A Preliminary Cross-Sectional Study of Bipolarity and Primary Pharmacotherapy in Long-Term Stable Patients with Major Depressive Disorder

A Preliminary Cross-Sectional Study of Bipolarity and Primary Pharmacotherapy in Long-Term Stable Patients with Major Depressive Disorder | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Preliminary Cross-Sectional Study of Bipolarity and Primary Pharmacotherapy in Long-Term Stable Patients with Major Depressive Disorder Taku Maruki, Takashi Tsuboi, Hitoshi Maeshima, Yasuyuki Matsumoto, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8946679/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Patients with major depressive disorder (MDD) who exhibit high bipolarity are at increased risk of future diagnostic conversion to bipolar disorder. However, treatment recommendations for MDD with bipolarity are constrained by limited direct evidence. We examined the association between bipolarity and primary pharmacotherapy in long-term stable outpatients with MDD and explored a clinically useful Bipolarity Index (BI) threshold. Methods In this two-center cross-sectional study, participants were classified into an antidepressant (AD) group or a mood stabilizer/second-generation antipsychotic (MS/SGA) group. Bipolarity was assessed with the BI. Receiver operating characteristic (ROC) analysis was used to identify a BI cutoff discriminating MS/SGA from AD. Results Of 106 participants, 57 were assigned to the AD group and 49 to the MS/SGA group. The BI score was significantly higher in the MS/SGA group than in the AD group (24.1 ± 12.9 vs 13.3 ± 6.9; p < 0.001). ROC analysis indicated a BI cutoff of 16 (Area Under the Curve = 0.768), yielding 69.4% sensitivity and 78.9% specificity for identifying the MS/SGA group. Conclusion Among long-term stable MDD outpatients, higher BI scores were associated with MS and/or SGA rather than antidepressant monotherapy as primary pharmacotherapy. A BI total score ≥ 16 may serve as a pragmatic threshold for identifying MDD patients with multiple bipolarity features who are more likely to receive MS and/or SGA. Prospective studies are warranted to test whether BI-guided pharmacotherapy improves outcomes and clarifies the role of MS and/or SGA in MDD patient with high bipolarity. Major depressive disorder Bipolar disorder Bipolarity Bipolarity Index Mood stabilizer Second-generation antipsychotic pharmacotherapy Figures Figure 1 1. Introduction Approximately one-third of patients with major depressive disorder (MDD) develop treatment-resistant depression (TRD) despite standard therapies such as antidepressants. 1 One explanation highlights limitations of current DSM/ICD-based operational criteria: patients presenting with depressive episodes but without (hypo)mania are initially diagnosed with MDD, and a proportion subsequently meet criteria for bipolar disorder (BD). 2 – 5 About two-thirds of individuals with BD present with a depressive episode at illness onset, and when the illness begins with a depressive episode, the cumulative time spent in depressive states exceeds that spent in manic states across the lifespan. 6 , 7 Thus, an initial MDD label often persists until (hypo)mania emerges, with recognition of BD sometimes delayed by a decade or more. 8,9 During this interval, antidepressants—agents not generally recommended as monotherapy for bipolar depression— are commonly prescribed, which may contribute to poor response, treatment resistance, and increased risks of manic/hypomanic switching and suicide. 10 – 12 To address this challenge, several studies have evaluated bipolarity in patients diagnosed with MDD as a means to predict the risk of later diagnostic transition to BD. 13–17 In this context, bipolarity denotes clinical characteristics in MDD associated with such transition risk, commonly including early onset of depression, family history of BD, mixed features, recurrent depressive episodes, cyclothymic temperament, and a history of suicide attempts. However, even if the likelihood of diagnostic transition can be predicted, evidence remains limited regarding optimal pharmacotherapy for MDD patients with high bipolarity. For example, some treatment guidelines recommend pharmacotherapy aligned with bipolar depression such as mood stabilizers (MS) and second-generation antipsychotics (SGA) for MDD with mixed features, yet the supporting data largely derive from studies of bipolar depression with mixed features rather than from cohorts strictly diagnosed with MDD. 10 , 18 , 19 As a result, treatment recommendations for MDD with prominent bipolarity are constrained by a paucity of direct evidence, underscoring the need for studies that specifically examine pharmacotherapy for patients with MDD who exhibit high bipolarity but have not (yet) met criteria for BD. The aim of this study was to investigate the relationship between primary pharmacotherapy and bipolarity in patients with long-term stable MDD. We hypothesized that patients with lower bipolarity would be more likely to be treated with antidepressants alone, whereas those with higher bipolarity would be more likely to receive MS or SGA, with or without antidepressants. To that end, we sought to explore pharmacological strategies for MDD patients at elevated risk of future diagnostic conversion to BD. 2. Methods 2.1. Design and setting This two-center cross-sectional study was conducted from June 2022 to April 2024 at the Department of Neuropsychiatry, Kyorin University Hospital (Tokyo, Japan), and the Department of Psychiatry, Juntendo Koshigaya Hospital (Saitama, Japan). The study protocol was approved by the School of Medicine Research Ethics Committee, Kyorin University (R04-003-05) and the Reserch Ethics Committee, Faculty of Medicine, Juntendo University (E22-0225). The study adhered to the Declaration of Helsinki and its later amendments and to Japan’s Ethical Guidelines for Medical and Biological Research Involving Human Subjects. Written informed consent was obtained from all participants prior to enrollment after a full explanation of the study procedures. 2.2. Participants Eligible participants met the following criteria: (1) consecutive outpatients aged 18–65 years; (2) a DSM-5 diagnosis of MDD; and (3) no changes in the primary antidepressant, MS, or SGA for ≥ 6 months prior to enrollment (dose reduction permitted). Patients meeting criterion (3) were defined as having “long-term stable MDD”. Exclusion criteria were dementia (major neurocognitive disorder), current psychotic symptoms, alcohol- or substance-use disorder, and severe physical illness. 2.3. Procedures Participants completed the Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR) and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego–Auto Questionnaire (TEMPS-A). We also assessed the Bipolarity Index (BI) for each participant. The QIDS-SR is a widely recognized self-report questionnaire of depressive symptom severity. 20 It consists 16 items assessing nine symptom domains (sleep, sad mood, appetite/weight, concentration/decision making, self-view, suicidal ideation, general interest, energy/fatigue, and psychomotor changes); items are rated on a 4-point scale (0 = none, 3 = severe) with a total score of 0–27. Conventional severity bands are: no depression (0–5), mild (6–10), moderate (11–15), severe (16–20), and very severe (≥ 21). The TEMPS-A is a 110-item yes/no self-report questionnaire that evaluates five affective temperaments—depressive, cyclothymic, hyperthymic, irritable, and anxious. 21 Several studies have supported its utility in differentiating MDD from BD. 22–24 The BI is a clinician-rated tool designed to quantify manic/hypomanic factors and support the diagnosis of BD. 25–27 It has demonstrated high diagnostic accuracy. 28 The BI comprises five domains: (I) episode characteristics, (II) age of onset, (III) course of illness and associated features, (IV) response to treatment, and (V) family history. Each domain is scored 0–20, yielding a total score of 0-100; higher scores indicate greater bipolar features. Current psychotropic medications were abstracted from medical records and confirmed with patients. Participants were then classified into two groups based on primary pharmacotherapy: the AD group, treated with antidepressants alone, and the MS/SGA group, treated with MS or SGA (with or without concomitant antidepressants). Patients with MDD who were not receiving pharmacotherapy at the time of assessment were classified into the AD group by design to retain a comparator reflecting absence of MS/SGA exposure. Associations between pharmacotherapy and BI scores were analyzed as described below. The primary outcome was the BI score; secondary outcomes were the BI cutoff value and TEMPS-A scores in both groups. 2.4. Data analysis Continuous variables were compared using two-sided t tests, and dichotomous variables were compared using χ² tests or Fisher's exact test. Statically significance was set at p value of < 0.05 (two-sided) was considered statistically significant. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff of the BI total scores for discriminating the MS/SGA group from the AD group. The area under the curve (AUC) was calculated to assess discrimination, with AUC values of 0.7–0.8, 0.8–0.9, and 0.9–1.0 interpreted as acceptable, high, and excellent accuracy, respectively. 29 The Youden index (J = sensitivity + specificity − 1) was applied to identify the optimal cutoff value, representing the point with the highest combined sensitivity and specificity. All analyses were performed using IBM SPSS Statistics, version 29.0 (IBM Corp., Armonk, NY, USA). 3. Results 3.1. Participant characteristics A total of 106 participants (50 male and 56 female) were enrolled, and none withdrew consent. Of these, 57 were classified into the AD group and 49 into the MS/SGA group. The mean age was similar between groups (48.1 ± 11.0 years in the AD group vs 48.0 ± 12.6 years in the MS/SGA group). There were significant differences in age at onset (40.5 ± 9.4 years in the AD group vs 34.2 ± 10.8 years in the MS/SGA group, p = 0.002) and in QIDS-SR scores (6.8 ± 4.6 in the AD group vs 9.1 ± 5.7 in the MS/SGA group, p = 0.020). No other significant between-group differences were observed. Regarding pharmacotherapy, lithium, aripiprazole, and quetiapine were prescribed more frequently in the MS/SGA group. Participant characteristics are summarized in Table 1 . Table 1 Participants Characteristics AD ( n = 57) MS/SGA ( n = 49) P value Female 28 (49.1) 28 (57.1) 0.410 Age (y) 48.1 ± 11.0 48.0 ± 12.6 0.958 Onset age (y) * 40.5 ± 9.4 34.2 ± 10.8 0.002 Married 38 (66.7) 28 (57.1) 0.313 Bachelor’s Degree 40 (70.2) 28 (57.1) 0.163 Employee 40 (70.2) 30 (61.2) 0.332 QIDS-SR* 6.8 ± 4.6 9.1 ± 5.7* 0.020 Pharmacotherapy Antidepressants 54 (94.7) 37 (75.5) 0.05 SSRI 23 (40.4) 11 (22.4) 0.061 SNRI 10 (17.5) 14 (28.6) 0.245 Mirtazapine 17 (29.8) 9 (18.4) 0.184 TCA 3 (5.3) 3 (6.1) 1.00 Others 2 (3.5) 3 (6.1) MS 0 (0) 19 (38.8) Lithium 0 (0) 11 (22.4) Lamotrigine 0 (0) 6 (12.2) Valproic acid 0 (0) 4 (8.2) Other 0 (0) 1 (2.0) SGA 0 (0) 31 (63.3) Aripiprazole 0 (0) 19 (38.8) Quetiapine 0 (0) 13 (26.5) Olanzapine 0 (0) 5 (10.2) Lurasidone 0 (0) 3 (6.1) Others 0 (0) 4 (8.2) Hypnotics 10 (17.5) 15 (30.6) 0.168 Anxiolytics 6 (10.5) 11 (22.4) 0.116 * p < 0.05 Statistical analyses were performed using t-tests for continuous variables and chi-square tests or Fisher's exact test for dichotomous variables. Continuous variables are expressed as mean ± standard deviations (SDs). Dichotomous variables are indicated as n (%). Only medications prescribed to more than 5% of participants were reported. AD, antidepressants; MS, mood stabilizers; SGA, second-generation antipsychotics; TCA, tricyclic antidepressant; QIDS-SR, Quick Inventory of Depressive Symptomatology Self-Report. 3.2. BI score The mean BI total score was significantly higher in the MS/SGA group than in the AD group (24.1 ± 12.9 vs 13.3 ± 6.9; p < 0.001). By domain, the MS/SGA group showed higher scores on episode characteristics, age of onset, course of illness and associated features, and response to treatment (all p < 0.001) with no significant difference in family history (Table 2 ). Table 2 Comparison of Bipolarity Index Subscales between AD and MS/SGA groups AD ( n = 57) MS/SGA ( n = 49) P value BI (total score) * 13.3 ± 6.9 24.1 ± 12.9 < 0.001 Ⅰ: Episode Characteristics* 0.8 ± 1.6 2.8 ± 3.5 < 0.001 Ⅱ: Age of Onset* 9.1 ± 3.4 11.9 ± 3.9 < 0.001 Ⅲ: Course of Illness & Associated Features* 1.1 ± 2.5 2.9 ± 2.5 < 0.001 Ⅳ: Response to Treatment* 0.4 ± 1.4 3.9 ± 5.0 < 0.001 Ⅴ: Family History 1.0 ± 3.5 2.7 ± 6.2 0.088 * p < 0.05 Statistical analyses were performed using t-tests for continuous variables and chi-square tests for dichotomous variables. Continuous variables are expressed as mean ± standard deviations (SDs). Dichotomous variables are indicated as n (%). AD, antidepressants; BI, bipolarity index; MS, mood stabilizers; SGA, second-generation antipsychotics. 3.3. BI cutoff for identifying MS/SGA group The AUC for discriminating the MS/SGA group from the AD group using BI total score was 0.768 (95% CI, 0.67–0.862), indicating acceptable discrimination (Fig. 1 ). The Youden index identified 16 as the optimal cutoff, yielding 69.4% sensitivity and 78.9% specificity (Table 3 ). Accordingly, a BI total score ≥ 16 best identified patients in the MS/SGA group. Receiver Operating Characteristic (ROC) analysis was utilized to determine the optimal cutoff values between the two groups. Table 3 Cutoff values of the Bipolarity Index score for identifying patients receiving AD vs MS/SGA treatment Cutoff score Sensitivity Specificity Youden index 15/16 0.78 0.61 0.39 16/17 0.69 0.79 0.48 17/18 0.69 0.79 0.48 AD, antidepressants; MS, mood stabilizers; SGA, second-generation antipsychotics. 3.4. TEMPS-A There were no significant between-group differences on any TEMPS-A subscale (Table 4 ). Table 4 Comparison of TEMPS-A between AD and MS/SGA groups AD ( n = 57) MS/SGA ( n = 49) P value Depressive 43 (75) 37 (76) 0.993 Cyclothymic 30 (53) 34 (69) 0.079 Hyperthymic 12 (21) 15 (31) 0.260 Irritable 21 (37) 26 (53) 0.094 Anxious 28 (49) 32 (65) 0.094 Statistical analyses were performed using chi-square tests. Dichotomous variables are indicated as n (%). AD, antidepressants; MS, mood stabilizers; SGA, second-generation antipsychotics; TEMPS-A, the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego–Auto Questionnaire. 4. Discussion In a cohort of long-term stable outpatients with MDD, higher bipolarity as indexed by the BI was associated with receipt of MS and/or SGA as primary pharmacotherapy. ROC analysis suggested that a BI total score ≥ 16 differentiated the MS/SGA group from the AD group with acceptable discrimination (AUC = 0.768), indicating a potentially useful clinical threshold. These observations align with treatment guidelines that recommend avoiding antidepressant monotherapy and supporting MS or SGA in MDD with mixed features. 10,19 In the context of prior work focused on mixed features, our findings suggest a similar association across additional bipolarity characteristics captured by the BI. Whereas most previous studies focused primarily on mixed features, our BI-based approach integrates multiple validators within MDD, thereby broadening the clinical context for treatment selection. Prior reports have shown that cyclothymic and hyperthymic temperaments on the TEMPS-A can distinguish between MDD and bipolar disorder. 22–24 In our MDD-only cohort stratified by bipolarity level, however, no between-group differences were observed on TEMPS-A subscales. This discrepancy may reflect range restriction from excluding BD and the looser alignment between trait-like temperaments and the BI’s clinician-rated validators within an MDD sample. Several pharmacologic properties may help explain preferential selection of agents in the MS/SGA group among patients with higher BI scores. Aripiprazole—most used in the MS/SGA group in this study—exhibits D₂/5-HT₁A partial agonism and 5-HT₂A antagonism, a profile congruent with its adjunctive antidepressant signal in prior trials. 30 The antidepressant effect of quetiapine has been explained by its active metabolite, N-desalkylquetiapine, which acts as a potent norepinephrine reuptake inhibitor and a partial serotonin 5-HT₁A receptor agonist. 31 Lithium has been reported to exert antidepressant effects through enhancement of central serotonergic activity. 32 While speculative, these mechanisms are compatible with the BI-based gradient we observed and may inform pharmacotherapy considerations in patients exhibiting multiple bipolarity features. If replicated, BI ≥ 16 could serve as a pragmatic cue when considering MS/SGA in MDD patients exhibiting multiple bipolarity features. Strengths include a prespecified definition of long-term stability, two-center recruitment, and use of standardized instruments (QIDS-SR, TEMPS-A, BI). The finding that most BI subdomains—except family history—differed between groups, albeit with modest mean differences, supports the notion that cumulative rather than single features may guide real-world prescribing. This favors a comprehensive, measurement-based evaluation of bipolarity in routine care 33 . This study has several limitations. First, the cross-sectional design in a long-term stable outpatient sample precludes causal claims about medication effectiveness and may not generalize to acute or recurrent phases. Second, confounding by indication is likely: clinicians may preferentially prescribe MS/SGA to patients with higher bipolarity, producing the observed association. Third, group assignment rules (classifying medication-free patients into the AD group) and modest sample size may influence estimates. Fourth, family history effects might be underestimated if such cases were underrepresented among stable outpatients. 34 Fifth, all participants were recruited in Japan; generalizability may vary with health-system context and drug availability. Finally, BI is a clinician-rated composite reflecting validators rather than a diagnosis; measurement error and rater effects are possible. In conclusion, among long-term stable MDD outpatients, higher BI scores were associated with MS and/or SGA rather than antidepressant as primary pharmacotherapy. A BI total score of ≥ 16 emerged as a clinically useful threshold for identifying patients more likely to receive MS and/or SGA. Prospective studies should test whether BI-guided pharmacotherapy improves outcomes and clarifies the role of MS and/or SGA in MDD patients at elevated risk of future diagnostic conversion to BD. Abbreviations AD Antidepressants AUC Area under the curve BD Bipolar disorder BI Bipolarity Index CI Confidence interval DSM Diagnostic and Statistical Manual of Mental Disorders DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ICD International Classification of Diseases MDD Major depressive disorder MS Mood stabilizers QIDS-SR Quick Inventory of Depressive Symptomatology–Self Report ROC Receiver operating characteristic SGA Second-generation antipsychotics SPSS Statistical Package for the Social Sciences TCA Tricyclic antidepressants TEMPS-A Temperament Evaluation of Memphis, Pisa, Paris, and San Diego–Auto Questionnaire TRD Treatment-resistant depression Declarations Ethics approval and consent to participate The study protocol was approved by the School of Medicine Research Ethics Committee, Kyorin University (R04-003-05) and the Reserch Ethics Committee, Faculty of Medicine, Juntendo University (E22-0225). All procedures complied with relevant local legislation and institutional guidelines. Written informed consent was obtained from all participants prior to their enrollment in this study. Consent for publication Not applicable. Competing interests TM and Teruo Tada declared no conflicts of interest. Authors' information a Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan b Department of Psychiatry, Shizuoka hospital, Juntendo University School of Medicine, Shizuoka, Japan. Funding This work was supported by MEXT KAKENHI Grant Numbe JP 22K15792. Author Contribution TM: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing.Takashi Tsuboi: Conceptualization, Methodology, Investigation, Data curation, Supervision, Writing – review & editing.HM: Conceptualization, Methodology, Investigation, Data curation, Writing – review & editing.YM: Conceptualization, Investigation, Writing – review & editing.Teruo Tada: Investigation, Data curation, Writing – review & editing.KW: Supervision, Writing – review & editing. Acknowledgements We used DeepL and ChatGPT to assist with English writing and editing of the manuscript; the authors are responsible for the final content. Data Availability The raw data supporting the conclusions of this article will be made available by the authors upon reasonable request. References Rush AJ, Trivedi MH, Wisniewski SR, et al. 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Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 Mar, 2026 Reviews received at journal 15 Mar, 2026 Reviewers agreed at journal 11 Mar, 2026 Reviews received at journal 11 Mar, 2026 Reviewers agreed at journal 09 Mar, 2026 Reviewers agreed at journal 09 Mar, 2026 Reviewers invited by journal 09 Mar, 2026 Editor assigned by journal 24 Feb, 2026 Submission checks completed at journal 24 Feb, 2026 First submitted to journal 23 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8946679","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":604651892,"identity":"e1d7c140-fe09-491a-a7a4-b4b17daa3a47","order_by":0,"name":"Taku Maruki","email":"","orcid":"","institution":"Department of Neuropsychiatry, Kyorin University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Taku","middleName":"","lastName":"Maruki","suffix":""},{"id":604651894,"identity":"e39337fc-71b7-4229-9b4c-d73094313b88","order_by":1,"name":"Takashi Tsuboi","email":"data:image/png;base64,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","orcid":"","institution":"Department of Neuropsychiatry, Kyorin University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Tsuboi","suffix":""},{"id":604651895,"identity":"affda53c-4d5c-4e1b-97f4-adaf4909e2bd","order_by":2,"name":"Hitoshi Maeshima","email":"","orcid":"","institution":"Department of Psychiatry, Shizuoka hospital, Juntendo University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Maeshima","suffix":""},{"id":604651898,"identity":"1cab7ce9-f4c6-42a7-8d41-b6853c490823","order_by":3,"name":"Yasuyuki Matsumoto","email":"","orcid":"","institution":"Department of Neuropsychiatry, Kyorin University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yasuyuki","middleName":"","lastName":"Matsumoto","suffix":""},{"id":604651899,"identity":"b5fead7e-efa9-49cd-b5c0-c3fefa58f244","order_by":4,"name":"Teruo Tada","email":"","orcid":"","institution":"Department of Neuropsychiatry, Kyorin University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Teruo","middleName":"","lastName":"Tada","suffix":""},{"id":604651901,"identity":"b4e7a827-ec3f-4e75-93cf-61717e08678a","order_by":5,"name":"Koichiro Watanabe","email":"","orcid":"","institution":"Department of Neuropsychiatry, Kyorin University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Koichiro","middleName":"","lastName":"Watanabe","suffix":""}],"badges":[],"createdAt":"2026-02-23 11:43:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8946679/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8946679/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104582312,"identity":"79c344ce-f8a4-487e-9067-59dff7ebca6c","added_by":"auto","created_at":"2026-03-13 15:12:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":283328,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROC curve\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReceiver Operating Characteristic (ROC) analysis was utilized to determine the optimal cutoff values between the two groups.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8946679/v1/200e4146298c3eaea238a3b1.png"},{"id":104582417,"identity":"0cfda666-34ac-4ed2-a698-8ec93cc321d2","added_by":"auto","created_at":"2026-03-13 15:12:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":974884,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8946679/v1/58d54128-3aac-48cd-b98f-c9576c1ff92d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Preliminary Cross-Sectional Study of Bipolarity and Primary Pharmacotherapy in Long-Term Stable Patients with Major Depressive Disorder","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eApproximately one-third of patients with major depressive disorder (MDD) develop treatment-resistant depression (TRD) despite standard therapies such as antidepressants.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e One explanation highlights limitations of current DSM/ICD-based operational criteria: patients presenting with depressive episodes but without (hypo)mania are initially diagnosed with MDD, and a proportion subsequently meet criteria for bipolar disorder (BD).\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e About two-thirds of individuals with BD present with a depressive episode at illness onset, and when the illness begins with a depressive episode, the cumulative time spent in depressive states exceeds that spent in manic states across the lifespan.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Thus, an initial MDD label often persists until (hypo)mania emerges, with recognition of BD sometimes delayed by a decade or more. \u003csup\u003e8,9\u003c/sup\u003e During this interval, antidepressants\u0026mdash;agents not generally recommended as monotherapy for bipolar depression\u0026mdash; are commonly prescribed, which may contribute to poor response, treatment resistance, and increased risks of manic/hypomanic switching and suicide.\u003csup\u003e\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTo address this challenge, several studies have evaluated bipolarity in patients diagnosed with MDD as a means to predict the risk of later diagnostic transition to BD. \u003csup\u003e13\u0026ndash;17\u003c/sup\u003e In this context, bipolarity denotes clinical characteristics in MDD associated with such transition risk, commonly including early onset of depression, family history of BD, mixed features, recurrent depressive episodes, cyclothymic temperament, and a history of suicide attempts.\u003c/p\u003e \u003cp\u003eHowever, even if the likelihood of diagnostic transition can be predicted, evidence remains limited regarding optimal pharmacotherapy for MDD patients with high bipolarity. For example, some treatment guidelines recommend pharmacotherapy aligned with bipolar depression such as mood stabilizers (MS) and second-generation antipsychotics (SGA) for MDD with mixed features, yet the supporting data largely derive from studies of bipolar depression with mixed features rather than from cohorts strictly diagnosed with MDD.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e As a result, treatment recommendations for MDD with prominent bipolarity are constrained by a paucity of direct evidence, underscoring the need for studies that specifically examine pharmacotherapy for patients with MDD who exhibit high bipolarity but have not (yet) met criteria for BD.\u003c/p\u003e \u003cp\u003eThe aim of this study was to investigate the relationship between primary pharmacotherapy and bipolarity in patients with long-term stable MDD. We hypothesized that patients with lower bipolarity would be more likely to be treated with antidepressants alone, whereas those with higher bipolarity would be more likely to receive MS or SGA, with or without antidepressants. To that end, we sought to explore pharmacological strategies for MDD patients at elevated risk of future diagnostic conversion to BD.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Design and setting\u003c/h2\u003e \u003cp\u003eThis two-center cross-sectional study was conducted from June 2022 to April 2024 at the Department of Neuropsychiatry, Kyorin University Hospital (Tokyo, Japan), and the Department of Psychiatry, Juntendo Koshigaya Hospital (Saitama, Japan). The study protocol was approved by the School of Medicine Research Ethics Committee, Kyorin University (R04-003-05) and the Reserch Ethics Committee, Faculty of Medicine, Juntendo University (E22-0225). The study adhered to the Declaration of Helsinki and its later amendments and to Japan\u0026rsquo;s Ethical Guidelines for Medical and Biological Research Involving Human Subjects. Written informed consent was obtained from all participants prior to enrollment after a full explanation of the study procedures.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Participants\u003c/h2\u003e \u003cp\u003eEligible participants met the following criteria: (1) consecutive outpatients aged 18\u0026ndash;65 years; (2) a DSM-5 diagnosis of MDD; and (3) no changes in the primary antidepressant, MS, or SGA for \u0026ge;\u0026thinsp;6 months prior to enrollment (dose reduction permitted). Patients meeting criterion (3) were defined as having \u0026ldquo;long-term stable MDD\u0026rdquo;. Exclusion criteria were dementia (major neurocognitive disorder), current psychotic symptoms, alcohol- or substance-use disorder, and severe physical illness.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Procedures\u003c/h2\u003e \u003cp\u003eParticipants completed the Quick Inventory of Depressive Symptomatology\u0026ndash;Self Report (QIDS-SR) and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego\u0026ndash;Auto Questionnaire (TEMPS-A). We also assessed the Bipolarity Index (BI) for each participant.\u003c/p\u003e \u003cp\u003eThe QIDS-SR is a widely recognized self-report questionnaire of depressive symptom severity.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e It consists 16 items assessing nine symptom domains (sleep, sad mood, appetite/weight, concentration/decision making, self-view, suicidal ideation, general interest, energy/fatigue, and psychomotor changes); items are rated on a 4-point scale (0\u0026thinsp;=\u0026thinsp;none, 3\u0026thinsp;=\u0026thinsp;severe) with a total score of 0\u0026ndash;27. Conventional severity bands are: no depression (0\u0026ndash;5), mild (6\u0026ndash;10), moderate (11\u0026ndash;15), severe (16\u0026ndash;20), and very severe (\u0026ge;\u0026thinsp;21).\u003c/p\u003e \u003cp\u003eThe TEMPS-A is a 110-item yes/no self-report questionnaire that evaluates five affective temperaments\u0026mdash;depressive, cyclothymic, hyperthymic, irritable, and anxious.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Several studies have supported its utility in differentiating MDD from BD.\u003csup\u003e22\u0026ndash;24\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe BI is a clinician-rated tool designed to quantify manic/hypomanic factors and support the diagnosis of BD.\u003csup\u003e25\u0026ndash;27\u003c/sup\u003e It has demonstrated high diagnostic accuracy.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e The BI comprises five domains: (I) episode characteristics, (II) age of onset, (III) course of illness and associated features, (IV) response to treatment, and (V) family history. Each domain is scored 0\u0026ndash;20, yielding a total score of 0-100; higher scores indicate greater bipolar features.\u003c/p\u003e \u003cp\u003eCurrent psychotropic medications were abstracted from medical records and confirmed with patients. Participants were then classified into two groups based on primary pharmacotherapy: the AD group, treated with antidepressants alone, and the MS/SGA group, treated with MS or SGA (with or without concomitant antidepressants). Patients with MDD who were not receiving pharmacotherapy at the time of assessment were classified into the AD group by design to retain a comparator reflecting absence of MS/SGA exposure. Associations between pharmacotherapy and BI scores were analyzed as described below. The primary outcome was the BI score; secondary outcomes were the BI cutoff value and TEMPS-A scores in both groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Data analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were compared using two-sided t tests, and dichotomous variables were compared using χ\u0026sup2; tests or Fisher's exact test. Statically significance was set at p value of \u0026lt;\u0026thinsp;0.05 (two-sided) was considered statistically significant. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff of the BI total scores for discriminating the MS/SGA group from the AD group. The area under the curve (AUC) was calculated to assess discrimination, with AUC values of 0.7\u0026ndash;0.8, 0.8\u0026ndash;0.9, and 0.9\u0026ndash;1.0 interpreted as acceptable, high, and excellent accuracy, respectively.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e The Youden index (J\u0026thinsp;=\u0026thinsp;sensitivity\u0026thinsp;+\u0026thinsp;specificity\u0026thinsp;\u0026minus;\u0026thinsp;1) was applied to identify the optimal cutoff value, representing the point with the highest combined sensitivity and specificity. All analyses were performed using IBM SPSS Statistics, version 29.0 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Participant characteristics\u003c/h2\u003e \u003cp\u003e A total of 106 participants (50 male and 56 female) were enrolled, and none withdrew consent. Of these, 57 were classified into the AD group and 49 into the MS/SGA group. The mean age was similar between groups (48.1\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0 years in the AD group vs 48.0\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6 years in the MS/SGA group). There were significant differences in age at onset (40.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4 years in the AD group vs 34.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8 years in the MS/SGA group, p\u0026thinsp;=\u0026thinsp;0.002) and in QIDS-SR scores (6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6 in the AD group vs 9.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7 in the MS/SGA group, p\u0026thinsp;=\u0026thinsp;0.020). No other significant between-group differences were observed. Regarding pharmacotherapy, lithium, aripiprazole, and quetiapine were prescribed more frequently in the MS/SGA group. Participant characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eParticipants Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAD (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMS/SGA (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (49.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.410\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48.1\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.0\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.958\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnset age (y) *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.313\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBachelor\u0026rsquo;s Degree\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (70.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.163\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmployee\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (70.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30 (61.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.332\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQIDS-SR*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePharmacotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAntidepressants\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (94.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37 (75.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSSRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (40.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (22.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSNRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (17.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.245\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMirtazapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (29.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (18.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.184\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19 (38.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLithium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (22.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLamotrigine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (12.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValproic acid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSGA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31 (63.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAripiprazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19 (38.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQuetiapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (26.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlanzapine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (10.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLurasidone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypnotics\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (17.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (30.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.168\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnxiolytics\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (22.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.116\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eStatistical analyses were performed using t-tests for continuous variables and chi-square tests or Fisher's exact test for dichotomous variables.\u003c/p\u003e \u003cp\u003eContinuous variables are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations (SDs). Dichotomous variables are indicated as n (%).\u003c/p\u003e \u003cp\u003eOnly medications prescribed to more than 5% of participants were reported.\u003c/p\u003e \u003cp\u003eAD, antidepressants; MS, mood stabilizers; SGA, second-generation antipsychotics; TCA, tricyclic antidepressant; QIDS-SR, Quick Inventory of Depressive Symptomatology Self-Report.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2. BI score\u003c/h2\u003e \u003cp\u003eThe mean BI total score was significantly higher in the MS/SGA group than in the AD group (24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9 vs 13.3\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). By domain, the MS/SGA group showed higher scores on episode characteristics, age of onset, course of illness and associated features, and response to treatment (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) with no significant difference in family history (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of Bipolarity Index Subscales between AD and MS/SGA groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAD (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMS/SGA (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBI (total score) *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.3\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅠ: Episode Characteristics*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅡ: Age of Onset*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e11.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅢ: Course of Illness \u0026amp; Associated Features*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅣ: Response to Treatment*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eⅤ: Family History\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.088\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eStatistical analyses were performed using t-tests for continuous variables and chi-square tests for dichotomous variables.\u003c/p\u003e \u003cp\u003eContinuous variables are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations (SDs). Dichotomous variables are indicated as n (%).\u003c/p\u003e \u003cp\u003eAD, antidepressants; BI, bipolarity index; MS, mood stabilizers; SGA, second-generation antipsychotics.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3. BI cutoff for identifying MS/SGA group\u003c/h2\u003e \u003cp\u003eThe AUC for discriminating the MS/SGA group from the AD group using BI total score was 0.768 (95% CI, 0.67\u0026ndash;0.862), indicating acceptable discrimination (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The Youden index identified 16 as the optimal cutoff, yielding 69.4% sensitivity and 78.9% specificity (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Accordingly, a BI total score\u0026thinsp;\u0026ge;\u0026thinsp;16 best identified patients in the MS/SGA group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eReceiver Operating Characteristic (ROC) analysis was utilized to determine the optimal cutoff values between the two groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCutoff values of the Bipolarity Index score for identifying patients receiving AD vs MS/SGA treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCutoff score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSpecificity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYouden index\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15/16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16/17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17/18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAD, antidepressants; MS, mood stabilizers; SGA, second-generation antipsychotics.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4. TEMPS-A\u003c/h2\u003e \u003cp\u003eThere were no significant between-group differences on any TEMPS-A subscale (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of TEMPS-A between AD and MS/SGA groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAD (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMS/SGA (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepressive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyclothymic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.079\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperthymic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.260\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIrritable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnxious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eStatistical analyses were performed using chi-square tests.\u003c/p\u003e \u003cp\u003eDichotomous variables are indicated as \u003cem\u003en\u003c/em\u003e (%).\u003c/p\u003e \u003cp\u003eAD, antidepressants; MS, mood stabilizers; SGA, second-generation antipsychotics; TEMPS-A, the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego\u0026ndash;Auto Questionnaire.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn a cohort of long-term stable outpatients with MDD, higher bipolarity as indexed by the BI was associated with receipt of MS and/or SGA as primary pharmacotherapy. ROC analysis suggested that a BI total score\u0026thinsp;\u0026ge;\u0026thinsp;16 differentiated the MS/SGA group from the AD group with acceptable discrimination (AUC\u0026thinsp;=\u0026thinsp;0.768), indicating a potentially useful clinical threshold.\u003c/p\u003e \u003cp\u003e These observations align with treatment guidelines that recommend avoiding antidepressant monotherapy and supporting MS or SGA in MDD with mixed features. \u003csup\u003e10,19\u003c/sup\u003e In the context of prior work focused on mixed features, our findings suggest a similar association across additional bipolarity characteristics captured by the BI. Whereas most previous studies focused primarily on mixed features, our BI-based approach integrates multiple validators within MDD, thereby broadening the clinical context for treatment selection.\u003c/p\u003e \u003cp\u003ePrior reports have shown that cyclothymic and hyperthymic temperaments on the TEMPS-A can distinguish between MDD and bipolar disorder. \u003csup\u003e22\u0026ndash;24\u003c/sup\u003e In our MDD-only cohort stratified by bipolarity level, however, no between-group differences were observed on TEMPS-A subscales. This discrepancy may reflect range restriction from excluding BD and the looser alignment between trait-like temperaments and the BI\u0026rsquo;s clinician-rated validators within an MDD sample.\u003c/p\u003e \u003cp\u003eSeveral pharmacologic properties may help explain preferential selection of agents in the MS/SGA group among patients with higher BI scores. Aripiprazole\u0026mdash;most used in the MS/SGA group in this study\u0026mdash;exhibits D₂/5-HT₁A partial agonism and 5-HT₂A antagonism, a profile congruent with its adjunctive antidepressant signal in prior trials. \u003csup\u003e30\u003c/sup\u003eThe antidepressant effect of quetiapine has been explained by its active metabolite, N-desalkylquetiapine, which acts as a potent norepinephrine reuptake inhibitor and a partial serotonin 5-HT₁A receptor agonist. \u003csup\u003e31\u003c/sup\u003e Lithium has been reported to exert antidepressant effects through enhancement of central serotonergic activity.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e While speculative, these mechanisms are compatible with the BI-based gradient we observed and may inform pharmacotherapy considerations in patients exhibiting multiple bipolarity features.\u003c/p\u003e \u003cp\u003eIf replicated, BI\u0026thinsp;\u0026ge;\u0026thinsp;16 could serve as a pragmatic cue when considering MS/SGA in MDD patients exhibiting multiple bipolarity features. Strengths include a prespecified definition of long-term stability, two-center recruitment, and use of standardized instruments (QIDS-SR, TEMPS-A, BI). The finding that most BI subdomains\u0026mdash;except family history\u0026mdash;differed between groups, albeit with modest mean differences, supports the notion that cumulative rather than single features may guide real-world prescribing. This favors a comprehensive, measurement-based evaluation of bipolarity in routine care\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the cross-sectional design in a long-term stable outpatient sample precludes causal claims about medication effectiveness and may not generalize to acute or recurrent phases. Second, confounding by indication is likely: clinicians may preferentially prescribe MS/SGA to patients with higher bipolarity, producing the observed association. Third, group assignment rules (classifying medication-free patients into the AD group) and modest sample size may influence estimates. Fourth, family history effects might be underestimated if such cases were underrepresented among stable outpatients.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e Fifth, all participants were recruited in Japan; generalizability may vary with health-system context and drug availability. Finally, BI is a clinician-rated composite reflecting validators rather than a diagnosis; measurement error and rater effects are possible.\u003c/p\u003e \u003cp\u003eIn conclusion, among long-term stable MDD outpatients, higher BI scores were associated with MS and/or SGA rather than antidepressant as primary pharmacotherapy. A BI total score of \u0026ge;\u0026thinsp;16 emerged as a clinically useful threshold for identifying patients more likely to receive MS and/or SGA. Prospective studies should test whether BI-guided pharmacotherapy improves outcomes and clarifies the role of MS and/or SGA in MDD patients at elevated risk of future diagnostic conversion to BD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAntidepressants\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eArea under the curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBipolar disorder\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBipolarity Index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiagnostic and Statistical Manual of Mental Disorders\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSM-5\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiagnostic and Statistical Manual of Mental Disorders, Fifth Edition\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Classification of Diseases\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMDD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMajor depressive disorder\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMood stabilizers\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eQIDS-SR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eQuick Inventory of Depressive Symptomatology\u0026ndash;Self Report\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eReceiver operating characteristic\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSGA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSecond-generation antipsychotics\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSPSS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStatistical Package for the Social Sciences\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTricyclic antidepressants\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTEMPS-A\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTemperament Evaluation of Memphis, Pisa, Paris, and San Diego\u0026ndash;Auto Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTRD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTreatment-resistant depression\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eThe study protocol was approved by the School of Medicine Research Ethics Committee, Kyorin University (R04-003-05) and the Reserch Ethics Committee, Faculty of Medicine, Juntendo University (E22-0225). All procedures complied with relevant local legislation and institutional guidelines. Written informed consent was obtained from all participants prior to their enrollment in this study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eTM and Teruo Tada declared no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eAuthors' information\u003c/h2\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003e Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan\u003c/p\u003e \u003cp\u003e \u003csup\u003eb\u003c/sup\u003e Department of Psychiatry, Shizuoka hospital, Juntendo University School of Medicine, Shizuoka, Japan.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by MEXT KAKENHI Grant Numbe JP 22K15792.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eTM: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing.Takashi Tsuboi: Conceptualization, Methodology, Investigation, Data curation, Supervision, Writing \u0026ndash; review \u0026amp; editing.HM: Conceptualization, Methodology, Investigation, Data curation, Writing \u0026ndash; review \u0026amp; editing.YM: Conceptualization, Investigation, Writing \u0026ndash; review \u0026amp; editing.Teruo Tada: Investigation, Data curation, Writing \u0026ndash; review \u0026amp; editing.KW: Supervision, Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe used DeepL and ChatGPT to assist with English writing and editing of the manuscript; the authors are responsible for the final content.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe raw data supporting the conclusions of this article will be made available by the authors upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharma V, Khan M, Smith A. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord. 2005;84(2\u0026ndash;3):251\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInoue T, Nakagawa S, Kitaichi Y, et al. Long-term outcome of antidepressant-refractory depression: the relevance of unrecognized bipolarity. J Affect Disord. 2006;95(1\u0026ndash;3):61\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi CT, Bai YM, Huang YL, et al. Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study. Br J Psychiatry. 2012;200(1):45\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurao M, Matsumoto Y, Kurihara M, et al. Sociodemographic and clinical characteristics of suspected difficult-to-treat depression. Front Psychiatry. 2024;15:1371242.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaban C, Colom F, Sanchez-Moreno J, Garc\u0026iacute;a-Amador M, Vieta E. Clinical correlates of first-episode polarity in bipolar disorder. Compr Psychiatry. 2006;47(6):433\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBartoli F, Bassetti C, Gazzola M, et al. Prevalence and correlates of manic/hypomanic and depressive predominant polarity in bipolar disorder: systematic review and meta-analysis. BJPsych Open. 2024;10(3):e100.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64(2):161\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKessing LV, Willer I, Andersen PK, Bukh JD. Rate and predictors of conversion from unipolar to bipolar disorder: A systematic review and meta-analysis. Bipolar Disord. 2017;19(5):324\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStahl SM, Morrissette DA, Faedda G, et al. Guidelines for the recognition and management of mixed depression. CNS Spectr. 2017;22(2):203\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYatham LN, Kennedy SH, Parikh SV, 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\u0026ndash;170.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRybakowski JK. Bipolarity and inadequate response to antidepressant drugs: clinical and psychopharmacological perspective. J Affect Disord. 2012;136(1\u0026ndash;2):e13\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInoue T, Inagaki Y, Kimura T, Shirakawa O. Prevalence and predictors of bipolar disorders in patients with a major depressive episode: the Japanese epidemiological trial with latest measure of bipolar disorder (JET-LMBP). J Affect Disord. 2015;174:535\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakeshima M, Oka T. A comprehensive analysis of features that suggest bipolarity in patients with a major depressive episode: which is the best combination to predict soft bipolarity diagnosis? J Affect Disord. 2013;147(1\u0026ndash;3):150\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenazzi F. Intra-episode hypomanic symptoms during major depression and their correlates. Psychiatry Clin Neurosci. 2004;58(3):289\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKiejna A, Rymaszewska J, Hadryś T, Suwalska A, Łojko D, Rybakowski JK. Bipolar or unipolar? - the question for clinicians and researchers. J Affect Disord. 2006;93(1\u0026ndash;3):177\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerlis RH, Brown E, Baker RW, Nierenberg AA. Clinical features of bipolar depression versus major depressive disorder in large multicenter trials. Am J Psychiatry. 2006;163(2):225\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYatham LN, Chakrabarty T, Bond DJ, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) recommendations for the management of patients with bipolar disorder with mixed presentations. Bipolar Disord. 2021;23(8):767\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNatale A, Mineo L, Fusar-Poli L et al. Mixed Depression: A Mini-Review to Guide Clinical Practice and Future Research Developments. Brain Sci 2022;12(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54(5):573\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAkiskal 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\u0026ndash;2):3\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorishita C, Kameyama R, Toda H, et al. Utility of TEMPS-A in differentiation between major depressive disorder, bipolar I disorder, and bipolar II disorder. PLoS ONE. 2020;15(5):e0232459.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMendlowicz MV, Akiskal HS, Kelsoe JR, Rapaport MH, Jean-Louis G, Gillin JC. Temperament in the clinical differentiation of depressed bipolar and unipolar major depressive patients. J Affect Disord. 2005;84(2\u0026ndash;3):219\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMazzarini L, Pacchiarotti I, Colom F, et al. Predominant polarity and temperament in bipolar and unipolar affective disorders. J Affect Disord. 2009;119(1\u0026ndash;3):28\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAiken CB, Weisler RH, Sachs GS. The Bipolarity Index: a clinician-rated measure of diagnostic confidence. J Affect Disord. 2015;177:59\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSachs GS. Strategies for improving treatment of bipolar disorder: integration of measurement and management. Acta Psychiatr Scand Suppl 2004(422):7\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobins E, Guze SB. Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry. 1970;126(7):983\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSayyah M, Delirrooyfard A, Rahim F. Assessment of the diagnostic performance of two new tools versus routine screening instruments for bipolar disorder: a meta-analysis. Braz J Psychiatry. 2022;44(3):349\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSwets JA. Measuring the accuracy of diagnostic systems. Science. 1988;240(4857):1285\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTuplin EW, Holahan MR, Aripiprazole. A Drug that Displays Partial Agonism and Functional Selectivity. Curr Neuropharmacol. 2017;15(8):1192\u0026ndash;207.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL. N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity. Neuropsychopharmacology. 2008;33(10):2303\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScheuch K, H\u0026ouml;ltje M, Budde H, et al. Lithium modulates tryptophan hydroxylase 2 gene expression and serotonin release in primary cultures of serotonergic raphe neurons. Brain Res. 2010;1307:14\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFortney JC, Un\u0026uuml;tzer J, Wrenn G, et al. A Tipping Point for Measurement-Based Care. Psychiatr Serv. 2017;68(2):179\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePost RM, Altshuler L, Kupka R, et al. Multigenerational Positive Family History of Psychiatric Disorders Is Associated With a Poor Prognosis in Bipolar Disorder. J Neuropsychiatry Clin Neurosci. 2015;27(4):304\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-bipolar-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijbd","sideBox":"Learn more about [International Journal of Bipolar Disorders](http://journalbipolardisorders.springeropen.com/)","snPcode":"40345","submissionUrl":"https://submission.nature.com/new-submission/40345/3","title":"International Journal of Bipolar Disorders","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Major depressive disorder, Bipolar disorder, Bipolarity, Bipolarity Index, Mood stabilizer, Second-generation antipsychotic, pharmacotherapy","lastPublishedDoi":"10.21203/rs.3.rs-8946679/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8946679/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePatients with major depressive disorder (MDD) who exhibit high bipolarity are at increased risk of future diagnostic conversion to bipolar disorder. However, treatment recommendations for MDD with bipolarity are constrained by limited direct evidence. We examined the association between bipolarity and primary pharmacotherapy in long-term stable outpatients with MDD and explored a clinically useful Bipolarity Index (BI) threshold.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this two-center cross-sectional study, participants were classified into an antidepressant (AD) group or a mood stabilizer/second-generation antipsychotic (MS/SGA) group. Bipolarity was assessed with the BI. Receiver operating characteristic (ROC) analysis was used to identify a BI cutoff discriminating MS/SGA from AD.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf 106 participants, 57 were assigned to the AD group and 49 to the MS/SGA group. The BI score was significantly higher in the MS/SGA group than in the AD group (24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9 vs 13.3\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). ROC analysis indicated a BI cutoff of 16 (Area Under the Curve\u0026thinsp;=\u0026thinsp;0.768), yielding 69.4% sensitivity and 78.9% specificity for identifying the MS/SGA group.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAmong long-term stable MDD outpatients, higher BI scores were associated with MS and/or SGA rather than antidepressant monotherapy as primary pharmacotherapy. A BI total score\u0026thinsp;\u0026ge;\u0026thinsp;16 may serve as a pragmatic threshold for identifying MDD patients with multiple bipolarity features who are more likely to receive MS and/or SGA. Prospective studies are warranted to test whether BI-guided pharmacotherapy improves outcomes and clarifies the role of MS and/or SGA in MDD patient with high bipolarity.\u003c/p\u003e","manuscriptTitle":"A Preliminary Cross-Sectional Study of Bipolarity and Primary Pharmacotherapy in Long-Term Stable Patients with Major Depressive Disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-13 15:10:07","doi":"10.21203/rs.3.rs-8946679/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-16T14:19:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-15T19:35:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196297948759082121151934173534891979105","date":"2026-03-11T15:40:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-11T12:20:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"26297343401860455517662063444752922153","date":"2026-03-09T22:30:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"296340857807475962226741591670524983302","date":"2026-03-09T15:13:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-09T15:05:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-24T09:00:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-24T09:00:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Bipolar Disorders","date":"2026-02-23T11:30:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-bipolar-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijbd","sideBox":"Learn more about [International Journal of Bipolar Disorders](http://journalbipolardisorders.springeropen.com/)","snPcode":"40345","submissionUrl":"https://submission.nature.com/new-submission/40345/3","title":"International Journal of Bipolar Disorders","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"62719195-a220-41e5-95ed-6b7d3e1b065e","owner":[],"postedDate":"March 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T14:58:10+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-13 15:10:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8946679","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8946679","identity":"rs-8946679","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}