Neuropsychiatric Disease and Treatment Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Factors Associated with Non-Remission in Bipolar Disorder: The Multicenter Treatment Survey for Bipolar Disorder in Psychiatric Outpatient Clinics (MUSUBI) This article was published in the following Dove Press journal: Neuropsychiatric Disease and Treatment Takashi Tsuboi, 1,2 Purpose: The aim of this study was to identify factors associated with non-remission in 2,3 Ta kefum i Suzuk i, bipolar disorder. 4 Takaharu Azekawa, Patients and Methods: The multicenter treatment survey for bipolar disorder in psychia- 4 4 Naoto Adachi, Hitoshi Ueda, tric outpatient clinics (MUSUBI) study used a questionnaire administered at 176 clinics 4 Kouji Edagawa, throughout Japan from September to October 2016. Clinic psychiatrists performed Eiichi Katsumoto,4 a retrospective medical record survey of consecutive cases with bipolar disorder. Patients Yukihisa Kubota, 4 were considered to be in remission if they met all of the following criteria: they were not in Eiichiro Goto,4 Seiji Hongo,4 4 a mixed state, their manic or depressive symptoms were either borderline or nonexistent Yoichiro Watanabe, Masaki Kato, 2,5 Norio (corresponding to 2 or 1 points on the Clinical Global Impressions Scale, Bipolar Version), Yasui-Furukori,2,6 and their psychiatrists clinically considered them to be in remission. Enrolled patients were Reiji Yoshimura,2,7 classified into remitters group and non-remitters group and demographic and clinical char- Atsuo Nakagawa, 2,8 acteristics were contrasted between the groups. Non-remitters were compared with remitters, Toshiaki Kikuchi,2,8 using a series of logistic regression analyses. 1,2 Koichiro Watanabe Results: A total of 3130 patients (1420 men; mean age: 50.3 years) were included in this 1Department of Neuropsychiatry, Kyorin study; 1307 patients (41.8%) were in remission. Of the remaining 1823 patients, 1260 University School of Medicine, Tokyo, Japan; (40.3%) had mild to severe depression, 261 (8.3%) suffered from manic or hypomanic 2 The Japanese Society of Clinical episodes, and 302 (9.6%) were in a mixed state. Logistic regression analyses found the Neuropsychopharmacology, Tokyo, Japan; 3Department of Neuropsychiatry, University following eight factors to be significantly correlated with non-remission in patients with of Yamanashi Faculty of Medicine, Yamanashi, bipolar disorder: female gender, younger age, unemployed status, rapid cycling pattern, Japan; 4The Japanese Association of Neuro- Psychiatric Clinics, Tokyo, Japan; comorbid alcohol/substance abuse, poorer social function, lithium non-use, and antidepres- 5Department of Neuropsychiatry, Kansai sant use. Medical University, Osaka, Japan; The MUSUBI study, the largest nationwide investigation on bipolar disorder, 6 Conclusion: Department of Psychiatry, Dokkyo Medical fi University, Tochigi, Japan; 7Department of identi ed eight clinically relevant factors associated with non-remission in bipolar patients. Psychiatry, University of Occupational and They have important clinical implications; further prospective studies are necessary to Environmental Health, Fukuoka, Japan; replicate these findings and to guide better managements for those in serious needs. 8Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan Keywords: bipolar disorder, non-remission, nationwide study, mood stabilizer, antipsychotics Correspondence: Takashi Tsuboi Department of Neuropsychiatry, Kyorin Introduction University School of Medicine, 6-20-2, Bipolar disorder is frequently a severe, recurrent, and debilitating psychiatric Shinkawa, Mitaka-Shi, Tokyo 181-8611, 1 Japan disorder. Although several treatment-guidelines and meta-analyses on bipolar Tel +81 422 47 5511 disorder have been published across the globe,2–7 the problem of non-response Fax +81 422 45 4697 Email [email protected] and non-remission has been ubiquitous in the real-world clinical settings. As such, submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2020:16 881–890 881 DovePress © 2020 Tsuboi et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. – http://doi.org/10.2147/NDT.S246136 php and incorporate the Creative Commons Attribution Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Tsuboi et al Dovepress many individuals with bipolar disorders still suffer from Materials and Methods troublesome symptoms, resulting in substantial financial, 8 Study Design and Subjects social, or work-related issues. The multicenter treatment survey for bipolar disorder in fi Bipolar disorder is classi ed into bipolar I disorder, psychiatric outpatient clinics (MUSUBI) is a cross- bipolar II disorder, and bipolar disorder not otherwise spe- sectional study in which a questionnaire was administered fi ci ed, for which different psychopharmacological treat- at 176 clinics located across Japan from September to fi ment is recommended. In addition, the rst-line October 2016. Patients diagnosed with bipolar disorder medications are divided individually for acute mania according to the Tenth Revision of the International phase, bipolar depression phase, and maintenance phase. Classification of Diseases and Related Health Problems, Such a complexity constitutes the hurdles in conducting 10th edition (ICD-10) and treated at the aforementioned clinical research on bipolar disorders in a longitudinal man- clinics were included; patients with serious physical con- ner. Only a few large-scale studies are available to guide ditions such as terminal cancer or intractable diseases were clinical management (e.g., the Systematic Treatment excluded. Almost all psychiatrists involved in this study Enhancement Program for Bipolar Disorder (STEP-BD)9), were psychiatric specialists certified by the Japanese and maintenance treatment is complicated in that the studies Society of Psychiatry and Neurology, and/or designated usually adopt an enrichment design;10 information is criti- psychiatrists certified by the Japanese Ministry of Health, cally racking on what to do to who fail to show response or Labour and Welfare. remission with standard treatments. On the other hand, it is frequently challenging to dis- Study Procedures tinguish bipolar disorder from unipolar depression; the Clinic psychiatrists were asked to complete a questionnaire average delay in diagnosis of bipolar disorder is reported by performing a retrospective medical record survey of – 11,12 to be 5 10 years after the symptoms begin. Even after consecutive cases with bipolar disorder, beginning with the an accurate diagnosis is made, it still remains a challenge first patient who visited the clinic during the study period. to achieve complete remission of all symptoms with the The questionnaire included patient characteristics (age, gen- currently available psychotropic medications, and symp- der, height, weight, academic background, and occupational toms may even become progressively more severe over status), comorbidities, psychiatric symptoms, course of the 13–15 time. It is thus of high clinical importance to extract illness, the Global Assessment of Functioning (GAF) score, factors associated with remission of bipolar disorder. and details of pharmacological treatment. We mailed this According to the European Mania in Bipolar questionnaire to each outpatient clinic in 20 copies and Longitudinal Evaluation of Medication (EMBLEM) analyzed the responses. study, patients who had a higher overall score on the This study focused on factors associated with remission Clinical Global Impression Scale, Bipolar Version for (versus non-remission). Based on the proposal of the bipolar disorder (CGI-BP), who had depressive episodes International Society of Bipolar Disorders, this study defined in the year before, who had poor social functioning, and patients as being in remission if they met all three of the who were treated with typical antipsychotics or antidepres- following criteria: they were not in a mixed state, their manic sants were found to be less likely to achieve remission or or depressive symptoms were either borderline or nonexis- 17 recovery.16 However, while treatment response has usually tent (corresponding to 2 or 1 points on the CGI-BP), and expressed with a “relative” threshold (e.g., 50% decrease their psychiatrists clinically considered them to be in remis- in the representative rating scales), the definition of remis- sion. Non-remitted patients comprised all the rest of bipolar sion in patients with bipolar disorder, albeit often arbitra- patients and might have been in depressive, (hypo)manic and rily expressed with an absolute threshold (e.g., a score of mixed state; we hereby term them remitters and non- less than 7 on the Montgomery-Asberg depression rating remitters, respectively. scale18), has not been unequivocally established to date.17 With these backgrounds, the goal of this study was to Statistical Analysis perform a large-scale investigation of patients with bipolar SPSS version 25 (SPSS, IBM