title: Strategic use of new generation antidepressants for depression: SUN(^_^) D protocol update and statistical analysis plan.
abstract: BACKGROUND
  SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan.
  
  
  RESULTS
  We implemented two important changes to the original protocol. One is about the required sample size, reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primary and secondary outcomes in order to make the report of the main trial results as pertinent and interpretable as possible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary outcomes and their analyses. We will convene the blind interpretation committee before the randomization code is broken.
  
  
  CONCLUSIONS
  This paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D trial in order to avoid reporting bias and data-driven results.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01109693 (registered on 21 April 2010).
authors.affiliation: Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8553, Japan. nyonemoto@gmail.com.|Leuven Biostatistics and Statistical Bioinformatics Center, Katholic University of Leuven, Kapucijnenvoer 35, 3000, Leuven, Belgium. nyonemoto@gmail.com.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yonemoto
authors.affiliation: Department of Pharmacoepidemiology, Kyoto University Graduate School of Medicine/of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. tanaka.shiro.8n@kyoto-u.ac.jp.
authors.forename: Shiro
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. furukawa@kuhp.kyoto-u.ac.jp.|Department of Clinical Epidemiology, Kyoto University Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. furukawa@kuhp.kyoto-u.ac.jp.
authors.forename: Toshi A
authors.initials: TA
authors.lastname: Furukawa
authors.affiliation: Aratama Mental Clinic, 1-49 Suyama-cho, Mizuho-ku, Nagoya, 467-0066, Japan. tkato@spice.or.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Mantani Mental Clinic, 5-18 Itsukaichi Ekimae 1-chome, Saeki-ku, Hiroshima, 731-5125, Japan. akio@mantani-clinic.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Mantani
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. ogawa.yusuke.2u@kyoto-u.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. aran.tajika28@gmail.com.
authors.forename: Aran
authors.initials: A
authors.lastname: Tajika
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. n.takeshima@gmail.com.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takeshima
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. y.hy.hh.y3@gmail.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hayasaka
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. kiyomi-w@wb3.so-net.ne.jp.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Shinohara
authors.affiliation: Miki Mental Clinic, 1-3 Hiranuma 1-chome, Nishi-ku, Yokohama, 220-0023, Japan. k-miki@largo-yokohama.com.
authors.forename: Kazuhira
authors.initials: K
authors.lastname: Miki
authors.affiliation: Department of Neuropsychiatry, Okayama University Hospital, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. brainpet@gmail.com.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Inagaki
authors.affiliation: Department of Neuropsychiatry, Kochi Medical School, Kohasu, Okoh-cho, Nankoku, 783-8505, Japan. shimodes@kochi-u.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimodera
authors.affiliation: Department of Psychiatry and Cognitive-Behavioral Medicine, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan. takechi@med.nagoya-cu.ac.jp.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Akechi
authors.affiliation: Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8553, Japan. mitsu@ncnp.go.jp.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Translational Medical Center, National Center of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan. noriow@ncnp.go.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, West Hamilton, Ontario, L8N 3Z5, Canada. guyatt@mcmaster.ca.
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Guyatt
mesh_terms: D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage* / Q000009:adverse effects; D002985:Clinical Protocols; D003627:Data Interpretation, Statistical; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D004334:Drug Administration Schedule; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D006801:Humans; D007564:Japan; D008803:Mianserin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000078785:Mirtazapine; D010352:Patient Dropouts; D011569:Psychiatric Status Rating Scales; D012107:Research Design / Q000706:statistics & numerical data*; D018401:Sample Size; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D020280:Sertraline / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000929:Antidepressive Agents, Tricyclic; D008803:Mianserin; D000078785:Mirtazapine; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline