation and anxiety symptoms rather than depressed mood [26], and this tendency may have contributed to the measured prevalence of MDD without depressed mood. In addition, we cannot exclude the possibility that patients with subthreshold depression have been incorrectly regarded as without depressed mood, since co-morbidity with somatic illnesses and physical disability has been one of the characteristics of substhreshold depression [27].
In our study, the MDD patients without depressed mood tended to contain a lower proportion of females. Consistent with our findings, Eisenberger et al. [28] observed gender differences in the neural correlates that mediate the relationship between IL-6 and depressed mood. A positive association between increased IL-6 and increased depressive mood has been found in both males and females. Furthermore, we found that patients without depressed mood had lower severity of depression (especially of core symptoms), insomnia, anxiety, and suicidal ideation and a higher level of social functioning than those with depressed mood. Partly consistent with our findings, a strong association between depressed mood and sleep disturbance was seen in the general population of Germany [3]. Hence, our findings lead us to speculate that absence of depressed mood in MDD is associated with a lower illness burden. McLaren et al. [29] have shown significant associations between greater severity of depressed mood and larger volume of the left posterior cingulate/smaller volume of the isthmus cingulate, and between greater severity of somatic symptoms and smaller volume of the posterior cingulate. Hence, the neural correlates of MDD without depressed mood may include differential volume changes of the cingulate subregions.
There are certain limitations for our study. First, the small number of MDD patients without depressed mood could have influenced statistical significance. We cannot exclude a possibility that significantly different numbers of the MDD patients with and without depressive mood may contribute to the study results. Second, inter-rater reliability was not assessed. Despite these limitations, our study has the virtue of pioneering investigation of the prevalence and clinical characteristics of MDD patients without depressed mood.
In conclusion, MDD without depressed mood is less severe (especially in terms of core and insomnia symptoms), anxiety and suicidal ideation than MDD, and may have the distinctive clinical characteristics of MDD. Replication studies with larger samples and  [12]; adding the scores on the mood, guilt, work and interest, psychic anxiety, agitation and retardation items. d Defined by Manber et al. [13]; adding the scores on initial insomnia, middle insomnia. and terminal insomnia items. e n = 305.
further investigation of its neural correlates are warranted.