Optimising first- and second-line treatment strategies for untreated major depressive disorder - the SUN☺D study: a pragmatic, multi-centre, assessor-blinded randomised controlled trial

Tadashi Kato, Toshi A Furukawa, Akio Mantani, Ken'ichi Kurata, Hajime Kubouchi, Susumu Hirota, Hirotoshi Sato, Kazuyuki Sugishita, Bun Chino, Kahori Itoh, Yoshio Ikeda, Yoshihiro Shinagawa, Masaki Kondo, Yasumasa Okamoto, Hirokazu Fujita, Motomu Suga, Shingo Yasumoto, Naohisa Tsujino, Takeshi Inoue, Noboru Fujise, Tatsuo Akechi, Mitsuhiko Yamada, Shinji Shimodera, Norio Watanabe, Masatoshi Inagaki, Kazuhira Miki, Yusuke Ogawa, Nozomi Takeshima, Yu Hayasaka, Aran Tajika, Kiyomi Shinohara, Naohiro Yonemoto, Shiro Tanaka, Qi Zhou, Gordon H Guyatt, SUN☺D Investigators, Tadashi Kato, Toshi A Furukawa, Akio Mantani, Ken'ichi Kurata, Hajime Kubouchi, Susumu Hirota, Hirotoshi Sato, Kazuyuki Sugishita, Bun Chino, Kahori Itoh, Yoshio Ikeda, Yoshihiro Shinagawa, Masaki Kondo, Yasumasa Okamoto, Hirokazu Fujita, Motomu Suga, Shingo Yasumoto, Naohisa Tsujino, Takeshi Inoue, Noboru Fujise, Tatsuo Akechi, Mitsuhiko Yamada, Shinji Shimodera, Norio Watanabe, Masatoshi Inagaki, Kazuhira Miki, Yusuke Ogawa, Nozomi Takeshima, Yu Hayasaka, Aran Tajika, Kiyomi Shinohara, Naohiro Yonemoto, Shiro Tanaka, Qi Zhou, Gordon H Guyatt, SUN☺D Investigators

Abstract

Background: For patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline strategies remain unestablished.

Methods: This multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixed-model repeated-measures analysis adjusted for key baseline covariates.

Results: Between December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9 score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), - 0.58 to 1.07, P = 0.55). Other outcomes proved similar in the two groups. In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine (n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points (0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage of remission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects.

Conclusions: In patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs 50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 by switching sertraline to mirtazapine or by adding mirtazapine.

Trial registration: ClinicalTrials.gov, NCT01109693 . Registered on 23 April 2010.

Keywords: Antidepressive agents: first-line treatment; Major depressive disorder; Randomised controlled trial; Second-line treatment.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol was approved by the ethics committees/institutional review boards of Kyoto University Graduate School of Medicine (C0446), Nagoya City University Hospital (45–10-0004), Kochi Medical School (22–96), Kumamoto University (No. 1341), Yatsushiro Kosei Hospital (dated October 28, 2011), Yuge Hospital (No. 86), Kurume University Medical School (No. 11151), St. Lucia Hospital (dated January 11, 2012), Hiroshima University Hospital (Rin 297), University of Tokyo Hospital (P2011062-11X), Toho University School of Medicine (No. 23053), Hokkaido University Hospital (JI011–0292) and Sapporo Hanazono Hospital (dated June 4, 2014). All participants provided written informed consent.

Competing interests

TK has received lecture fees from Eli Lilly and Mitsubishi-Tanabe and has contracted research with GSK, MSD and Mitsubishi-Tanabe. He has received royalties from Kyowa Yakuhin. TAF has received lecture fees from Eli Lilly, Janssen, Meiji, MSD, Otsuka, Pfizer and Mitsubishi-Tanabe and consultancy fees from Takeda Science Foundation. He has received research support from Mochida and Mitsubishi-Tanabe. AM has received lecture fees from Mochida, Eli Lilly and Meiji. SH has received lecture fees from MSD, Pfizer, Meiji, Tanabe-Mitsubishi and Otsuka. HS has received lecture fees from Daiichi-Sankyo and Mochida. KSu has received lecture and/or consultant fees from Eli Lilly, Mochida, Eisai, Meiji and Daiichi-Sankyo. BC has received lecture fees from Eli Lilly, Meiji and Mitsubishi-Tanabe. KI has received lecture fees from Dainippon-Sumitomo, Eli Lilly, Otsuka, Takeda, Kyowa Yakuhin, Mitsubishi-Tanabe, Meiji and Shionogi. YI has received lecture fees from Meiji, Eli Lilly, Janssen and Otsuka. YS has received lecture fees from Janssen, Kyowa Yakuhin, Meiji, MSD, Otsuka and Mitsubishi-Tanabe. MK has received lecture fees from Yoshitomi and a research grant from Novartis. YOk has received lecture fees from Otsuka, Dainippon-Sumitomo, Astellas, Pfizer, Eli Lilly, Janssen, Meiji, Mochida, Yoshitomi, Eisai and GSK. HF has received lecture fees from Meiji, Mochida, MSD and Otsuka. SY has received lecture fees from Daiichi-Sankyo and Otsuka. NTs has received lecture fees from Astellas, Shionogi, Novartis, Fujifilm RI Pharma, Meiji, Mochida, Janssen, Eli Lilly and Dainippon-Sumitomo. TI has received lecture fees from GSK, Mochida, Asahi Kasei, Shionogi, Otsuka, Dainippon-Sumitomo, Eli Lilly, Eisai, Mitsubishi-Tanabe, Pfizer, AbbVie, MSD, Yoshitomi, Takeda and Meiji. He has received grants from Shionogi, Astellas, Otsuka, Dainippon-Sumitomo, Eli Lilly, Eisai, Mitsubishi-Tanabe, Pfizer, AbbVie, MSD, Yoshitomi, Takeda and Meiji. He is on advisor boards for GSK, Mochida, Otsuka, Eli Lilly, Mitsubishi-Tanabe, Pfizer and Takeda. NF has received lecture fees from Pfizer, Eisai, Mochida, Ono, Shionogi, MSD and Otsuka. TA has received lecture fees and/or research funds from Daiichi-Sankyo, Eisai, Hisamitsu, Eli Lilly, MSD, Meiji, Mochida, Otsuka, Pfizer, Novartis and Terumo. MY has received lecture fees from Meiji, MSD and Asahi Kasei and has contracted research with Nippon Chemiphar. SS has received lecture fees from Otsuka, MSD, Meiji, Eli Lilly, Mochida and Shionogi. MI has received a grant from Novartis Pharma. He has received lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji and Takeda. KM has received lecture fees from Eisai, GSK, Meiji, MSD, Otsuka, Pfizer, Eli Lilly, Mochida, Yoshitomi, Dainippon-Sumitomo, Takeda and Shionogi. YOg has received a lecture fee from Eli Lilly. NTa has received lecture fees from Otsuka and Meiji. YH has received a lecture fee from Yoshitomi. AT has received lecture fees from Eli Lilly and Mitsubishi-Tanabe. ST has received lecture fees from AstraZeneca, Taiho and Ono. He has received consultation fees from DeNA Life Science and CanBus. He has received outsourcing fees from Satt and Asahi Kasei Pharma. His wife has been engaged in a research project of Bayer. All these fees have been outside the submitted work. KK, HK, MS, NW, KSh, NY, QZ and GHG declare that they have no competing interests.

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Figures

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Fig. 1
Trial profile. ® randomised, EDC electronic data capture system

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