Utility of TEMPS-A in differentiation between major depressive disorder, bipolar I disorder, and bipolar II disorder.

BACKGROUND: The association between temperament characteristics and mood disorders has gained much attention in recent years. The Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A) is a self-rating scale measuring 5 affective temperament dimensions. In this study, we aimed to clarify whether each affective temperament of TEMPS-A is a differentiating factor between major depressive disorder (MDD), bipolar I disorder (BD-I), and bipolar II disorder (BD-II), and analyzed the utility of TEMPS-A in their differential diagnosis in a clinical setting.
METHODS: A total of 346 patients (MDD, n = 176; BD-II, n = 112; BD-I, n = 58) filled out TEMPS-A. To assess the patients' mood state at the time of temperament assessment, Patient Health Questionnaire-9 (PHQ-9) and Young Mania Rating Scale (YMRS) were also conducted.
RESULTS: Multivariate logistic regression analysis demonstrated that cyclothymic and anxious temperament scores were significant factors differentiating the diagnosis of BD-I and BD-II from the diagnosis of MDD, and hyperthymic temperament score was a specific factor for the differential diagnosis of BD-I versus the diagnosis of BD-II. LIMITATIONS: All of the patients included in our study received treatment in large general hospitals. Because the nature of the present study was cross-sectional, some MDD subjects in this study might have unrecognized BD-I/BD-II.
CONCLUSIONS: Cyclothymic and anxious temperament scores assessed by TEMPS-A might enable differentiation between MDD and BD, and hyperthymic temperament score on TEMPS-A might be useful in distinguishing between BD-I and BD-II.

Introduction

Differentiating between major depressive disorder (MDD), bipolar I disorder (BD-I), and bipolar II disorder (BD-II) in the early stages of disease is clinically important [1, 2], because clinicians should take different treatment approaches for the 3 disorders and inappropriate treatment can be associated with poor prognoses. For example, clinicians should not provide antidepressant monotherapy to patients with BD, particularly those with BD-I, according to many treatment guidelines for mood disorders [3, 4], and inappropriate treatment of BD and an extended duration of untreated BD may increase the risk of mood instabilities and suicide attempts [1, 2]. However, this distinction often requires a large amount of time and effort for clinicians, owing to various reasons. One reason is that in two-thirds of patients, the onset of BD is a major depressive episode [5]. Another reason is the lack of patient self-awareness of prior or future manic or hypomanic episodes [6].

In recent years, the association between mood disorders and temperament characteristics has gathered much attention. The Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A) is a 110-item true-false self-reported questionnaire that quantitatively assesses 5 domains of affective temperament, i.e., depressive, hyperthymic, cyclothymic, irritable, and anxious temperaments [7]. Vazquez et al. showed the association between some affective temperaments on TEMPS-A and a suicidal risk in both psychiatric and general population samples [8]. The association between some affective temperaments on TEMPS-A and treatment resistance in MDD and BD patients has also been studied [9-11]. Moreover, Goto et al. suggested that cyclothymic and hyperthymic temperaments were associated with bipolarity, and also investigated the association between treatments and remission rates in patients with bipolarity [12]. Furthermore, several studies have shown the possibility of the usefulness of TEMPS-A to differentiate between MDD and BD [13-18]. However, most previous studies had limitations, such as a small sample size or that the data were not analyzed by multivariate analyses, including current mental status as an independent variable, although mood state is known to influence the self-evaluation of affective temperament [19]. Moreover, Solmi et al. [20] performed a meta-analysis and found that patients with a diagnosis of BD had significantly higher cyclothymic, hyperthymic, and irritable temperament scores compared with patients with a diagnosis of MDD. To our knowledge, this is the only study to date that performed a meta-analysis to assess the association between affective temperament scores on TEMPS-A and the diagnosis of mood disorders; however, the subjects included were of various mental states, and the possible effects of their mental states were ignored in the meta-analysis.

On the other hand, our previous studies demonstrated that cyclothymic and anxious temperaments were factors differentiating MDD and BD patients from healthy subjects [9, 10]. The data of our studies were analyzed by multivariate logistic regression analyses to take into account several relevant factors, such as depression severity, but we did not include manic or hypomanic symptoms in the analyses. Moreover, we did not compare the characteristics of TEMPS-A between MDD patients and BD patients, or between BD-I patients and BD-II patients. Takeshima and Oka [11] demonstrated that cyclothymic and hyperthymic temperaments are independent differentiating factors of BD in their comparison between MDD and BD patients. The data of their study were analyzed by multivariate logistic regression analysis, including the severity of depressive symptoms as an independent variable, but they ignored manic symptoms at the time of temperament assessment, and they did not consider BD-I and BD-II separately.

There have been few studies in which the severity of mood symptoms and the effects of other temperaments were taken into account in the comparison between MDD and BD. In other words, in previous studies, the effects of relevant factors were not considered. Moreover, no study to date has performed multivariate analysis to identify affective temperaments as differentiating factors of BD-I compared with BD-II. For these reasons, it has not yet been clarified whether TEMPS-A is useful for the differential diagnosis of mood disorders. Therefore, we hypothesized that each subscale of affective temperaments assessed by TEMPS-A is a differentiating factor of the diagnosis of MDD, BD-I, and BD-II.

The aim of this study was to test this hypothesis, and to clarify whether TEMPS-A is useful for a differential diagnosis in a clinical setting.

Subjects and methods

Subjects

Subjects were 157 outpatients and 189 inpatients (MDD, n = 176; BD-II, n = 112; BD-I, n = 58). Approximately 70 or more subjects for each disorder group were required for our analyses, because we planned to conduct multivariate logistic regression analyses including 7 factors as independent variables. Patient diagnoses were performed by psychiatric specialists who were responsible for the treatment of these patients, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-Ⅳ-TR). The outpatients were those who received treatment at the Department of Psychiatry of either Hokkaido University Hospital or Self-Defense Forces Sapporo Hospital, both in Sapporo, National Defense Medical College Hospital in Tokorozawa, or Self-Defense Forces Central Hospital in Tokyo, between April 2012 and April 2013. The inpatients were those who received treatment at the Department of Psychiatry, Hokkaido University Hospital, between January 2010 and December 2017. The inclusion criteria of the patients were as follows: (1) a principal diagnosis of MDD, BD-I, or BD-II according to the DSM-Ⅳ-TR criteria; (2) 20 years of age or older; (3) the ability to complete the self-reported questionnaires; and (4) the ability to provide written informed consent. The exclusion criteria were as follows: (1) having serious physical or mental symptoms that hinder the completion of the self-reported questionnaires; (2) having organic mental disorders or a previous history of them; (3) meeting the diagnostic criteria of substance-use disorders; and (4) having a diagnosis of axis II according to the DSM-Ⅳ-TR criteria. Patients meeting the eligibility criteria were informed about our research by their doctors in charge, and those who gave written consent were included in the study. The sample might not be a nationally representative sample, as the sample was limited to a convenience sample, and consisted of only patients who received treatment at general or university hospitals in specific parts of Japan. In other words, the sample did not include patients who received treatment at psychiatric hospitals or clinics. The present study was performed in accordance with the Declaration of Helsinki, and was approved by the ethics committees of National Defense Medical College, Hokkaido University Hospital, and Tokyo Medical University. The approval number is SH4098.

Table 1 presents the demographic data, Patient Health Questionnaire-9 (PHQ-9) and Young Mania Rating Scale (YMRS) scores, and TEMPS-A subscores of the subjects.

Table 1

Demographic and clinical characteristics and TEMPS-A scores of the patients analyzed in this study.

	MDD (n = 176)	BD-II (n = 112)	BD-I (n = 58)	Statistical difference
Demographics
Age, years: mean (S.D.)	46.5 (13.1)	45.5 (12.7)	49.2 (11.5)	F(2,343) = 1.66	p = 0.193
Sex (male): n (%)	92 (52.3)	49 (43.8)	35 (60.3)		p = 0.106
Education, years: mean (S.D.)	14.0 (2.4)	14.2 (2.4)	14.7 (1.9)	F(2,343) = 2.03	p = 0.133
Employment status (employed): n (%)	64 (36.4)	38 (33.9)	14 (24.1)		p = 0.764
Marital status (married): n (%)	91 (51.7)	63 (56.3)	32 (55.2)		p = 0.237
Clinical features
PHQ-9 score: mean (S.D.)	8.9 (7.0)	9.0 (6.1)	8.5 (7.6)	F(2,343) = 0.13	p = 0.881
YMRS score: mean (S.D.)	0.7 (2.2)	1.6 (2.8)*	1.8 (2.9)*	F(2,343) = 5.92	p = 0.003
TEMPS-A scores
Depressive score: mean (S.D.)	1.50 (0.21)	1.51 (0.22)	1.49 (0.17)	F(2,343) = 0.22	p = 0.800
Cyclothymic score: mean (S.D.)	1.29 (0.22)	1.40 (0.27)**	1.43 (0.30)**	F(2,343) = 10.75	p = 0.000
Hyperthymic score: mean (S.D.)	1.19 (0.17)	1.19 (0.16)	1.27 (0.25) **#	F(2,343) = 5.15	p = 0.006
Irritability score: mean (S.D.)	1.19 (0.16)	1.23 (0.20)	1.21 (0.22)	F(2,343) = 1.79	p = 0.168
Anxiety score: mean (S.D.)	1.42 (0.25)	1.42 (0.24)	1.41 (0.26)	F(2,343) = 0.56	p = 0.946

MDD, major depressive disorder; BD-I, bipolar I disorder; BD-II, bipolar II disorder; S.D., standard deviation; PHQ-9, Patient Health Questionnaire-9; YMRS, Young Mania Rating Scale; TEMPS-A, Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire

*p < 0.05 vs MDD

**p < 0.01 vs MDD

#p < 0.05 vs BD-II.

Measures and procedures

The patients completed the Japanese standardized version of the TEMPS-A. The validity and reliability of TEMPS-A for psychiatric disorders, particularly for mood disorders, was suggested by Akiskal et al. [7], and the validity and reliability of the Japanese version was also shown by Matsumoto et al. [14]. In the analyses, True was scored as 2 and False was scored as 1, and final values were obtained by dividing the total points of each affective temperament subscale by the number of question items measuring each subscale.

The inpatients filled out the TEMPS-A at the time of hospital discharge, after their symptoms were improved by adequate treatment. The outpatients filled out the TEMPS-A at some point in their continuous visits, but not at their first visit. In other words, they completed it after they received treatment for months or years.

To assess the severity of depressive symptoms, patients were also asked to complete the Japanese version of PHQ-9 at the same time as completing the TEMPS-A. The PHQ-9 is a self-reported questionnaire consisting of 9 items on a 4-point Likert scale, used as an index of depressive symptom severity and as a screening test for major depressive episodes. The Japanese version of the PHQ-9 was used in this study. Some studies suggested that the PHQ-9 yields an index of depressive symptom severity and has diagnostic validity, and also validates the Japanese version of the PHQ-9 [21-23]. Additionally, to assess manic symptoms, evaluation using the Young Mania Rating Scale (YMRS) was performed by psychiatrists. The YMRS is an assessment sheet consisting of 11 items, which are each rated on a 0–4 scale. The rating of severity is based on both the subjective statements of patients and objective observation by clinicians. The construct validity and reliability of YMRS was demonstrated by Young et al. [24]. Demographic features, such as age, sex, duration of education, employment, and marital status were also analyzed. Data were anonymized and sent to our research group.

Statistical analyses

Continuous variables were compared using analysis of variance, and categorical variables were compared by the Kruskal-Wallis test. Post-hoc analyses were performed by the Bonferroni test. Multivariate logistic regression analyses using the backward stepwise method were performed to identify factors of the distinction of MDD, BD-I, and BD-II. Then, receiver operating characteristic (ROC) curves were used to assess the performances. Moreover, multivariate logistic regression analyses using the forced entry method were performed to confirm the reproducibility of the results.

Statistical analyses were performed using SPSS 24.0J for Windows (SPSS Inc., Chicago, IL, USA). A p-value of less than 0.05 was considered to indicate a statistically significant difference.

Results

Demographic and clinical characteristics and TEMPS-A subscale scores (Table 1)

YMRS scores were higher in the BD-I and BD-II groups than in the MDD group, although a statistically significant difference between the BD-I and BD-II groups was not detected. Differences of age, sex, education years, employment status, marital status, and PHQ-9 scores were not statistically significant among the 3 disease groups.

Three-group comparisons of MDD, BD-I, and BD-II demonstrated statistically significant differences in cyclothymic and hyperthymic temperaments, but we did not find statistically significant differences in depressive, irritable, or anxious temperaments among the 3 groups. Substantially higher cyclothymic temperament scores were found in the BD-I and BD-II groups than in the MDD group, and substantially higher hyperthymic temperament scores were found in the BD-I group than in the MDD and BD-II groups.

Analysis of differentiating factors of the diagnosis of MDD, BD-I, and BD-II

Taking into account the results shown in Table 1, multivariate logistic regression analysis was conducted for the severity of mood symptoms and TEMPS-A subscores, to identify independent differentiating factors of the diagnosis of mood disorders.

In Table 2, we summarized the results of backward stepwise multivariate logistic regression analysis performed to identify independent differentiating factors of the diagnosis of BD-I versus the diagnosis of MDD. Among the PHQ-9 scores, YMRS scores, and 5 TEMPS-A subscale scores, cyclothymic and anxious temperament scores on the TEMPS-A as well as YMRS scores were significant independent differentiating factors of the diagnosis of BD-I versus the diagnosis of MDD, whereas PHQ-9 scores and depressive, hyperthymic, and irritable temperament scores on the TEMPS-A were not considered as significant differentiating factors of the diagnosis of BD-I.

Table 2

Stepwise multivariate logistic regression analysis of the diagnosis of MDD and BD-I.

Variable	Stepwise analysis
	B	S.E.	p-value	OR	95% CI
Cyclothymic temperament	3.68	0.87	0.000	39.52	7.14–218.75
Anxious temperament	–2.44	0.88	0.005	0.09	0.02–0.49
YMRS score	0.13	0.06	0.049	1.13	1.00–1.28
Constant	–2.79	0.99	0.005	0.06

Fit index of this model: χ2 = 28.11 (p-value < 0.05), Cox-Snell R2 = 0.11, Hosmer–Lemeshow test p = 0.275, sensitivity = 0.17, specificity = 0.96, positive predictive value = 0.56, negative predictive value = 0.78, AUC of ROC = 0.71

dependent variable: the diagnosis of MDD (1) and BD-I (2)

7 independent variables: scores of 5 subscales of the TEMPS-A and the severity of depressive and manic symptoms (PHQ-9 and YMRS scores, respectively).

AUC, area under the curve; BD- I, bipolar I disorder; CI, confidence interval; MDD, major depressive disorder; OR, odds ratio; PHQ-9, Patient Health Questionnaire-9; ROC, receiver-operating characteristic; B, partial regression coefficient; S.E., standard error; TEMPS-A, Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire; YMRS, Young Mania Rating Scale.

Table 3 demonstrates the results of stepwise multivariate logistic regression analysis conducted to identify variables distinguishing BD-II from MDD. Cyclothymic and anxious temperament scores were identified as significant independent differentiating factors of the diagnosis of BD-II versus the diagnosis of MDD, whereas the other variables were not considered as significant differentiating factors of the diagnosis of BD-II.

Table 3

Stepwise multivariate logistic regression analysis of the diagnosis of MDD and BD-II.

Variable	Stepwise analysis
	B	S.E.	p-value	OR	95%CI
Cyclothymic temperament	2.91	0.72	0.000	18.32	4.44–75.65
Hyperthymic temperament	–0.73	0.80	0.363	0.48	0.10–2.32
Anxious temperament	–1.81	0.70	0.010	0.17	0.04–0.65
YMRS score	0.10	0.06	0.067	1.11	0.99–1.24
Constant	–1.04	1.22	0.396	0.35

Fit index of this model: χ2 = 25.84 (p-value < 0.05), Cox-Snell R2 = 0.09, Hosmer–Lemeshow test p = 0.678, sensitivity = 0.32, specificity = 0.89, positive predictive value = 0.66, negative predictive value = 0.67, AUC of ROC = 0.66

dependent variable: diagnosis of MDD (1) and BD-II (2)

7 independent variables: scores of 5 subscales of the TEMPS-A and the severity of depressive and manic symptoms (PHQ-9 and YMRS scores, respectively)

BD-II, bipolar II disorder; MDD, major depressive disorder

As shown in Table 4, stepwise multivariate logistic regression analysis of the diagnosis of BD-I compared with the diagnosis of BD-II demonstrated that only hyperthymic temperament score was a significant independent differentiating factor correlating with the diagnosis of BD-I.

Table 4

Stepwise multivariate logistic regression analysis of the diagnosis of BD-II and BD-I.

Variable	Stepwise analysis
	B	S.E.	p-value	OR	95%CI
Hyperthymic temperament	2.01	0.82	0.014	7.44	1.50–36.94
Constant	–3.12	1.02	0.002	0.04

Fit index of this model: χ2 = 6.20 (p-value < 0.05), Cox-Snell R2 = 0.04, Hosmer–Lemeshow test p = 0.378, sensitivity = 0.16, specificity = 0.97, positive predictive value = 0.75, negative predictive value = 0.69, AUC of ROC = 0.57

dependent variable: the diagnosis of BD-II (1) and BD-I (2)

7 independent variables: scores of 5 subscales of the TEMPS-A and the severity of depressive and manic symptoms (PHQ-9 and YMRS scores, respectively)

BD- II, bipolar II disorder; BD- I, bipolar I disorder

We also conducted the multivariate logistic regression analyses using the forced entry method, including PHQ-9 and YMRS scores, and TEMPS-A subscores as independent variables, to confirm the robustness of our results. The results are shown in S1–S3 Tables. S1 and S2 Tables show that only cyclothymic temperament score is a significant differentiating factor of the diagnosis of BD-I and BD-II from the diagnosis of MDD. S3 Table demonstrates that hyperthymic temperament score is a specific factor for the differential diagnosis of BD-I versus the diagnosis of BD-II.

Discussion

The principle findings of our study are as follows. Cyclothymic temperament and anxious temperament may differentiate the diagnosis of BD-I and BD-II compared with MDD, and hyperthymic temperament may differentiate the diagnosis of BD-I compared with BD-II. These findings supported the hypothesis that some affective temperaments assessed by TEMPS-A can be used as differentiating factors of the diagnosis of MDD, BD-I, and BD-II. Affective temperament is a concept proposed by Akiskal and his colleagues. They described that temperaments are more than just forme frustes of mood disorders and temperamental dysregulation is present in the subclinical stages, before patients experience mood episodes [25, 26]. Based on their descriptions and our present results, our findings may indicate that clinicians should keep in mind the possibility that MDD patients with high cyclothymic and low anxious scores on TEMPS-A may subsequently have manic/hypomanic episodes, and BD-II patients with a high hyperthymic temperament score may have manic episodes. We believe that this diagnostic conversion should be kept in mind clinically, although we should verify the role of affective temperaments prospectively.

The periods of the illness of the subjects were various. As shown in S4 Table, approximately 30% of the patients in each disease group were in remission. From a perspective of the impact of affective symptoms on the questionnaire answers [19], it is preferable that all subjects are in euthymic state when answering the questionnaires. However, we aimed to verify whether TEMPS-A was useful for the differential diagnosis of mood disorders in real-world clinical settings, and therefore, we included patients with various symptom severity. Moreover, we performed multivariate logistic regression analyses including the severity of mood symptoms and 5 affective temperaments as independent variables, considering the impact of them on TEMPS-A.

This is the first report to our knowledge that used multivariate analysis to show that affective temperament is a statistically significant differentiating factor of mood disorders, considering BD-I and BD-II separately, and taking into account manic and depressive symptoms as well as the 5 affective temperaments. On the other hand, Di Florio et al. compared patients with MDD and BD, taking into account depressive symptoms and hypomanic symptoms at the time of temperament assessment, but found no significant differences in all the subscales of the short version of the TEMPS-A [27]. A possible interpretation of this discrepancy is that, in the study by Di Florio et al., the MDD group included only the subjects diagnosed with recurrent MDD with hypomanic features, because recurrent major depressive episodes is a predictor of bipolarity [18]. The utilization of the short version of the TEMPS-A may also explain the difference between the results of their studies and ours, as the short version of the TEMPS-A (39 items) shows only weak or moderate correlation with the full version of the TEMPS-A (109/110 items) [28].

We conducted multivariate logistic regression analyses using the forced entry method as well as the backward stepwise selection method, and confirmed the robustness of the results of the original analysis of BD-I versus BD-II, although the fit index of this model might not be accepted. On the other hand, we obtained partially different results using the forced entry method from the original results. In the forced entry method, only cyclothymic temperament score was a significant differentiating factor of the diagnosis of BD-I and BD-II from the diagnosis of MDD, and anxious temperament and YMRS scores were not significant differentiating factors of BD-I and BD-II versus MDD. The reason for this discrepancy might be that, although we attempted to construct the best model by taking into account mood symptoms and other affective temperaments, there is still a possibility that the effects of the excluded variables in the backward stepwise selection method were adjusted inadequately. We should hence confirm the reproducibility of our original results using larger samples in the future.

In addition, this study has several limitations. First, the design of our study was cross-sectional. Therefore, patients with MDD in this study may subsequently have a manic/hypomanic episode, leading to changes in their diagnoses. We should hence conduct follow-up observations to confirm their diagnoses. Secondly, all of the subjects included in the present study were patients treated in general or university hospitals, and consequently, there may be sampling biases.

In conclusion, the present study identified cyclothymic and anxious temperaments as differentiating factors of the diagnosis of BD compared with MDD, and hyperthymic temperament as a differentiating factor of BD-I compared with BD-II. These results indicate that evaluating affective temperaments with TEMPS-A in patients with mood disorders may be useful for distinguishing between MDD, BD-I, and BD-II.

Multivariate logistic regression analysis of the diagnosis of MDD and BD-I by the forced entry method.

(DOCX)

Click here for additional data file.

Multivariate logistic regression analysis of the diagnosis of MDD and BD-II by the forced entry method.

(DOCX)

Click here for additional data file.

Multivariate logistic regression analysis of the diagnosis of BD-II and BD-I using the forced entry method.

(DOCX)

Click here for additional data file.

Depressive symptoms assessed by the PHQ-9 and manic symptoms assessed by the YMRS in the subjects.

(DOCX)

Click here for additional data file.

20 Feb 2020

PONE-D-20-02514

Utility of TEMPS-A in differentiation between major depressive disorder, bipolar I disorder, and bipolar II disorder

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors investigated the utility of TEMPS-A for differential diagnosis of major depressive disorder (MDD) and bipolar disorders (BDs). They found that cyclothymic and anxious temperament scores were associated with the diagnoses of BDs versus MDD. They also found that hyperthymic temperament score was associated with the diagnoses of BD-I versus BD-II. The topic seems to be interesting for researchers in this field. However, I have the following concerns.

1. Categorical variables should be assessed by the Chi-square test or Fisher’s exact test rather than the Kruskal-Wallis test.

2. Sensitivity analysis is lacking. The stepwise multivariate logistic regression model automatically selects the best combination of predictive variables from the entered independent variables. In Table 2, the 3 independent variables, i.e. cyclothymic, anxious and YMRS, were selected for the best model, and the other variables, i.e. PHQ-9 and the other 3 TEMPS-A subscales, were just excluded from the model. This does not mean that the selected best model was adjusted for the effects of the excluded variables. The model in the Table 2 was not adjusted for the effects of PHQ-9 and the other 3 TEMPS-A subscales. The same is true for the results in Table 3 and 4. Therefore, in order to confirm the robustness of the original results, the authors should conduct the multivariate logistic regression analyses mandatorily including the 7 independent variables, and ideally demographic variables. These results from the sensitivity analyses should be mentioned in the main text and might be presented as supplementary tables.

3. In the first paragraph of the Discussion, “after adjusting for manic and depressive symptoms and 5 affective temperaments.” As mentioned above, the selected models did not adjust for several excluded variables.

4. It seems to be difficult for clinicians to predict the accurate differential diagnosis of MDD, BD-I and BD-II using TEMPS-A scores due to their relatively lower AUC values. This point should be briefly discussed. The authors need to tone down the language in the Conclusion, especially for predictive ability and accuracy.

5. In the Conclusion of the Abstract, the words “at early stages” should be removed.

Reviewer #2: This is a cross-sectional-study in the differentiation between major depressive disorder, bipolar I disorder, and bipolar II disorder using TEMPS-A. The study is interesting and important to patients with mood disorders. However, there are some concerns.

1. In introduction section, authors stated “Differentiating between major depressive disorder (MDD), bipolar I disorder (BD-I), and bipolar II disorder (BD-II) in the early stages of disease is clinically important.” Why is the differentiation needed? Authors need to explain in more detail.

2. In introduction section, authors stated “In recent years, the association between mood disorders and temperament characteristics has gathered much attention. ” What is the recent trend about these associations concretely?

3. In introduction section, there is no hypothesis. Authors need to clarify the hypotheses of this study, and discussion section should be made in accordance with authors’ hypotheses.

4. In methods section, authors described “TEMPS-A was measured at the time of visit.” What does this visit mean? First visit? Continuous visit?

5. In methods section, a statement as to whether your sample can be considered representative of a larger population is needed.

6. In methods section, authors need to clarify the sample size calculation.

7. Kawamura et al demonstrated that temperaments evaluated by TEMPS-A did not change substantially over 6 years (Kawamura Y, Akiyama T, Shimada T, Minato T, Umekage T, Noda Y, et al. Six-year stability of affective temperaments as measured by TEMPS-A. Psychopathology. 2010; 43(4):240–7. ) However, inpatients’ data in this study are over 8 years. How do authors explain about this point?

8. This study design is cross-sectional as authors mentioned in the lmitation section. So, the description, “predictor, predictive factor” are unsuitable.

9. The AUC between BD-I vs MDD is 0.708, between BD-II vs MDD is 0.655, between BD-I vs BD-II is 0.573. These AUCs are relatively low accuracy. I also think “predictor, predictive factor” is overstatement. Authors have to mention this point.

10. There are a few repetitions in the text. The paper could be improved by further editing.

Reviewer #3: The aim of this study is to evaluation of affective temperament measuring by TEMPS-A autoquestionaire in affective disorder and analyze of the utility of affective temperament dimensions in prediction of differential diagnosis. This study is interesting, however I have some remarks listed below:

1. There is a lack of detail about the data collection instrument. The PHQ-9 questionaire should be further described.

2. What is the reliability and validity of scales used?

3. The sample size was 346, 157 outpatients and 189 inpatients. How was it determined? Which is the method was used to recruit the sample? What are the eligibility criteria of the study sample?

4. The demographic data and the clinical characteristic should be present in method section (subject), not in results section.

4. Is the investigated group homogenous? What was the period of the illness (acute, partial remission) and the intensity of affective symptoms during the research procedure?

5. What was the current medication received by patients? Did authors observed differences in dosage of the drugs received by inpatients and outpatients?

4. In discussion - consider adding more recommendations for practice.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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4 Apr 2020

Point- by-point responses to the Reviewer’s comments

Reviewer #1

Comment 1: Categorical variables should be assessed by the Chi-square test or Fisher’s exact test rather than the Kruskal-Wallis test.

Response:

As you indicated, in general, differences between 2 groups are analyzed by the Chi-square test or Fisher’s exact test. However, in this study, we used the Kruskal-Wallis test to analyze differences among 3 groups, and planned to use the Bonferroni test for multiple comparison between groups if there were statistically significant differences among the 3 groups. This is because a multiple comparison cannot be performed using the Chi-square test or the Fisher’s exact test.

Comment 2: Sensitivity analysis is lacking. The stepwise multivariate logistic regression model automatically selects the best combination of predictive variables from the entered independent variables. In Table 2, the 3 independent variables, i.e. cyclothymic, anxious and YMRS, were selected for the best model, and the other variables, i.e. PHQ-9 and the other 3 TEMPS-A subscales, were just excluded from the model. This does not mean that the selected best model was adjusted for the effects of the excluded variables. The model in the Table 2 was not adjusted for the effects of PHQ-9 and the other 3 TEMPS-A subscales. The same is true for the results in Table 3 and 4. Therefore, in order to confirm the robustness of the original results, the authors should conduct the multivariate logistic regression analyses mandatorily including the 7 independent variables, and ideally demographic variables. These results from the sensitivity analyses should be mentioned in the main text and might be presented as supplementary tables.

Response:

Thank you for pointing out this important point. In accordance with the comment, we conducted multivariate logistic regression analyses using the forced entry method including the 7 independent variables, although we could not include demographic variables owing to the sample size. We have added these results as Tables S1-3, and a description of the results was added to the Results and Discussion sections of the revised manuscript, as follows.

In the Results section (page 19, lines 251-257)

“We also conducted the multivariate logistic regression analyses using the forced entry method, including PHQ-9 and YMRS scores, and TEMPS-A subscores as independent variables, to confirm the robustness of our results. The results are shown in Tables S1-3. Tables S1 and S2 show that only cyclothymic temperament score is a significant differentiating factor of the diagnosis of BD-I and BD-II from the diagnosis of MDD. Table S3 demonstrates that hyperthymic temperament score is a specific factor for the differential diagnosis of BD-I versus the diagnosis of BD-II.”

In the Discussion section (page 22, lines 297-309)

“We conducted multivariate logistic regression analyses using the forced entry method as well as the backward stepwise selection method, and confirmed the robustness of the results of the original analysis of BD-I versus BD-II, although the fit index of this model might not be accepted. On the other hand, we obtained partially different results using the forced entry method from the original results. In the forced entry method, only cyclothymic temperament score was a significant differentiating factor of the diagnosis of BD-I and BD-II from the diagnosis of MDD, and anxious temperament and YMRS scores were not significant differentiating factors of BD-I and BD-II versus MDD. The reason for this discrepancy might be that, although we attempted to construct the best model by taking into account mood symptoms and other affective temperaments, there is still a possibility that the effects of the excluded variables in the backward stepwise selection method were adjusted inadequately. We should hence confirm the reproducibility of our original results using larger samples in the future.”

Comment 3: In the first paragraph of the Discussion, “after adjusting for manic and depressive symptoms and 5 affective temperaments.” As mentioned above, the selected models did not adjust for several excluded variables.

Response:

We thank you for pointing this out. As you suggested, there is a possibility that we inadequately adjusted for several excluded variables in our original analyses. We hence changed the phrase “after adjusting for manic and depressive symptoms and 5 affective temperaments” to “taking into account manic and depressive symptoms as well as 5 affective temperaments” in the revised manuscript.

Comment 4: It seems to be difficult for clinicians to predict the accurate differential diagnosis of MDD, BD-I and BD-II using TEMPS-A scores due to their relatively lower AUC values. This point should be briefly discussed. The authors need to tone down the language in the Conclusion, especially for predictive ability and accuracy.

Response:

We agree that it appears to be difficult for clinicians to predict an accurate differential diagnosis of MDD, BD-I, and BD-II by only TEMPS-A subscores, owing to their relatively lower AUC values. We hence changed the term “predictor” to “differentiating factor,” and deleted the term “accurately” in the Results and Discussion sections of the revised manuscript. We also toned down our conclusions.

Comment 5: In the Conclusion of the Abstract, the words “at early stages” should be removed.

Response:

Thank you for your suggestion. We removed the words “at early stages” from the revised manuscript.

Reviewer #2

Comment 1: In introduction section, authors stated “Differentiating between major depressive disorder (MDD), bipolar I disorder (BD-I), and bipolar II disorder (BD-II) in the early stages of disease is clinically important.” Why is the differentiation needed? Authors need to explain in more detail.

Response:

Thank you for your suggestion. To make this point clear, we added the reasons to the Introduction section, as follows (page 5, lines 52-59).

“Differentiating between major depressive disorder (MDD), bipolar I disorder (BD-I), and bipolar II disorder (BD-II) in the early stages of disease is clinically important (Altamura et al., 2010; Drancourt et al., 2013), because clinicians should take different treatment approaches for the 3 disorders and inappropriate treatment can be associated with poor prognoses. For example, clinicians should not provide antidepressant monotherapy to patients with BD, particularly those with BD-I, according to many treatment guidelines for mood disorders ([3] Kanba et al., 2013; [4] Yatham et al., 2018), and inappropriate treatment of BD and an extended duration of untreated BD may increase the risk of mood instabilities and suicide attempts (Altamura et al., 2010; Drancourt et al., 2013).”

Furthermore, the following 2 references were added to the References section.

[3] Kanba S, Kato T, Terao T, Yamada K, Committee for Treatment Guidelines of Mood Disorders JSoMD. Guideline for treatment of bipolar disorder by the Japanese Society of Mood Disorders, 2012. Psychiatry Clin Neurosci. 2013;67(5):285-300. https://doi.org/10.1111/pcn.12060. PMID: 23773266.

[4] Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. https://doi.org/10.1111/bdi.12609. PMID: 29536616; PubMed Central PMCID: PMCPMC5947163.

Comment 2: In introduction section, authors stated “In recent years, the association between mood disorders and temperament characteristics has gathered much attention. ” What is the recent trend about these associations concretely?

Response:

Thank you for pointing out this important point. As mentioned in our original manuscript, several studies have shown the possibility of the usefulness of TEMPS-A to differentiate between MDD and BD. Moreover, in accordance with the comment, we added the following description to the Introduction section (page 6, lines 67-73).

“Vazquez et al. showed the association between some affective temperaments on TEMPS-A and a suicidal risk in both psychiatric and general population samples ([8] Vazquez et al., 2018). The association between some affective temperaments on TEMPS-A and treatment resistance in MDD and BD patients has also been studied (Toda et al., 2015; Toda et al., 2018; Takeshima and Oka, 2016). Moreover, Goto et al. suggested that cyclothymic and hyperthymic temperaments were associated with bipolarity, and also investigated the association between treatments and remission rates in patients with bipolarity ([12] Goto et al., 2011).”

Furthermore, the following 2 references were added to the References section.

[8] Vazquez GH, Gonda X, Lolich M, Tondo L, Baldessarini RJ. Suicidal risk and affective temperaments, evaluated with the TEMPS-A scale: A systematic review. Harv Rev Psychiatry. 2018;26(1):8-18. https://doi.org/10.1097/HRP.0000000000000153. PMID: 29303918.

[12] Goto S, Terao T, Hoaki N, Wang Y. Cyclothymic and hyperthymic temperaments may predict bipolarity in major depressive disorder: a supportive evidence for bipolar II1/2 and IV. J Affect Disord. 2011;129(1-3):34-8. https://doi.org/10.1016/j.jad.2010.07.016. PMID: 20699193.

Comment 3: In introduction section, there is no hypothesis. Authors need to clarify the hypotheses of this study, and discussion section should be made in accordance with authors’ hypotheses.

Response:

We apologize that there was no hypothesis in the original manuscript. We included our hypothesis that each subscale of affective temperaments assessed by TEMPS-A is a differentiating factor of the diagnosis of MDD, BD-I, and BD-II in the Introduction section of the revised manuscript (page 8, lines 103-104).

Comment 4: In methods section, authors described “TEMPS-A was measured at the time of visit.” What does this visit mean? First visit? Continuous visit?

Response:

Thank you for your valuable suggestion. We rephrased our expression in the Methods section, as follows (page 12, lines 154-157).

“The inpatients filled out the TEMPS-A at the time of hospital discharge, after their symptoms were improved by adequate treatment. The outpatients filled out the TEMPS-A at some point in their continuous visits, but not at their first visit. In other words, they completed it after they received treatment for months or years.”

Comment 5: In methods section, a statement as to whether your sample can be considered representative of a larger population is needed.

Response:

Thank you for your valuable suggestion. We believe that our sample may not be a nationally representative sample for various reasons. To make this point clear, we added the following sentences to the Methods section (page 10, lines132-136).

“The sample might not be a nationally representative sample, as the sample was limited to a convenience sample, and consisted of only patients who received treatment at general or university hospitals in specific parts of Japan. In other words, the sample did not include patients who received treatment at psychiatric hospitals or clinics.”

Comment 6: In methods section, authors need to clarify the sample size calculation.

Response:

Thank you for your suggestion. Approximately 70 or more subjects for each disorder group were required for our analyses, because we planned to conduct multivariate logistic regression analyses including 7 factors as independent variables. This description was added to the Methods section of the revised manuscript (page 9, lines 113-115).

Comment 7: Kawamura et al demonstrated that temperaments evaluated by TEMPS-A did not change substantially over 6 years (Kawamura Y, Akiyama T, Shimada T, Minato T, Umekage T, Noda Y, et al. Six-year stability of affective temperaments as measured by TEMPS-A. Psychopathology. 2010; 43(4):240–7.) However, inpatients’ data in this study are over 8 years. How do authors explain about this point?

Response:

As you pointed out, Kawamura et al. showed the 6-year stability of affective temperaments measured by TEMPS-A in a nonclinical adult population. However, our design was cross-sectional, and we did not follow up the patients prospectively. Moreover, to avoid confusion, we changed the expression of subjects from “those who received treatment from April 2012 to April 2013” to “those who received treatment between April 2012 and April 2013,” and from “those who received treatment from January 2010 to December 2017” to “those who received treatment between January 2010 and December 2017” in the revised manuscript.

Comment 8: This study design is cross-sectional as authors mentioned in the lmitation section. So, the description, “predictor, predictive factor” are unsuitable.

Response:

As you pointed out, we also think that TEMPS-A subscores are not necessarily predictive factors, owing to the study design. Therefore, we replaced the description “predictor and predictive factor” with the phrase “differentiating factor” throughout the revised manuscript.

Comment 9: The AUC between BD-I vs MDD is 0.708, between BD-II vs MDD is 0.655, between BD-I vs BD-II is 0.573. These AUCs are relatively low accuracy. I also think “predictor, predictive factor” is overstatement. Authors have to mention this point.

Response:

We apologize for using this overstatement. We also think that it is difficult for clinicians to predict the diagnosis of MDD, BD-I, and BD-II by only TEMPS-A, owing to their relatively lower AUC values. As mentioned in our answer to comment 8, we toned down our statement in the revised manuscript. However, we believe that subscores on the TEMPS-A may play a supplementary role in the differential diagnoses of mood disorders. In other words, utilizing TEMPS-A with other factors may help clinicians to differentiate between the diagnosis of MDD, BD-I, and BD-II.

Comment 10: There are a few repetitions in the text. The paper could be improved by further editing.

Response:

We apologize for this point. We reread the manuscript and deleted the repetitions.

Reviewer #3

Comment 1: There is a lack of detail about the data collection instrument. The PHQ-9 questionaire should be further described.

Response:

We apologize for our insufficient explanation. We added the following explanation to the Methods section of the revised manuscript (page 12, lines 159-162).

“The PHQ-9 is a self-reported questionnaire consisting of 9 items on a 4-point Likert scale, used as an index of depressive symptom severity and as a screening test for major depressive episodes. The Japanese version of the PHQ-9 was used in this study.”

Comment 2: What is the reliability and validity of scales used?

Response:

Thank you for pointing this out. To make this point clear, we added an explanation together with 2 references of the scales that were used, to the Methods section, as follows.

“The validity and reliability of TEMPS-A for psychiatric disorders, particularly for mood disorders, was suggested by Akiskal et al. ([7] Akiskal et al., 2005), and the validity and reliability of the Japanese version was also shown by Matsumoto et al. (Matsumoto et al., 2005).” (page 12, lines 148-151)

“Some studies suggested that the PHQ-9 yields an index of depressive symptom severity and has diagnostic validity, and also validates the Japanese version of the PHQ-9 (Muramatsu et al., 2007; Spitzer et al., 1999; [23] Muramatsu et al., 2018).” (page 12, line 162 to page 13, line 164)

“The construct validity and reliability of YMRS was demonstrated by Young et al. (Young et al., 1978).” (page 13, lines 168-169)

Furthermore, the following 2 references were added to the References section.

[7] Akiskal HS, Akiskal KK, Haykal RF, Manning JS, Connor PD. TEMPS-A: progress towards validation of a self-rated clinical version of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire. J Affect Disord. 2005;85(1-2):3-16. https://doi.org/10.1016/j.jad.2004.12.001. PMID: 15780671.

[23] Muramatsu K, Miyaoka H, Kamijima K, Muramatsu Y, Tanaka Y, Hosaka M, et al. Performance of the Japanese version of the Patient Health Questionnaire-9 (J-PHQ-9) for depression in primary care. Gen Hosp Psychiatry. 2018;52:64-9. https://doi.org/10.1016/j.genhosppsych.2018.03.007. PMID: 29698880.

Comment 3: The sample size was 346, 157 outpatients and 189 inpatients. How was it determined? Which is the method was used to recruit the sample? What are the eligibility criteria of the study sample?

Response:

We apologize that we did not adequately explain about our sample. As mentioned in our responses to the Comments 5 and 6 by Reviewer #2 partly, we added the following explanations to the Methods section.

“Approximately 70 or more subjects for each disorder group were required for our analyses, because we planned to conduct multivariate logistic regression analyses including 7 factors as independent variables.” (page 9, lines 113-115)

“The inclusion criteria of the patients were as follows: (1) a principal diagnosis of MDD, BD-I, or BD-II according to the DSM-Ⅳ-TR criteria; (2) 20 years of age or older; (3) the ability to complete the self-reported questionnaires; and (4) the ability to provide written informed consent. The exclusion criteria were as follows: (1) having serious physical or mental symptoms that hinder the completion of the self-reported questionnaires; (2) having organic mental disorders or a previous history of them; (3) meeting the diagnostic criteria of substance-use disorders; and (4) having a diagnosis of axis II according to the DSM-Ⅳ-TR criteria. Patients meeting the eligibility criteria were informed about our research by their doctors in charge, and those who gave written consent were included in the study. The sample might not be a nationally representative sample, as the sample was limited to a convenience sample, and consisted of only patients who received treatment at general or university hospitals in specific parts of Japan. In other words, the sample did not include patients who received treatment at psychiatric hospitals or clinics.” (page 9, line 123 to page 10, line 136)

Comment 4: The demographic data and the clinical characteristic should be present in method section (subject), not in results section.

Response:

In accordance with this comment, we moved the demographic data and the clinical characteristics (Table 1) to the Methods section of our revised manuscript (page10, line140 to page 11, line 144). The statistical results of these data were shown in the Results section.

Comment 5: Is the investigated group homogenous? What was the period of the illness (acute, partial remission) and the intensity of affective symptoms during the research procedure?

Response:

Thank you for your suggestion. The investigated group was not homogenous. To explain the investigated group more clearly, we added the following description to the Discussion section (page20, line 275 to page 21, line 283) and Table S4 of the revised manuscript.

“The periods of the illness of the subjects were various. As shown in Table S4, approximately 30% of the patients in each disease group were in remission. From a perspective of the impact of affective symptoms on the questionnaire answers (Baba et al., 2014), it is preferable that all subjects are in euthymic state when answering the questionnaires. However, we aimed to verify whether TEMPS-A was useful for the differential diagnosis of mood disorders in real-world clinical settings, and therefore, we included patients with various symptom severity. Moreover, we performed multivariate logistic regression analyses including the severity of mood symptoms and 5 affective temperaments as independent variables, considering the impact of them on TEMPS-A.”

Comment 6: What was the current medication received by patients? Did authors observed differences in dosage of the drugs received by inpatients and outpatients?

Response:

Most patients used several types of psychotropics, but we did not investigate their use of medication in this study. We would hence like to investigate this point in the future.

Comment 7: In discussion - consider adding more recommendations for practice.

Response:

In accordance with the suggestion, we added more recommendations, with 2 references to the Discussion section, as follows (page 20, lines 266-274).

“Affective temperament is a concept proposed by Akiskal and his colleagues. They described that temperaments are more than just forme frustes of mood disorders and temperamental dysregulation is present in the subclinical stages, before patients experience mood episodes ([25] Akiskal and Mallya, 1987; [26] Akiskal et al., 1995). Based on their descriptions and our present results, our findings may indicate that clinicians should keep in mind the possibility that MDD patients with high cyclothymic and low anxious scores on TEMPS-A may subsequently have manic/hypomanic episodes, and BD-II patients with a high hyperthymic temperament score may have manic episodes. We believe that this diagnostic conversion should be kept in mind clinically, although we should verify the role of affective temperaments prospectively.”

Furthermore, the following references were added to the References section.

[25] Akiskal HS, Mallya G. Criteria for the "soft" bipolar spectrum: treatment implications. Psychopharmacol Bull. 1987;23(1):68-73. PMID: 3602332.

[26] Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Keller M, et al. Switching from 'unipolar' to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry. 1995;52(2):114-23. https://doi.org/10.1001/archpsyc.1995.03950140032004. PMID: 7848047.

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16 Apr 2020

Utility of TEMPS-A in differentiation between major depressive disorder, bipolar I disorder, and bipolar II disorder

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Reviewer #3: The article was corrected in line with the reviewer's comments. The study group is not homogeneous, which is a serious limitation of the study, however the authors characterized the study group much better than before. After revision, the article meets the publication criteria in PlosOne.

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13 May 2020

PONE-D-20-02514R1

Utility of TEMPS-A in differentiation between major depressive disorder, bipolar I disorder, and bipolar II disorder

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