Effect of prior depression diagnosis on bipolar disorder outcomes: a retrospective cohort study using a medical claims database

Effect of prior depression diagnosis on bipolar disorder outcomes: a retrospective cohort study using a medical claims database | 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 Effect of prior depression diagnosis on bipolar disorder outcomes: a retrospective cohort study using a medical claims database Hitoshi Sakurai, Masayuki Nakashima, Takashi Tsuboi, Kenji Baba, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3976192/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Bipolar disorder often emerges from depressive episodes and is initially diagnosed as depression. This study aimed to explore the effects of a prior depression diagnosis on outcomes in patients diagnosed with bipolar disorder. Methods This cohort study analyzed data of patients aged 18–64 years who received a new bipolar disorder diagnosis in Japan, using medical claims data from January 2005 to October 2020 provided by JMDC, Inc. The index month was defined as the time of the bipolar diagnosis. The study assessed the incidence of psychiatric hospitalization, all-cause hospitalization, and mortality, stratified by the presence of a preceding depression diagnosis and its duration (≥ 1 or < 1 year). Hazard ratios (HRs) and p-values were estimated using Cox proportional hazards models, adjusted for potential confounders, and supported by log-rank tests. Results Of the 5,595 patients analyzed, 2,460 had a history of depression, with 1,049 experiencing it for over a year and 1,411 for less than a year. HRs for psychiatric hospitalization, all hospitalizations, and death in patients with a history of depression versus those without were 0.92 (95% CI = 0.78–1.08, p = 0.30), 0.87 (95% CI = 0.78–0.98, p = 0.017), and 0.61 (95% CI = 0.33–1.12, p = 0.11), respectively. In patients with preceding depression ≥ 1 year versus < 1 year, HRs were 0.89 (95% CI = 0.67–1.19, p = 0.43) for psychiatric hospitalization, 0.85 (95% CI = 0.71-1.00, p = 0.052) for all hospitalizations, and 0.25 (95% CI = 0.07–0.89, p = 0.03) for death. Conclusion A prior history and duration of depression may not elevate psychiatric hospitalization risk after bipolar disorder diagnosis, and might even correlate with reduced hospitalization and mortality rates. bipolar disorder depression diagnosis hospitalization rate mortality Figures Figure 1 Figure 2 Introduction Bipolar disorder is a multifaceted mental health condition characterized by episodes of mania and depression, affecting approximately 1–2% of the global population over a lifetime (Geddes and Miklowitz 2013 ; McIntyre et al. 2020 ). The onset of bipolar disorder in a majority of cases is characterized by depressive episodes rather than mania or hypomania, with 58–71% of bipolar I cases and over 90% of bipolar II cases initially presenting with depression (Etain et al. 2012 ; Tondo et al. 2010 ). Consequently, between 37% and 69% of those eventually diagnosed with bipolar disorder were initially diagnosed with major depressive disorder (MDD) [Ghaemi et al. 2000 ; Ghaemi et al. 1999 ; Hirschfeld et al. 2003 ]. There is typically a delay of about 4 to 9 years from the first psychiatric consultation or provisional MDD diagnosis to a confirmed bipolar disorder diagnosis [Ghaemi et al. 2000 ; Ghaemi et al. 1999 ; Watanabe et al. 2016 ; Inoue et al. 2015 ]. The rate at which diagnoses change from MDD to bipolar disorder varies significantly, ranging from 2% over 21 years to 20% within 3 years [Mattisson et al. 2007 ; Akiskal et al. 1983 ; Kessing et al. 2017 ]. Some studies indicate a consistent yearly transition rate of about 1.25%, while others report the highest rate of change, 3.9%, in the first year, which then decreases to 0.8% after five years [McIntyre et al. 2020 ; Angst et al. 2005 ; Kessing et al. 2017 ]. Factors that increase the likelihood of transitioning from MDD to bipolar disorder include younger age at onset, psychotic features, atypical features, mixed features, a recurrent course, family history of bipolar disorder, and non-response to antidepressants [Mitchell et al. 2008 ]. While psychotherapy and pharmacotherapy are commonly utilized in the early stages of bipolar disorder, the debate over the most effective treatment strategy continues [Vieta et al. 2018 ]. Notably, antidepressants are frequently prescribed in cases initially diagnosed with MDD before bipolar disorder is recognized, owing to their primary role in MDD treatment [American Psychiatric Association 2010 ; Kennedy et al. 2016 ; Bauer et al. 2013 ]. However, prevailing clinical guidelines for bipolar disorder generally advise against using antidepressants as the main treatment for bipolar depression [Fountoulakis et al. 2017 ; Yatham et al. 2018 ; Grunze et al. 2010 ]. This recommendation arises from concerns about their limited efficacy in bipolar disorder and the potential risk of inducing manic episodes or rapid cycling [Tondo et al. 2010 ; Ross J. Baldessarini et al. 2013 ; El-Mallakh et al. 2015 ]. Despite these concerns, the effect of prior antidepressant use on the clinical outcomes after a bipolar diagnosis remains under-explored. To effectively assess the risks and benefits of treating preexisting MDD in the context of subsequent bipolar disorder outcomes, more definitive research is required. Medical record databases, comprising extensive archives of healthcare interactions including diagnoses and prescriptions, serve as invaluable resources for clinical research. These databases encapsulate real-world outcomes, including hospitalization and mortality, covering large and diverse patient cohorts across various healthcare settings. A significant advantage of these databases lies their ability to facilitate longitudinal tracking of patients, encompassing periods both before and after changes in diagnoses if any. The objective of the current study is to investigate the impact of diagnosis of pre-existing depression on the clinical outcomes of patients who are subsequently diagnosed with bipolar disorder. To accomplish this, we utilized a comprehensive medical record database, reflecting real-world scenarios. Method Study Design and Setting This cohort study undertook a comprehensive examination of patients newly diagnosed with bipolar disorder in Japan. It tracked patients from the month of diagnosis, retrospectively reviewing prior depression diagnoses and subsequent event occurrences. Claims records and health examination data was sourced from JMDC, Inc., covering the period from January 1, 2005, to October 30, 2020. The JMDC Claims Database is an epidemiological medical claims database that has accumulated claims data (inpatient, outpatient, dispensing) and medical examination data received from multiple employer-based health insurance associations since 2005. The present study was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines [Vandenbroucke et al. 2007 ]. This study was approved by the Ethics Committee of the Graduate School and Faculty of Medicine, Kyoto University (approval number: R3098; date: August 31st, 2021), which waived the requirement for an informed consent due to the anonymous nature of the data. Patient To accurately select patients with bipolar disorder for the study, three clinical psychiatrists (HS, TT, and KW) conducted a thorough review of 100 randomly chosen cases diagnosed with bipolar disorder from the JMDC claims dataset, focusing on their diagnoses and medications prescribed both before and after their bipolar diagnosis. This thorough examination led to the establishment of specific selection criteria for the study population: (1) patients newly diagnosed with bipolar disorder according to the International Classification of Diseases 10th Revision (ICD-10, F31) between July 1, 2005, and October 30, 2020, (2) patients aged between 18 and 64 years at the time of diagnosis, and (3) patients with data available for six or more months prior to their bipolar disorder diagnosis, to confirm the initial diagnosis of bipolar disorder. The study divided these individuals into two cohorts: one with a prior MDD (F32) diagnosis according to the ICD-10 and one without. For those with an MDD history, only patients with data spanning at least six months before their MDD diagnosis were included for further analysis, ensuring the diagnosis was a new occurrence. Exclusion criteria were as follows: (1) patients diagnosed with bipolar disorder only within one month, (2) patients previously diagnosed with organic mental disorders (F00-09), substance-related disorders (F10-19) (excluding psychotropic drugs or tobacco (F13 or F17)), obsessive-compulsive disorder (F42), dissociative disorder (F44), or severe intellectual disability (F72-73), (3) patients not prescribed (including prescriptions within 1 month), or only prescribed low doses of, antipsychotics or mood stabilizers (i.e. aripiprazole < 6 mg/d, olanzapine < 2.5 mg/d, lurasidone < 20 mg/d, quetiapine < 50 mg/d, carbamazepine < 200 mg/d, lamotrigine < 25 mg/d, lithium carbonate < 200 mg/d, or valproic acid < 200 mg/d), (4) patients not prescribed mood stabilizers but prescribed two or more antipsychotics not indicated for bipolar disorder (i.e. antipsychotics except for aripiprazole, olanzapine, lurasidone, or quetiapine), or (5) patients prescribed three or more antidepressants following their bipolar disorder diagnosis. Assessment Measures The present retrospective analysis tracked key clinical outcomes from the time of bipolar disorder diagnosis up to October 30, 2020. The primary outcomes of interest were psychiatric hospitalization, hospitalization for any reason, and mortality. Patients received treatment and care following standard clinical practices. Statistical Analysis Patients were stratified into groups based on their history of MDD diagnosis prior to the bipolar disorder diagnosis. The psychiatric hospitalization rate, overall hospitalization rate, and crude mortality rate were calculated for each group. The incidence rates for these outcomes were then compared between those with and without a preceding diagnosis of MDD. To adjust for potential confounders, hazard ratios and p-values were estimated using Cox proportional hazards models, supplemented by log-rank tests. Adjustments were made for several variables, including gender, age, insured person status (i.e. an insured individual or a dependent), comorbidity levels as measured by the Charlson Comorbidity Index (CCI) (i.e. CCI scores of ≥ 1 or 0), year of bipolar disorder diagnosis (i.e. 2012 or earlier, or 2013 or later), and prior history of overall hospitalization. The CCI was utilized to quantify the burden of comorbidities that might influence mortality risk, with a higher score indicating a greater risk. Similarly, for patients with a history of MDD diagnosis, analyses were conducted separately for those with a duration of preceding MDD diagnosis ≥ 1 year and < 1 year. The same statistical approaches were applied to compare incidence rates of psychiatric hospitalization, overall hospitalization, and mortality across these subgroups. Statistical significance was set at a p-value of < 0.05 (two-tailed). All analyses were performed using SAS 9.4 statistical software (SAS Institute, Cary, NC). Results Patient Characteristics A total of 5,595 patients were included in the present analysis. Among them, 2,460 (44.0%) had a preceding diagnosis of MDD. Baseline demographic and clinical characteristics are presented in Table 1 . In the group with a preceding diagnosis of MDD, the mean duration between the diagnoses of MDD and subsequent bipolar disorder was 18.2 ± 23.6 months. Among the 2,460 patients with a preceding diagnosis of MDD, 1,049 had experienced MDD diagnosis for ≥ 1 year, while 1,411 had a history of MDD diagnosis lasting < 1 year. Table 1 Baseline Demographic and Clinical Characteristics Characteristics Preceding MDD diagnosis (n = 2460) No preceding MDD diagnosis (n = 3135) Age, years, mean (SD) 37.3 (11.3) 36.0 (11.8) Male, n (%) 1420 (57.7) 1607 (51.3) Insured individual, n (%) 1718 (69.8) 1938 (61.8) Physical comorbidity (CCI ≥ 1), n (%) 203 (8.3) 283 (9.0) History of psychiatric admission, n (%) 238 (9.7) 205 (6.5) CCI, Charlson Comorbidity Index; MDD, major depressive disorder; SD, standard deviation Effect of Preceding MDD Diagnosis on Clinical Outcome The crude rate of psychiatric hospitalization was 8.0% (196/2,460) in the group with a preceding diagnosis of MDD and 7.6% (239/3,135) in the group without a preceding diagnosis of MDD. No significance was observed in the incidence rates of psychiatric hospitalization between the two groups (2.63/1,000 person-months vs. 2.56/1,000 person-months, adjusted hazard ratio (HR): 0.92, 95% confidence interval (CI): 0.78–1.08, p value: 0.30). The crude rate of overall hospitalization was 23.2% (571/2,460) in the group with a preceding diagnosis of MDD and 23.8% (746/3,135) in the group without a preceding diagnosis of MDD. There was a statistical significance in the incidence rates of overall hospitalization between the two groups (9.07/1,000 person-months vs. 9.39/1,000 person-months, adjusted HR: 0.87, 95%CI: 0.78–0.98, p value: 0.02, Fig. 1). The crude mortality rate was 0.69% (17/2,460) in the group with a preceding diagnosis of MDD and 0.96% (30/3,135) in the group without a preceding diagnosis of MDD. The mortality incidence rates were 2.70/100,000 person-months and 3.81/100,000 person-months, respectively. No significant difference was found in the mortality incidence rates between the two groups (adjusted HR: 0.61, 95% CI: 0.33–1.12, p-value: 0.11). Effect of Duration of Preceding MDD Diagnosis on Clinical Outcome The crude rate of psychiatric hospitalization was 8.6% (90/1,049) in the group with preceding MDD diagnosis ≥ 1 year and 7.5% (106/1,411) in the group with preceding MDD diagnosis < 1 year. There was no significant difference in the incidence rates of psychiatric hospitalization between the two groups (2.93/1,000 person-months vs. 2.42/1,000 person-months, adjusted HR: 0.89, 95%CI: 0.67–1.19, p value: 0.43). The crude rate of overall hospitalization was 23.2% (243/1,049) in the group with preceding MDD diagnosis ≥ 1 year and 23.2% (328/1,411) in the group with preceding MDD diagnosis < 1 year. There was no significance in the incidence rates of overall hospitalization between the two groups (9.25/1,000 person-months vs. 8.94/1,000 person-months, adjusted HR: 0.85, 95%CI: 0.71-1.00, p value: 0.052). The crude mortality rate was 0.29% (3/1,049) in the group with preceding MDD diagnosis ≥ 1 year and 0.99% (14/1,411) in the group with preceding MDD diagnosis < 1 year. The mortality incidence rates were 1.16/100,000 person-months and 3.77/100,000 person-months, respectively. There was a significant difference in the mortality incidence rates between the two groups (adjusted HR: 0.25, 95% CI: 0.07–0.89, p-value: 0.03, Fig. 2 ). Discussion This study is the first to examine the impact of a prior MDD diagnosis and its duration on outcomes following a bipolar disorder diagnosis. The analysis indicated that neither a history of MDD diagnosis nor the length of diagnosed duration significantly predicted the changes in rates of psychiatric hospitalization post-diagnosis of bipolar disorder. Intriguingly, a history of MDD diagnosis was associated with reduced hospitalization rates for all causes, and a diagnosis of MDD for more than a year showed decreased mortality rates. Given that these patients were treated and cared for according to standard clinical practices, it appears that a prior diagnosis and treatment for MDD may not lead to more severe psychiatric states following a bipolar disorder diagnosis. Instead, they may be linked to a reduction in adverse physical health outcomes. The present study established that neither a prior diagnosis of MDD nor its duration significantly impacted psychiatric hospitalization rates following a bipolar disorder diagnosis. When MDD is diagnosed, treatment is generally conducted as per standard practice guidelines, including the use of antidepressant medications [American Psychiatric Association 2010 ; Kennedy et al. 2016 ; Bauer et al. 2013 ]. This indicates that antidepressant therapy prior to the emergence of bipolar disorder may be acceptable without worsening the mental conditions in subsequent bipolar disorder. Existing literature has not addressed the impact of antidepressants prescribed prior to a bipolar disorder diagnosis, while studies focusing on their effects post-diagnosis reveal mixed results regarding psychiatric hospitalization rates. For instance, a database study of 190,824 patients with bipolar or schizoaffective disorder over three months on average reported that valproic acid, aripiprazole, and bupropion were associated with lower hospitalization rates than lithium carbonate, while most antidepressants were correlated with higher rates [Nestsiarovich et al. 2018 ]. On the other hand, one cohort study of 519 hospitalized bipolar patients over a year showed that no form of pharmacotherapy, including antidepressants, significantly affected rehospitalization rates [O’Hagan et al. 2017 ]. A pertinent factor influencing the present results may be the relatively brief average interval of 1.5 years between MDD and bipolar disorder diagnoses in this study, contrasting with the 4-9-year span reported in previous research [Ghaemi et al. 2000 ; Ghaemi et al. 1999 ; Watanabe et al. 2016 ; Inoue et al. 2015 ]. Recent advancements in psychiatric care may enable earlier diagnosis of bipolar disorder. Under these circumstances, treating depression prior to its diagnosis may not markedly impact the long-term prognosis of the condition. Patients with a history of MDD diagnosis experienced lower hospitalization rates for all causes compared to those without such a history. In an analysis of general hospital admissions over two years for 18,380 patients with bipolar disorder, schizophrenia, and schizoaffective disorder, common reasons for admission were diseases of the urinary tract, gastrointestinal system, oncology, and respiratory system [Jayatilleke et al. 2018 ]. Their hospitalization rates, particularly for conditions such as poisoning, injuries, endocrine/metabolic, hematologic, neurologic, dermatologic, and infectious diseases, were notably higher compared to the general population [Jayatilleke et al. 2018 ]. These health complications can often be linked to factors such as psychiatric symptom-related self-neglect, limited access to medical care, and self-harm. A pre-existing diagnosis of MDD, followed by appropriate treatment and care, may improve psychiatric symptoms and enhance access to medical care, potentially reducing the incidence of hospitalizations for physical health issues. Individuals diagnosed with MDD for over a year exhibited lower mortality rates compared to those with a shorter MDD history in the present study, suggesting that shorter intervals between depressive and manic phases might be linked to increased mortality. Notably, rapid-cycling bipolar disorder, characterized by frequent and brief phase changes, is associated with higher rates of obesity, hyperglycemia, metabolic syndrome, and substance use disorders as well as elevated suicide attempts [Calkin et al. 2009 ; Calkin et al. 2015 ; Buoli et al. 2017 ; Giménez-Palomo et al. 2022 ; Miola, Fountoulakis, et al. 2023; Garcia-Amador et al. 2009 ; Miola, Tondo, et al. 2023 ]. The suicide rate in bipolar disorder is approximately 0.1 to 0.4 per 100 person-years, with suicide accounting for an estimated 15 to 20% of deaths [Osborn et al. 2008 ; Simon et al. 2007 ; Søndergård et al. 2008 ; Dong et al. 2019 ]. Furthermore, suicide attempts are more frequent in cases where depressive episodes predominate, normally beginning with a depressive phase, compared to those primarily experiencing manic episodes [Baldessarini et al. 2012 ]. These findings underscore the importance of heightened vigilance for mortality risks, including suicide, particularly in the early stages following a change in mood episodes [Cho et al. 2024 ]. This study has several limitations. Firstly, being an analysis of medical record datasets, the classification of study patients relied on disease names from claims records rather than specific operational diagnostic criteria. This methodology could lead to potential discrepancies in clinical judgments. Moreover, the study did not take into account various factors that could influence the findings, such as the severity of the patients' conditions and a range of biological and clinical characteristics, including aspects of bipolarity. Secondly, the detection of prior MDD diagnosis is contingent upon medical examination. Consequently, there is a possibility that cases with a history of MDD diagnosis may have been inaccurately classified as having no prior MDD diagnosis. Thirdly, the specific nature of MDD treatments post-diagnosis, particularly antidepressant use, was not examined. Finally, the study was limited to outcomes that could be identified through medical claims data, focusing only on significant adverse outcomes like hospitalization or death. In conclusion, the present study indicates that a history and duration of prior MDD diagnosis do not increase the risk of psychiatric hospitalization after a bipolar disorder diagnosis. On the contrary, they may be linked to lower rates of hospitalization for any reason and decreased mortality rates. Our findings suggest that general treatment and care for MDD can be administered prior to a bipolar disorder diagnosis without concerns of exacerbating the severity of the bipolar disorder that follows. To corroborate these findings, future research in the form of prospective cohort studies with the accurate assessment of patients' medical histories and psychiatric symptoms is necessary. Declarations Acknowledgments: None Author Contributions: All authors contributed to the conception and design of the study. NM and KK contributed to statistical analysis of the study. HS contributed to drafting of this manuscript. All authors contributed to review and approval of the final manuscript. Funding/Support: This study was funded by Sumitomo Pharma Co.,Ltd. Availability of data and materials: The data that support the findings of this study are available from JMDC, Inc., but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of JMDC, Inc. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the Graduate School and Faculty of Medicine, Kyoto University (approval number: R3098; date: August 31st, 2021), which waived the requirement for an informed consent due to the anonymous nature of the data. Potential Conflicts of interest: HS received grants from Japan Society for the Promotion of Science, Japan Research Foundation Clinical Pharmacology, and Takeda Science Foundation, and honorarium from Eisai, Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, and Lundbeck Japan. MN has nothing to declare. TT received a grant from Japan Society for the Promotion of Science and honorarium from Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, Nippon Boehringer lngelheim, Mylan EPD, Mitsubishi Tanabe Pharma, Viatris, Mochida Pharmaceutical, Janssen Pharmaceutical, TEIJIN PHARMA, and Lundbeck Japan. KB and TN are full-time employees of Sumitomo Pharma Co., Ltd., Tokyo, Japan. KW has received manuscript fees or speaker’s honoraria from Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Pfizer, Shionogi, Sumitomo Pharma, and Takeda Pharmaceutical and received research/grant support from Daiichi Sankyo, Eisai, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsu-ka Pharmaceutical, Pfizer, Sumitomo Pharma, and Takeda Pharmaceutical. In addition, KW is a consultant of Boehringer Ingelheim, Daiichi Sankyo, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Luye Pharma, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharma-ceutical, and Takeda Pharmaceutical. KK has received consulting fees from Advanced Medical Care Inc., JMDC Inc., and Shin Nippon Biomedical Laboratories Ltd.; executive compensation from Cancer Intelligence Care Systems, Inc.; honoraria from Shionogi Pharmaceutical Co., Ltd., Taisho Pharmaceutical, and Pharma Business Academy; and grants from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., OMRON Corporation, and Toppan Inc. References Akiskal HS, Walker P, Puzantian VR, King D, Rosenthal TL, Dranon M. Bipolar Outcome in the Course of Depressive Illness. Phenomenologic, Familial, and Pharmacologic Predictors. J Affect Disord. 1983;5(2):115–28. American Psychiatric Association. 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Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and Elaboration. Epidemiology. 2007;18(6):805–35. Vieta E, Salagre E, Grande I, et al. Early Intervention in Bipolar Disorder. Am J Psychiatry. 2018;175(5):411–26. Watanabe K, Harada E, Inoue T, Tanji Y, Kikuchi T. Perceptions and Impact of Bipolar Disorder in Japan: Results of an Internet Survey. Neuropsychiatr Dis Treat. 2016;12:2981–7. Yatham 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):97–170. Additional Declarations Competing interest reported. HS received grants from Japan Society for the Promotion of Science, Japan Research Foundation Clinical Pharmacology, and Takeda Science Foundation, and honorarium from Eisai, Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, and Lundbeck Japan. MN has nothing to declare. TT received a grant from Japan Society for the Promotion of Science and honorarium from Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, Nippon Boehringer lngelheim, Mylan EPD, Mitsubishi Tanabe Pharma, Viatris, Mochida Pharmaceutical, Janssen Pharmaceutical, TEIJIN PHARMA, and Lundbeck Japan. KB and TN are full-time employees of Sumitomo Pharma Co., Ltd., Tokyo, Japan. KW has received manuscript fees or speaker’s honoraria from Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Pfizer, Shionogi, Sumitomo Pharma, and Takeda Pharmaceutical and received research/grant support from Daiichi Sankyo, Eisai, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsu-ka Pharmaceutical, Pfizer, Sumitomo Pharma, and Takeda Pharmaceutical. In addition, KW is a consultant of Boehringer Ingelheim, Daiichi Sankyo, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Luye Pharma, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharma-ceutical, and Takeda Pharmaceutical. KK has received consulting fees from Advanced Medical Care Inc., JMDC Inc., and Shin Nippon Biomedical Laboratories Ltd.; executive compensation from Cancer Intelligence Care Systems, Inc.; honoraria from Shionogi Pharmaceutical Co., Ltd., Taisho Pharmaceutical, and Pharma Business Academy; and grants from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., OMRON Corporation, and Toppan Inc. Cite Share Download PDF Status: Posted Version 1 posted 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-3976192","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":274260338,"identity":"d761b20c-a9da-4d4c-a72b-c9b4d2ec9ee9","order_by":0,"name":"Hitoshi Sakurai","email":"data:image/png;base64,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","orcid":"","institution":"Kyorin University Faculty of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Sakurai","suffix":""},{"id":274260339,"identity":"703d934e-b56e-4e27-bc2b-73a1952b2002","order_by":1,"name":"Masayuki Nakashima","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Nakashima","suffix":""},{"id":274260340,"identity":"5f5681ff-0147-463a-bb26-d9518a7a4715","order_by":2,"name":"Takashi Tsuboi","email":"","orcid":"","institution":"Kyorin University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Tsuboi","suffix":""},{"id":274260343,"identity":"6c2f0589-1e27-4b81-a24a-ae8faae7bacb","order_by":3,"name":"Kenji Baba","email":"","orcid":"","institution":"Sumitomo Pharma Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Baba","suffix":""},{"id":274260345,"identity":"d0e76dd6-ec20-465f-bb9b-dfadaca72d6d","order_by":4,"name":"Tadashi Nosaka","email":"","orcid":"","institution":"Sumitomo Pharma Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Tadashi","middleName":"","lastName":"Nosaka","suffix":""},{"id":274260346,"identity":"7eb01a11-8298-4d26-a265-4eb38fabaa36","order_by":5,"name":"Koichiro Watanabe","email":"","orcid":"","institution":"Kyorin University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Koichiro","middleName":"","lastName":"Watanabe","suffix":""},{"id":274260347,"identity":"577fb247-5247-4edd-b92b-c76582fd2b05","order_by":6,"name":"Koji Kawakami","email":"","orcid":"","institution":"Kyoto University","correspondingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Kawakami","suffix":""}],"badges":[],"createdAt":"2024-02-21 15:59:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3976192/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3976192/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51563918,"identity":"3d4121b2-a639-4773-9508-4edd47b93502","added_by":"auto","created_at":"2024-02-23 18:47:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":75976,"visible":true,"origin":"","legend":"\u003cp\u003eTime to hospitalization for any reason based on a preceding diagnosis of MDD.\u003c/p\u003e\n\u003cp\u003eThe red line represents individuals with a prior diagnosis of MDD, while the blue line denotes those without a preceding diagnosis of MDD.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3976192/v1/d84c85b1450682de7b8a219d.png"},{"id":51563919,"identity":"8718284d-257f-43cb-837c-d7c54e06f647","added_by":"auto","created_at":"2024-02-23 18:47:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":53593,"visible":true,"origin":"","legend":"\u003cp\u003eTime to mortality relative to duration of a prior MDD diagnosis.\u003c/p\u003e\n\u003cp\u003eThe red line indicates individuals who had been diagnosed with MDD for one year or more, and the blue line represents those with a preceding diagnosis of MDD for less than one year.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3976192/v1/f68e1ba647b07690f26cc132.png"},{"id":54684047,"identity":"a889c962-9d41-433f-b41f-4d029b5b65bf","added_by":"auto","created_at":"2024-04-15 08:35:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":426996,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3976192/v1/bf7153f7-7679-460b-bbe0-3946fee3ccc4.pdf"}],"financialInterests":"Competing interest reported. HS received grants from Japan Society for the Promotion of Science, Japan Research Foundation Clinical Pharmacology, and Takeda Science Foundation, and honorarium from Eisai, Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, and Lundbeck Japan.\nMN has nothing to declare.\nTT received a grant from Japan Society for the Promotion of Science and honorarium from Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, Nippon Boehringer lngelheim, Mylan EPD, Mitsubishi Tanabe Pharma, Viatris, Mochida Pharmaceutical, Janssen Pharmaceutical, TEIJIN PHARMA, and Lundbeck Japan.\nKB and TN are full-time employees of Sumitomo Pharma Co., Ltd., Tokyo, Japan.\nKW has received manuscript fees or speaker’s honoraria from Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Pfizer, Shionogi, Sumitomo Pharma, and Takeda Pharmaceutical and received research/grant support from Daiichi Sankyo, Eisai, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsu-ka Pharmaceutical, Pfizer, Sumitomo Pharma, and Takeda Pharmaceutical. In addition, KW is a consultant of Boehringer Ingelheim, Daiichi Sankyo, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Luye Pharma, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharma-ceutical, and Takeda Pharmaceutical.\nKK has received consulting fees from Advanced Medical Care Inc., JMDC Inc., and Shin Nippon Biomedical Laboratories Ltd.; executive compensation from Cancer Intelligence Care Systems, Inc.; honoraria from Shionogi Pharmaceutical Co., Ltd., Taisho Pharmaceutical, and Pharma Business Academy; and grants from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., OMRON Corporation, and Toppan Inc.","formattedTitle":"Effect of prior depression diagnosis on bipolar disorder outcomes: a retrospective cohort study using a medical claims database","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBipolar disorder is a multifaceted mental health condition characterized by episodes of mania and depression, affecting approximately 1\u0026ndash;2% of the global population over a lifetime (Geddes and Miklowitz \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; McIntyre et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). The onset of bipolar disorder in a majority of cases is characterized by depressive episodes rather than mania or hypomania, with 58\u0026ndash;71% of bipolar I cases and over 90% of bipolar II cases initially presenting with depression (Etain et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Tondo et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Consequently, between 37% and 69% of those eventually diagnosed with bipolar disorder were initially diagnosed with major depressive disorder (MDD) [Ghaemi et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Ghaemi et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Hirschfeld et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2003\u003c/span\u003e]. There is typically a delay of about 4 to 9 years from the first psychiatric consultation or provisional MDD diagnosis to a confirmed bipolar disorder diagnosis [Ghaemi et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Ghaemi et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Watanabe et al. \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Inoue et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2015\u003c/span\u003e]. The rate at which diagnoses change from MDD to bipolar disorder varies significantly, ranging from 2% over 21 years to 20% within 3 years [Mattisson et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Akiskal et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1983\u003c/span\u003e; Kessing et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2017\u003c/span\u003e]. Some studies indicate a consistent yearly transition rate of about 1.25%, while others report the highest rate of change, 3.9%, in the first year, which then decreases to 0.8% after five years [McIntyre et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Angst et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Kessing et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2017\u003c/span\u003e]. Factors that increase the likelihood of transitioning from MDD to bipolar disorder include younger age at onset, psychotic features, atypical features, mixed features, a recurrent course, family history of bipolar disorder, and non-response to antidepressants [Mitchell et al. \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2008\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile psychotherapy and pharmacotherapy are commonly utilized in the early stages of bipolar disorder, the debate over the most effective treatment strategy continues [Vieta et al. \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2018\u003c/span\u003e]. Notably, antidepressants are frequently prescribed in cases initially diagnosed with MDD before bipolar disorder is recognized, owing to their primary role in MDD treatment [American Psychiatric Association \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Kennedy et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Bauer et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2013\u003c/span\u003e]. However, prevailing clinical guidelines for bipolar disorder generally advise against using antidepressants as the main treatment for bipolar depression [Fountoulakis et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Yatham et al. \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Grunze et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2010\u003c/span\u003e]. This recommendation arises from concerns about their limited efficacy in bipolar disorder and the potential risk of inducing manic episodes or rapid cycling [Tondo et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Ross J. Baldessarini et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; El-Mallakh et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2015\u003c/span\u003e]. Despite these concerns, the effect of prior antidepressant use on the clinical outcomes after a bipolar diagnosis remains under-explored. To effectively assess the risks and benefits of treating preexisting MDD in the context of subsequent bipolar disorder outcomes, more definitive research is required.\u003c/p\u003e \u003cp\u003eMedical record databases, comprising extensive archives of healthcare interactions including diagnoses and prescriptions, serve as invaluable resources for clinical research. These databases encapsulate real-world outcomes, including hospitalization and mortality, covering large and diverse patient cohorts across various healthcare settings. A significant advantage of these databases lies their ability to facilitate longitudinal tracking of patients, encompassing periods both before and after changes in diagnoses if any.\u003c/p\u003e \u003cp\u003eThe objective of the current study is to investigate the impact of diagnosis of pre-existing depression on the clinical outcomes of patients who are subsequently diagnosed with bipolar disorder. To accomplish this, we utilized a comprehensive medical record database, reflecting real-world scenarios.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Setting\u003c/h2\u003e \u003cp\u003eThis cohort study undertook a comprehensive examination of patients newly diagnosed with bipolar disorder in Japan. It tracked patients from the month of diagnosis, retrospectively reviewing prior depression diagnoses and subsequent event occurrences. Claims records and health examination data was sourced from JMDC, Inc., covering the period from January 1, 2005, to October 30, 2020. The JMDC Claims Database is an epidemiological medical claims database that has accumulated claims data (inpatient, outpatient, dispensing) and medical examination data received from multiple employer-based health insurance associations since 2005. The present study was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines [Vandenbroucke et al. \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2007\u003c/span\u003e]. This study was approved by the Ethics Committee of the Graduate School and Faculty of Medicine, Kyoto University (approval number: R3098; date: August 31st, 2021), which waived the requirement for an informed consent due to the anonymous nature of the data.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatient\u003c/h2\u003e \u003cp\u003eTo accurately select patients with bipolar disorder for the study, three clinical psychiatrists (HS, TT, and KW) conducted a thorough review of 100 randomly chosen cases diagnosed with bipolar disorder from the JMDC claims dataset, focusing on their diagnoses and medications prescribed both before and after their bipolar diagnosis. This thorough examination led to the establishment of specific selection criteria for the study population: (1) patients newly diagnosed with bipolar disorder according to the International Classification of Diseases 10th Revision (ICD-10, F31) between July 1, 2005, and October 30, 2020, (2) patients aged between 18 and 64 years at the time of diagnosis, and (3) patients with data available for six or more months prior to their bipolar disorder diagnosis, to confirm the initial diagnosis of bipolar disorder. The study divided these individuals into two cohorts: one with a prior MDD (F32) diagnosis according to the ICD-10 and one without. For those with an MDD history, only patients with data spanning at least six months before their MDD diagnosis were included for further analysis, ensuring the diagnosis was a new occurrence. Exclusion criteria were as follows: (1) patients diagnosed with bipolar disorder only within one month, (2) patients previously diagnosed with organic mental disorders (F00-09), substance-related disorders (F10-19) (excluding psychotropic drugs or tobacco (F13 or F17)), obsessive-compulsive disorder (F42), dissociative disorder (F44), or severe intellectual disability (F72-73), (3) patients not prescribed (including prescriptions within 1 month), or only prescribed low doses of, antipsychotics or mood stabilizers (i.e. aripiprazole\u0026thinsp;\u0026lt;\u0026thinsp;6 mg/d, olanzapine\u0026thinsp;\u0026lt;\u0026thinsp;2.5 mg/d, lurasidone\u0026thinsp;\u0026lt;\u0026thinsp;20 mg/d, quetiapine\u0026thinsp;\u0026lt;\u0026thinsp;50 mg/d, carbamazepine\u0026thinsp;\u0026lt;\u0026thinsp;200 mg/d, lamotrigine\u0026thinsp;\u0026lt;\u0026thinsp;25 mg/d, lithium carbonate\u0026thinsp;\u0026lt;\u0026thinsp;200 mg/d, or valproic acid\u0026thinsp;\u0026lt;\u0026thinsp;200 mg/d), (4) patients not prescribed mood stabilizers but prescribed two or more antipsychotics not indicated for bipolar disorder (i.e. antipsychotics except for aripiprazole, olanzapine, lurasidone, or quetiapine), or (5) patients prescribed three or more antidepressants following their bipolar disorder diagnosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAssessment Measures\u003c/h2\u003e \u003cp\u003eThe present retrospective analysis tracked key clinical outcomes from the time of bipolar disorder diagnosis up to October 30, 2020. The primary outcomes of interest were psychiatric hospitalization, hospitalization for any reason, and mortality. Patients received treatment and care following standard clinical practices.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003ePatients were stratified into groups based on their history of MDD diagnosis prior to the bipolar disorder diagnosis. The psychiatric hospitalization rate, overall hospitalization rate, and crude mortality rate were calculated for each group. The incidence rates for these outcomes were then compared between those with and without a preceding diagnosis of MDD. To adjust for potential confounders, hazard ratios and p-values were estimated using Cox proportional hazards models, supplemented by log-rank tests. Adjustments were made for several variables, including gender, age, insured person status (i.e. an insured individual or a dependent), comorbidity levels as measured by the Charlson Comorbidity Index (CCI) (i.e. CCI scores of \u0026ge;\u0026thinsp;1 or 0), year of bipolar disorder diagnosis (i.e. 2012 or earlier, or 2013 or later), and prior history of overall hospitalization. The CCI was utilized to quantify the burden of comorbidities that might influence mortality risk, with a higher score indicating a greater risk. Similarly, for patients with a history of MDD diagnosis, analyses were conducted separately for those with a duration of preceding MDD diagnosis\u0026thinsp;\u0026ge;\u0026thinsp;1 year and \u0026lt;\u0026thinsp;1 year. The same statistical approaches were applied to compare incidence rates of psychiatric hospitalization, overall hospitalization, and mortality across these subgroups. Statistical significance was set at a p-value of \u0026lt;\u0026thinsp;0.05 (two-tailed). All analyses were performed using SAS 9.4 statistical software (SAS Institute, Cary, NC).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient Characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 5,595 patients were included in the present analysis. Among them, 2,460 (44.0%) had a preceding diagnosis of MDD. Baseline demographic and clinical characteristics are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. In the group with a preceding diagnosis of MDD, the mean duration between the diagnoses of MDD and subsequent bipolar disorder was 18.2\u0026thinsp;\u0026plusmn;\u0026thinsp;23.6 months. Among the 2,460 patients with a preceding diagnosis of MDD, 1,049 had experienced MDD diagnosis for \u0026ge;\u0026thinsp;1 year, while 1,411 had a history of MDD diagnosis lasting\u0026thinsp;\u0026lt;\u0026thinsp;1 year.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline Demographic and Clinical Characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePreceding MDD diagnosis (n\u0026thinsp;=\u0026thinsp;2460)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo preceding MDD diagnosis (n\u0026thinsp;=\u0026thinsp;3135)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, years, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37.3 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36.0 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1420 (57.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1607 (51.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInsured individual, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1718 (69.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1938 (61.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePhysical comorbidity (CCI\u0026thinsp;\u0026ge;\u0026thinsp;1), n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e203 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e283 (9.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistory of psychiatric admission, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e238 (9.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e205 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eCCI, Charlson Comorbidity Index; MDD, major depressive disorder; SD, standard deviation\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eEffect of Preceding MDD Diagnosis on Clinical Outcome\u003c/h2\u003e\n \u003cp\u003eThe crude rate of psychiatric hospitalization was 8.0% (196/2,460) in the group with a preceding diagnosis of MDD and 7.6% (239/3,135) in the group without a preceding diagnosis of MDD. No significance was observed in the incidence rates of psychiatric hospitalization between the two groups (2.63/1,000 person-months vs. 2.56/1,000 person-months, adjusted hazard ratio (HR): 0.92, 95% confidence interval (CI): 0.78\u0026ndash;1.08, p value: 0.30).\u003c/p\u003e\n \u003cp\u003eThe crude rate of overall hospitalization was 23.2% (571/2,460) in the group with a preceding diagnosis of MDD and 23.8% (746/3,135) in the group without a preceding diagnosis of MDD. There was a statistical significance in the incidence rates of overall hospitalization between the two groups (9.07/1,000 person-months vs. 9.39/1,000 person-months, adjusted HR: 0.87, 95%CI: 0.78\u0026ndash;0.98, p value: 0.02, Fig. 1).\u003c/p\u003e\n \u003cp\u003eThe crude mortality rate was 0.69% (17/2,460) in the group with a preceding diagnosis of MDD and 0.96% (30/3,135) in the group without a preceding diagnosis of MDD. The mortality incidence rates were 2.70/100,000 person-months and 3.81/100,000 person-months, respectively. No significant difference was found in the mortality incidence rates between the two groups (adjusted HR: 0.61, 95% CI: 0.33\u0026ndash;1.12, p-value: 0.11).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eEffect of Duration of Preceding MDD Diagnosis on Clinical Outcome\u003c/h2\u003e\n \u003cp\u003eThe crude rate of psychiatric hospitalization was 8.6% (90/1,049) in the group with preceding MDD diagnosis\u0026thinsp;\u0026ge;\u0026thinsp;1 year and 7.5% (106/1,411) in the group with preceding MDD diagnosis\u0026thinsp;\u0026lt;\u0026thinsp;1 year. There was no significant difference in the incidence rates of psychiatric hospitalization between the two groups (2.93/1,000 person-months vs. 2.42/1,000 person-months, adjusted HR: 0.89, 95%CI: 0.67\u0026ndash;1.19, p value: 0.43).\u003c/p\u003e\n \u003cp\u003eThe crude rate of overall hospitalization was 23.2% (243/1,049) in the group with preceding MDD diagnosis\u0026thinsp;\u0026ge;\u0026thinsp;1 year and 23.2% (328/1,411) in the group with preceding MDD diagnosis\u0026thinsp;\u0026lt;\u0026thinsp;1 year. There was no significance in the incidence rates of overall hospitalization between the two groups (9.25/1,000 person-months vs. 8.94/1,000 person-months, adjusted HR: 0.85, 95%CI: 0.71-1.00, p value: 0.052).\u003c/p\u003e\n \u003cp\u003eThe crude mortality rate was 0.29% (3/1,049) in the group with preceding MDD diagnosis\u0026thinsp;\u0026ge;\u0026thinsp;1 year and 0.99% (14/1,411) in the group with preceding MDD diagnosis\u0026thinsp;\u0026lt;\u0026thinsp;1 year. The mortality incidence rates were 1.16/100,000 person-months and 3.77/100,000 person-months, respectively. There was a significant difference in the mortality incidence rates between the two groups (adjusted HR: 0.25, 95% CI: 0.07\u0026ndash;0.89, p-value: 0.03, Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study is the first to examine the impact of a prior MDD diagnosis and its duration on outcomes following a bipolar disorder diagnosis. The analysis indicated that neither a history of MDD diagnosis nor the length of diagnosed duration significantly predicted the changes in rates of psychiatric hospitalization post-diagnosis of bipolar disorder. Intriguingly, a history of MDD diagnosis was associated with reduced hospitalization rates for all causes, and a diagnosis of MDD for more than a year showed decreased mortality rates. Given that these patients were treated and cared for according to standard clinical practices, it appears that a prior diagnosis and treatment for MDD may not lead to more severe psychiatric states following a bipolar disorder diagnosis. Instead, they may be linked to a reduction in adverse physical health outcomes.\u003c/p\u003e \u003cp\u003eThe present study established that neither a prior diagnosis of MDD nor its duration significantly impacted psychiatric hospitalization rates following a bipolar disorder diagnosis. When MDD is diagnosed, treatment is generally conducted as per standard practice guidelines, including the use of antidepressant medications [American Psychiatric Association \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Kennedy et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Bauer et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2013\u003c/span\u003e]. This indicates that antidepressant therapy prior to the emergence of bipolar disorder may be acceptable without worsening the mental conditions in subsequent bipolar disorder. Existing literature has not addressed the impact of antidepressants prescribed prior to a bipolar disorder diagnosis, while studies focusing on their effects post-diagnosis reveal mixed results regarding psychiatric hospitalization rates. For instance, a database study of 190,824 patients with bipolar or schizoaffective disorder over three months on average reported that valproic acid, aripiprazole, and bupropion were associated with lower hospitalization rates than lithium carbonate, while most antidepressants were correlated with higher rates [Nestsiarovich et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2018\u003c/span\u003e]. On the other hand, one cohort study of 519 hospitalized bipolar patients over a year showed that no form of pharmacotherapy, including antidepressants, significantly affected rehospitalization rates [O\u0026rsquo;Hagan et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2017\u003c/span\u003e]. A pertinent factor influencing the present results may be the relatively brief average interval of 1.5 years between MDD and bipolar disorder diagnoses in this study, contrasting with the 4-9-year span reported in previous research [Ghaemi et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Ghaemi et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Watanabe et al. \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Inoue et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2015\u003c/span\u003e]. Recent advancements in psychiatric care may enable earlier diagnosis of bipolar disorder. Under these circumstances, treating depression prior to its diagnosis may not markedly impact the long-term prognosis of the condition.\u003c/p\u003e \u003cp\u003ePatients with a history of MDD diagnosis experienced lower hospitalization rates for all causes compared to those without such a history. In an analysis of general hospital admissions over two years for 18,380 patients with bipolar disorder, schizophrenia, and schizoaffective disorder, common reasons for admission were diseases of the urinary tract, gastrointestinal system, oncology, and respiratory system [Jayatilleke et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2018\u003c/span\u003e]. Their hospitalization rates, particularly for conditions such as poisoning, injuries, endocrine/metabolic, hematologic, neurologic, dermatologic, and infectious diseases, were notably higher compared to the general population [Jayatilleke et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2018\u003c/span\u003e]. These health complications can often be linked to factors such as psychiatric symptom-related self-neglect, limited access to medical care, and self-harm. A pre-existing diagnosis of MDD, followed by appropriate treatment and care, may improve psychiatric symptoms and enhance access to medical care, potentially reducing the incidence of hospitalizations for physical health issues.\u003c/p\u003e \u003cp\u003eIndividuals diagnosed with MDD for over a year exhibited lower mortality rates compared to those with a shorter MDD history in the present study, suggesting that shorter intervals between depressive and manic phases might be linked to increased mortality. Notably, rapid-cycling bipolar disorder, characterized by frequent and brief phase changes, is associated with higher rates of obesity, hyperglycemia, metabolic syndrome, and substance use disorders as well as elevated suicide attempts [Calkin et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Calkin et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Buoli et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Gim\u0026eacute;nez-Palomo et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Miola, Fountoulakis, et al. 2023; Garcia-Amador et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Miola, Tondo, et al. \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2023\u003c/span\u003e]. The suicide rate in bipolar disorder is approximately 0.1 to 0.4 per 100 person-years, with suicide accounting for an estimated 15 to 20% of deaths [Osborn et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Simon et al. \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; S\u0026oslash;nderg\u0026aring;rd et al. \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Dong et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2019\u003c/span\u003e]. Furthermore, suicide attempts are more frequent in cases where depressive episodes predominate, normally beginning with a depressive phase, compared to those primarily experiencing manic episodes [Baldessarini et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2012\u003c/span\u003e]. These findings underscore the importance of heightened vigilance for mortality risks, including suicide, particularly in the early stages following a change in mood episodes [Cho et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2024\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study has several limitations. Firstly, being an analysis of medical record datasets, the classification of study patients relied on disease names from claims records rather than specific operational diagnostic criteria. This methodology could lead to potential discrepancies in clinical judgments. Moreover, the study did not take into account various factors that could influence the findings, such as the severity of the patients' conditions and a range of biological and clinical characteristics, including aspects of bipolarity. Secondly, the detection of prior MDD diagnosis is contingent upon medical examination. Consequently, there is a possibility that cases with a history of MDD diagnosis may have been inaccurately classified as having no prior MDD diagnosis. Thirdly, the specific nature of MDD treatments post-diagnosis, particularly antidepressant use, was not examined. Finally, the study was limited to outcomes that could be identified through medical claims data, focusing only on significant adverse outcomes like hospitalization or death.\u003c/p\u003e \u003cp\u003eIn conclusion, the present study indicates that a history and duration of prior MDD diagnosis do not increase the risk of psychiatric hospitalization after a bipolar disorder diagnosis. On the contrary, they may be linked to lower rates of hospitalization for any reason and decreased mortality rates. Our findings suggest that general treatment and care for MDD can be administered prior to a bipolar disorder diagnosis without concerns of exacerbating the severity of the bipolar disorder that follows. To corroborate these findings, future research in the form of prospective cohort studies with the accurate assessment of patients' medical histories and psychiatric symptoms is necessary.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eAll authors contributed to the conception and design of the study. NM and KK contributed to statistical analysis of the study. HS contributed to drafting of this manuscript. All authors contributed to review and approval of the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/Support:\u0026nbsp;\u003c/strong\u003eThis study was funded by Sumitomo Pharma Co.,Ltd.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe data that support the findings of this study are available from JMDC, Inc., but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of JMDC, Inc.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThis study was approved by the Ethics Committee of the Graduate School and Faculty of Medicine, Kyoto University (approval number: R3098; date: August 31st, 2021), which waived the requirement for an informed consent due to the anonymous nature of the data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePotential Conflicts of interest:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHS received grants from Japan Society for the Promotion of Science, Japan Research Foundation Clinical Pharmacology, and Takeda Science Foundation, and honorarium from Eisai, Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, and Lundbeck Japan.\u003c/p\u003e\n\u003cp\u003eMN has nothing to declare.\u003c/p\u003e\n\u003cp\u003eTT received a grant from Japan Society for the Promotion of Science and honorarium from Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomiyakuhin, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, Nippon Boehringer lngelheim, Mylan EPD, Mitsubishi Tanabe Pharma, Viatris, Mochida Pharmaceutical, Janssen Pharmaceutical, TEIJIN PHARMA, and Lundbeck Japan.\u003c/p\u003e\n\u003cp\u003eKB and TN are full-time employees of Sumitomo Pharma Co., Ltd., Tokyo, Japan.\u003c/p\u003e\n\u003cp\u003eKW has received manuscript fees or speaker\u0026rsquo;s honoraria from Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Pfizer, Shionogi, Sumitomo Pharma, and Takeda Pharmaceutical and received research/grant support from Daiichi Sankyo, Eisai, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsu-ka Pharmaceutical, Pfizer, Sumitomo Pharma, and Takeda Pharmaceutical. In addition, KW is a consultant of Boehringer Ingelheim, Daiichi Sankyo, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Luye Pharma, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharma-ceutical, and Takeda Pharmaceutical.\u003c/p\u003e\n\u003cp\u003eKK has received consulting fees from Advanced Medical Care Inc., JMDC Inc., and Shin Nippon Biomedical Laboratories Ltd.; executive compensation from Cancer Intelligence Care Systems, Inc.; honoraria from Shionogi Pharmaceutical Co., Ltd., Taisho Pharmaceutical, and Pharma Business Academy; and grants from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., OMRON Corporation, and Toppan Inc.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAkiskal HS, Walker P, Puzantian VR, King D, Rosenthal TL, Dranon M. Bipolar Outcome in the Course of Depressive Illness. Phenomenologic, Familial, and Pharmacologic Predictors. J Affect Disord. 1983;5(2):115\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Washington, DC: American Psychiatric Association; 2010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAngst J, Sellaro R, Stassen HH, Gamma A. Diagnostic Conversion from Depression to Bipolar Disorders: Results of a Long-Term Prospective Study of Hospital Admissions. J Affect Disord. 2005;84(2\u0026ndash;3):149\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaldessarini RJ, Undurraga J, V\u0026aacute;zquez GH, et al. Predominant Recurrence Polarity among 928 Adult International Bipolar I Disorder Patients. Acta Psychiatr Scand. 2012;125(4):293\u0026ndash;302.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaldessarini RJ, Faedda GL, Offidani E, et al. Antidepressant-Associated Mood-Switching and Transition from Unipolar Major Depression to Bipolar Disorder: A Review. J Affect Disord. 2013;148(1):129\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBauer M, Pfennig A, Severus E, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Update 2013 on the Acute and Continuation Treatment of Unipolar Depressive Disorders. World J Biol Psychiatry. 2013;14(5):334\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuoli M, Dell\u0026rsquo;Osso B, Caldiroli A, et al. Obesity and Obstetric Complications Are Associated with Rapid-Cycling in Italian Patients with Bipolar Disorder. J Affect Disord. 2017;208:278\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCalkin CV, Ruzickova M, Uher R, et al. Insulin Resistance and Outcome in Bipolar Disorder. Br J Psychiatry. 2015;206(1):52\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCalkin C, van de Velde C, Růzickov\u0026aacute; M, et al. Can Body Mass Index Help Predict Outcome in Patients with Bipolar Disorder? Bipolar Disord. 2009;11(6):650\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCho W, Hsu T, Cheng C, et al. Cause-Specific Mortality and Comorbid Neurodevelopmental Disorder in 167,515 Patients with Bipolar Disorder: An Entire Population Longitudinal Study. J Affect Disord. 2024;347:463\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDong M, Lu L, Zhang L, et al. Prevalence of Suicide Attempts in Bipolar Disorder: A Systematic Review and Meta-Analysis of Observational Studies. Epidemiol Psychiatr Sci. 2019;29:e63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl-Mallakh RS, V\u0026ouml;hringer PA, Ostacher MM, et al. Antidepressants Worsen Rapid-Cycling Course in Bipolar Depression: A STEP-BD Randomized Clinical Trial. J Affect Disord. 2015;184:318\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEtain B, Lajnef M, Bellivier F, et al. Clinical Expression of Bipolar Disorder Type I as a Function of Age and Polarity at Onset: Convergent Findings in Samples from France and the United States. J Clin Psychiatry. 2012;73(4):e561\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFountoulakis KN, Yatham L, Grunze H, et al. The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 2: Review, Grading of the Evidence, and a Precise Algorithm. Int J Neuropsychopharmacol. 2017;20(2):121\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarcia-Amador M, Colom F, Valenti M, Horga G, Vieta E. Suicide Risk in Rapid Cycling Bipolar Patients. J Affect Disord. 2009;117(1\u0026ndash;2):74\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeddes JR, Miklowitz DJ. Treatment of Bipolar Disorder. Lancet. 2013;381(9878):1672\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhaemi SN, Boiman EE, Goodwin FK. Diagnosing Bipolar Disorder and the Effect of Antidepressants: A Naturalistic Study. J Clin Psychiatry. 2000;61(10):804\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhaemi SN, Sachs GS, Chiou AM, Pandurangi AK, Goodwin K. Is Bipolar Disorder Still Underdiagnosed? Are Antidepressants Overutilized? J Affect Disord. 1999;52(1\u0026ndash;3):135\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGim\u0026eacute;nez-Palomo A, Gomes-da-Costa S, Dodd S, et al. Does Metabolic Syndrome or Its Component Factors Alter the Course of Bipolar Disorder? A Systematic Review. Neurosci Biobehav Rev. 2022;132:142\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Update 2010 on the Treatment of Acute Bipolar Depression. World J Biol Psychiatry. 2010;11(2):81\u0026ndash;109.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirschfeld RMA, 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\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\u003eJayatilleke N, Hayes RD, Chang C, Stewart R. Acute General Hospital Admissions in People with Serious Mental Illness. Psychol Med. 2018;48(16):2676\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. Can J Psychiatry. 2016;61(9):540\u0026ndash;60.\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\u003eMattisson C, Bogren M, Horstmann V, Munk-J\u0026ouml;rgensen P, Nettelbladt P. The Long-Term Course of Depressive Disorders in the Lundby Study. Psychol Med. 2007;37(6):883\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcIntyre RS, Berk M, Brietzke E, et al. Bipolar Disorders Lancet. 2020;396(10265):1841\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiola A, Fountoulakis KN, Baldessarini RJ, et al. Prevalence and Outcomes of Rapid Cycling Bipolar Disorder: Mixed Method Systematic Meta-Review. J Psychiatr Res. 2023;164:404\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiola A, Tondo L, Pinna M, Contu M, Baldessarini RJ. Characteristics of Rapid Cycling in 1261 Bipolar Disorder Patients. Int J Bipolar Disord. 2023;11(1):21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMitchell PB, Goodwin GM, Johnson GF, Hirschfeld RMA. Diagnostic Guidelines for Bipolar Depression: A Probabilistic Approach. Bipolar Disord. 2008;10(1 Pt 2):144\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNestsiarovich A, Mazurie AJ, Hurwitz NG, et al. Comprehensive Comparison of Monotherapies for Psychiatric Hospitalization Risk in Bipolar Disorders. Bipolar Disord. 2018;20(8):761\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Hagan M, Cornelius V, Young AH, Taylor D. Predictors of Rehospitalization in a Naturalistic Cohort of Patients with Bipolar Affective Disorder. Int Clin Psychopharmacol. 2017;32(3):115\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOsborn D, Levy G, Nazareth I, King M. Suicide and Severe Mental Illnesses. 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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\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"bipolar disorder, depression, diagnosis, hospitalization rate, mortality","lastPublishedDoi":"10.21203/rs.3.rs-3976192/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3976192/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBipolar disorder often emerges from depressive episodes and is initially diagnosed as depression. This study aimed to explore the effects of a prior depression diagnosis on outcomes in patients diagnosed with bipolar disorder.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis cohort study analyzed data of patients aged 18\u0026ndash;64 years who received a new bipolar disorder diagnosis in Japan, using medical claims data from January 2005 to October 2020 provided by JMDC, Inc. The index month was defined as the time of the bipolar diagnosis. The study assessed the incidence of psychiatric hospitalization, all-cause hospitalization, and mortality, stratified by the presence of a preceding depression diagnosis and its duration (\u0026ge;\u0026thinsp;1 or \u0026lt;\u0026thinsp;1 year). Hazard ratios (HRs) and p-values were estimated using Cox proportional hazards models, adjusted for potential confounders, and supported by log-rank tests.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the 5,595 patients analyzed, 2,460 had a history of depression, with 1,049 experiencing it for over a year and 1,411 for less than a year. HRs for psychiatric hospitalization, all hospitalizations, and death in patients with a history of depression versus those without were 0.92 (95% CI\u0026thinsp;=\u0026thinsp;0.78\u0026ndash;1.08, p\u0026thinsp;=\u0026thinsp;0.30), 0.87 (95% CI\u0026thinsp;=\u0026thinsp;0.78\u0026ndash;0.98, p\u0026thinsp;=\u0026thinsp;0.017), and 0.61 (95% CI\u0026thinsp;=\u0026thinsp;0.33\u0026ndash;1.12, p\u0026thinsp;=\u0026thinsp;0.11), respectively. In patients with preceding depression\u0026thinsp;\u0026ge;\u0026thinsp;1 year versus \u0026lt;\u0026thinsp;1 year, HRs were 0.89 (95% CI\u0026thinsp;=\u0026thinsp;0.67\u0026ndash;1.19, p\u0026thinsp;=\u0026thinsp;0.43) for psychiatric hospitalization, 0.85 (95% CI\u0026thinsp;=\u0026thinsp;0.71-1.00, p\u0026thinsp;=\u0026thinsp;0.052) for all hospitalizations, and 0.25 (95% CI\u0026thinsp;=\u0026thinsp;0.07\u0026ndash;0.89, p\u0026thinsp;=\u0026thinsp;0.03) for death.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eA prior history and duration of depression may not elevate psychiatric hospitalization risk after bipolar disorder diagnosis, and might even correlate with reduced hospitalization and mortality rates.\u003c/p\u003e","manuscriptTitle":"Effect of prior depression diagnosis on bipolar disorder outcomes: a retrospective cohort study using a medical claims database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-23 18:47:50","doi":"10.21203/rs.3.rs-3976192/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3f3019af-bda4-45f6-ad12-924e08b839cc","owner":[],"postedDate":"February 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-15T08:27:45+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-23 18:47:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3976192","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3976192","identity":"rs-3976192","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}