Efficacy of aripiprazole augmentation in Japanese patients with major depressive disorder: A subgroup analysis and Montgomery–Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression item analyses of the Aripiprazole Depression Multicenter Efficacy study

Authors


  • Clinical Trials Registration: ClinicalTrials.gov identifier NCT00876343.

Abstract

Aim

Results from this randomized, placebo-controlled study of aripiprazole augmentation to antidepressant therapy (ADT) in Japanese patients with major depressive disorder (MDD) (the Aripiprazole Depression Multicenter Efficacy [ADMIRE] study) revealed that aripiprazole augmentation was superior to ADT alone and was well tolerated. In subgroup analyses, we investigated the influence of demographic- and disease-related factors on the observed responses. We also examined how individual symptom improvement was related to overall improvement in MDD.

Methods

Data from the ADMIRE study were analyzed. Subgroup analyses were performed on the primary outcome measures: the mean change in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score from the end of selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI) treatment to the end of the randomized treatment.

Results

Changes in the MADRS total scores were consistently greater with aripiprazole than placebo in each of the subgroups. Efficacy was not related to sex, age, number of adequate ADT trials in the current episode, MDD diagnosis, number of depressive episodes, duration of the current episode, age at first depressive episode, time since the first depressive episode, type of SSRI/SNRI, or severity at the end of SSRI/SNRI treatment phase. Compared to placebo, aripiprazole resulted in significant and rapid improvement on seven of the 10 MADRS items, including sadness.

Conclusion

These post-hoc analyses indicated that aripiprazole was effective for a variety of Japanese patients with MDD who had exhibited inadequate responses to ADT. Additionally, we suggest that aripiprazole significantly and rapidly improved the core depressive symptoms.

Major depressive disorder (MDD) has a greater contribution to disability and the deterioration of quality of life than almost all the other diseases in the world combined. It has been estimated that more than 350 million people are affected.[1] MDD can lead to suicide, and such suicide results in an estimated 1 million deaths every year. Indeed, MDD accounts for 40.5% (31.7–49.2) of the disability-adjusted life years (DALY) that are caused by mental and substance use disorders and is the leading cause of years lived with disability (YLD) worldwide.[2]

Although a number of antidepressants are available, approximately two-thirds of patients who receive initial antidepressant therapy (ADT) do not achieve remission.[3, 4] Sequenced treatment steps using augmentation strategies are known to be effective for some patients with MDD who exhibit inadequate or partial responses to ADT. Currently, major guidelines[5, 6] and meta-analyses[7, 8] indicate that the augmentation of ADT with atypical antipsychotics is a commonly used and promising approach for this clinical situation. However, as each antipsychotic has a different pharmacological profile, the patterns of improvement and side-effects are different between antipsychotics.

Aripiprazole has a unique pharmacological profile with D2/D3 receptor partial agonism, 5-HT1A receptor partial agonism, and 5-HT2A receptor antagonism.[9, 10] Aripiprazole was the first atypical antipsychotic approved by the US Food and Drug Administration for adjunctive treatment of MDD in patients showing inadequate responses to ADT. Recently, aripiprazole was also approved for the treatment of MDD by the Pharmaceuticals and Medical Devices Agency of Japan. The efficacy and safety of aripiprazole augmentation to ADT have been demonstrated in three US trials[11-13] and one Japanese trial.[14]

The US trials demonstrated that the mean changes in MADRS total scores in aripiprazole augmentation were significantly greater than those in placebo, independent of factors such as race, age, episode duration, severity of depressive symptoms and antidepressant.[15] Additionally, Reimherr et al. showed that aripiprazole rapidly improved core depressive symptoms, such as mood, lassitude, inability to feel, self-worth, and suicidal thoughts, according to assessments by both the clinicians and the patients.[16] In the Japanese trial, which was called the ‘Aripiprazole Depression Multicenter Efficacy (ADMIRE) study’, aripiprazole augmentation at 3 mg/day and 3–15 mg/day resulted in significant improvements in depressive symptoms from week 1 compared to the placebo group in Japanese patients with MDD. However, a detailed analysis in Japanese patients was not performed. To further elucidate the profiles of the MDD patients from whom adjunctive aripiprazole was efficacious in improving MDD, we examined the differential responses in terms of relevant clinical characteristics and subgroups of Japanese patients with MDD.

Additionally, we investigated the individual item scores from the Montgomery–Åsberg Depression Rating Scale (MADRS) and the 17-item Hamilton Rating Scale for Depression (HAM-D17) to clarify which symptoms were improved by adjunctive aripiprazole.

Methods

Study design

The details of the study methods have been described previously.[14] Briefly, a multicenter, 6-week, randomized, double-blind, placebo-controlled study (the ADMIRE study) was conducted in Japan between 2009 and 2012 to evaluate the efficacy and safety of aripiprazole augmentation to ADT in patients with MDD. The enrolled patients were 20–65 years old and met DSM-IV-TR criteria for a major depressive episode of at least 8 weeks' duration and had reported an inadequate response to prior ADT. The details of the inclusion and exclusion criteria have been reported previously. The study was conducted in accordance with the Declaration of Helsinki and written informed consent was obtained from all patients.

This study consisted of three phases: a screening phase of 1–28 days; an 8-week, single-blind, prospective treatment phase designed to establish the inadequate responses to SSRI/SNRI (paroxetine, fluvoxamine, sertraline, milnacipran, and duloxetine); and a 6-week double-blind, randomized phase. The patients received an SSRI/SNRI in accordance with current product labeling guidelines and also received a single-blind, adjunctive placebo during the SSRI/SNRI treatment phase. The patients with an inadequate response (<50% reduction in HAM-D17 total score, HAM-D17 total score of >14 and Clinical Global Impression Improvement [CGI-I] score of >3) at the end of the SSRI/SNRI treatment phase were randomly assigned in a 1:1:1 ratio to continue the same SSRI/SNRI (no dose adjustment was permitted) plus either an adjunctive placebo, adjunctive aripiprazole at a fixed dose (3 mg/day), or adjunctive aripiprazole at a flexible dose (3–15 mg/day) using the permuted block method.[17] The patients who were assigned to the aripiprazole flexible dose group started with a dose of 3 mg/day, and the investigators could increase the dose by 3 mg/day once per week to a maximum of 15 mg/day if well tolerated. Dose reductions for tolerability reasons were permitted at any visit. No dose increases were permitted during the last week of the study. Most psychotropics, including mood stabilizers, neuroleptics and benzodiazepines (with the exception of short-acting benzodiazepines), were prohibited. A short-acting benzodiazepine was allowed in the double-blind phase only when used in the SSRI/SNRI treatment phase. An anti-cholinergic treatment for extrapyramidal symptoms was permitted in the double-blind phase.

Assessments and statistical analyses

The primary efficacy end-point was the mean change in the MADRS total score[18] from the end of the prospective treatment phase (week 8 visit) to the end of the randomized, double-blind treatment phase (week 14, the last observation carried forward).

Subgroup analyses according to sex, age (20–30, 30–40, 40–50, 50–60, or ≥60 years), number of adequate ADT in the current episode (1, 2, or 3), major depressive disorder diagnosis (single episode or recurrent episode), number of depressive episodes (1, 2, or ≥3), duration of current episode (<6, 6–12, 12–24, or ≥24 months), age at first depressive episode (<20, 20–30, 30–40, 40–50, 50–60, or ≥60 years), time since first depressive episode (<12, 12–24, 24–36, or ≥36 months), type of SSRI/SNRI (paroxetine, fluvoxamine, sertraline, milnacipran or duloxetine), and severity at the end of the SSRI/SNRI treatment phase (MADRS total score and HAM-D17 total score <the median, ≥the median, CGI – Severity [S] score: ≤3, 4, or ≥5) were performed on the primary efficacy outcome measure (the mean change in MADRS total score during the 6-week double-blind treatment phase). Interaction effects between treatment and subgroup were assessed by ancova with the end of the SSRI/SNRI treatment phase measure as the covariate, treatment and subgroup as the main effects, and the treatment by subgroup as the interaction effect.

The mean change in individual items scores of the MADRS and HAM-D17 were evaluated using ancova with the score at the end of SSRI/SNRI treatment phase as a covariate.

All analyses were conducted on the dataset from the last observation carried forward dataset. The results of all statistical tests were considered significant at the 5% significance level.

Results

Patient disposition

In total, 586 patients with an inadequate response with the 8-week SSRI/SNRI treatment were randomly assigned to a double-blind treatment with adjunctive placebo (n = 195), adjunctive fixed-dose (3 mg/day) aripiprazole (n = 197) or adjunctive flexible-dose (3–15 mg/day) aripiprazole (n = 194). The completion rates were high in each group (placebo 94%, 3 mg/day 91%, 3–15 mg/day 91%). The baseline demographics and clinical characteristics were similar between the treatment groups (Table 1).

Table 1. Baseline demographic and clinical characteristics of randomized patients
Treatment groupFlexible dose (3–15 mg/day)Fixed dose (3 mg/day)Placebo
  1. HAM-D17, 17-item Hamilton Rating Scale for Depression; MADRS, Montgomery–Åsberg Depression Rating Scale; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
Patients (n)194197195
SexMale101(52.1%)124(62.9%)115(59.0%)
Female93(47.9%)73(37.1%)80(41.0%)
Age (years), mean ± SD 38.1 ± 9.639.2 ± 9.138.7 ± 9.2
Inpatient/ outpatient (at the end of SSRI/SNRI treatment)Inpatients1(0.5%)3(1.5%)3(1.5%)
Outpatients193(99.5%)194(98.5%)192(98.5%)
DSM-IV-TR diagnosisSingle episode102(52.6%)122(61.9%)113(57.9%)
Recurrent episode92(47.4%)75(38.1%)82(42.1%)
SeverityMild12(6.2%)8(4.1%)10(5.1%)
Moderate163(84.0%)152(77.2%)151(77.4%)
Severe (without psychosis)19(9.8%)37(18.8%)34(17.4%)
No. of adequate antidepressant trials in current episode1 trial119(61.3%)130(66.0%)124(63.6%)
2 trials54(27.8%)53(26.9%)49(25.1%)
3 trials21(10.8%)14(7.1%)22(11.3%)
≥4 trials0(0%)0(0%)0(0%)
No. of depressive episodesFirst episode102(52.6%)122(61.9%)113(57.9%)
2 episode62(32.0%)47(23.9%)49(25.1%)
3 episode15(7.7%)19(9.6%)18(9.2%)
4 episode8(4.1%)7(3.6%)10(5.1%)
≥5 episode7(3.6%)2(1.0%)5(2.6%)
Duration of current episode (months), mean ± SD 17.5 ± 26.115.7 ± 21.615.6 ± 16.4
Type of SSRI/SNRIParoxetine25(12.9%)47(23.9%)41(21.0%)
Fluvoxamine36(18.6%)35(17.8%)46(23.6%)
Sertraline88(45.4%)68(34.5%)69(35.4%)
Milnacipran27(13.9%)24(12.2%)24(12.3%)
Duloxetine18(9.3%)23(11.7%)15(7.7%)
MADRS total score at the end of SSRI/SNRI treatment, mean ± SD25.3 ± 7.325.2 ± 7.225.5 ± 7.4
HAM-D17 total score at the end of SSRI/SNRI treatment, mean ± SD19.8 ± 4.020.0 ± 4.020.2 ± 4.1

The distributions of the specific ADT used in the placebo and aripiprazole groups were as follows: sertraline, 38.4%; fluvoxamine, 20.0%; paroxetine, 19.3%; milnacipran, 12.8%; and duloxetine, 9.6%. In the aripiprazole flexible-dose group, the proportion of paroxetine was lower and the proportion of sertraline was higher than that in the placebo and aripiprazole fixed-dose groups. The other ADT distributions were similar among the placebo and aripiprazole treatment arms (Table 1). The mean dose of SSRI/SNRI was similar in the placebo and aripiprazole treatment arms and comparable to the upper limits of the approved dose in all groups (Table 2).

Table 2. Mean daily dose of SSRI/SNRI chosen
TreatmentAripiprazole 3–15 mg flexible dose n = 194Aripiprazole 3 mg fixed dose n = 197Placebo n = 195
SSRI/SNRInMean dose (mg/day)nMean dose (mg/day)nMean dose (mg/day)
  1. SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
Paroxetine2538.124736.394136.39
Fluvoxamine36131.4435138.2846134.49
Sertraline8892.696893.366995.68
Milnacipran2795.712497.5224102.11
Duloxetine1855.182355.401555.71

The mean daily dose of aripiprazole in the flexible group at the end-point was 9.8 mg/day. Considering each ADT separately, the mean daily dose of aripiprazole in the flexible group for the patients receiving different antidepressants were as follows: paroxetine, 8.2 mg/day; fluvoxamine, 9.6 mg/day; sertraline, 10.5 mg/day; milnacipran, 9.8 mg/day; and duloxetine, 9.3 mg/day.

Subgroup analyses

The mean MADRS total scores were improved to significantly greater extents in the fixed-dose aripiprazole and flexible-dose aripiprazole groups (−10.5 and −9.6, respectively) than in the placebo group (−7.4). Table 3 shows the mean changes in the MADRS total scores from the end of SSRI/SNRI treatment to the double-blind treatment for each of the subpopulations. The changes in the MADRS total scores at the end-point were consistently greater with aripiprazole groups than the placebo group across each of the subgroups. There were no interaction effects of treatment and subgroups. Efficacy was not related to sex, age, number of adequate ADT trials in the current episode, MDD diagnosis, number of depressive episodes, duration of current episode, age at first depressive episode, time since first depressive episode, type of SSRI/SNRI or severity at the end of the SSRI/SNRI treatment phase (in terms of the MADRS total score, HAM-D17 total score and CGI-S score).

Table 3. Mean change in MADRS total score from the end of SSRI/SNRI treatment to double-blind phase (LOCF)
 Aripiprazole flexible dose (3–15 mg/day)Aripiprazole fixed dose (3 mg/day)PlaceboInteraction test (P-value)
nBaselineMean changeDifference from placebonBaselineMean changeDifference from placebonBaselineMean change
  1. aMADRS total score median: 25.0.
  2. bHAM-D17 score median: 19.0.
  3. CGI-S, Clinical Global Impression Severity Scale; HAM-D17, 17-item Hamilton Rating Scale for Depression; LOCF, last observation carried forward; MADRS, Montgomery–Åsberg Depression Rating Scale; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
SexMale10125.9−9.0−1.412425.4−10.9−3.311525.4−7.50.376
Female9324.7−10.2−2.97324.9−9.8−2.68025.7−7.2
Age20–30 years old4126.2−9.4−0.62724.6−9.7−0.93924.0−8.80.269
30–40 years old7825.6−8.9−2.07925.1−12.1−5.26426.5−6.9
40–50 years old4423.9−9.3−2.16525.6−9.2−2.17026.2−7.2
50–60 years old3025.8−11.5−4.82126.5−11.0−4.41921.6−6.6
≥60 years old117.0−14.8−2.7521.2−4.57.6334.0−12.2
No. of adequate antidepressant trials in current episode1 trial11924.3−9.7−1.913024.8−10.4−2.612424.9−7.80.331
2 trials5426.7−9.1−1.95326.5−9.7−2.54926.4−7.2
3 trials2127.5−10.3−5.01424.9−13.5−8.12226.8−5.4
DSM-IV-TR diagnosisSingle episode10225.2−9.8−2.312224.7−10.7−3.111325.9−7.50.997
Recurrent episode9225.4−9.3−2.27526.1−10.3−3.18225.0−7.1
No. of depressive episodesFirst episode10225.2−9.8−2.312224.7−10.7−3.111325.9−7.50.147
2 episodes6226.3−8.20.04725.1−10.6−2.44925.8−8.2
≥3 episodes3023.6−11.7−6.12827.8−9.8−4.23324.0−5.6
Duration of current episode<6 months5824.2−10.6−2.66324.2−9.4−1.35926.4−8.00.523
6–12 months6425.8−8.5−2.26524.9−10.8−4.55625.1−6.3
12–24 months3225.6−9.6−1.13526.4−11.8−3.33826.7−8.5
≥24 months4026.0−9.7−2.53426.7−10.3−3.14223.8−7.2
Age at first episode<20 years1425.1−10.6−0.6427.3−5.94.1524.8−10.00.799
20–30 years6126.7−9.2−1.05025.2−10.7−2.45624.7−8.2
30–40 years6625.2−8.9−2.68125.4−10.6−4.37726.3−6.3
40–50 years3522.9−9.4−1.74926.0−10.4−2.74026.0−7.7
50–60 years1726.4−12.3−3.91122.5−11.4−3.01724.0−8.4
≥60 years117.0−11.6 213.5−8.2 0  
Time since first depressive episode<12 months5425.2−9.6−2.47623.4−10.1−3.05726.3−7.10.859
12–24 months2523.4−9.9−0.62726.0−12.0−2.73226.9−9.3
24–36 months2324.6−10.8−4.51526.7−8.7−2.42224.0−6.3
≥36 months9226.1−9.0−1.77926.4−10.7−3.58424.9−7.2
Severity at the end of SSRI/SNRI treatmentaMADRS total score<Median9219.1−8.2−2.59519.8−8.1−2.48719.2-5.70.484
≥Median10230.9−10.8−1.910230.4−12.6−3.710830.6-8.9
bHAM-D17 total score<Median8020.0−9.2−1.97721.0−9.8−2.58221.0-7.30.772
≥Median11429.1−9.9−2.612028.0−10.9−3.611328.8-7.4
CGI-S≤33217.7−10.5−4.12218.9−8.5−2.23120.5-6.40.733
413825.9−9.2−2.313924.7−10.4−3.512924.6-7.0
≤52432.2−10.2−0.73631.0−12.2−2.73533.5-9.5
Type of SSRI/SNRIParoxetine2523.6−10.3−0.94724.6−9.6−0.34124.8−9.30.422
Fluvoxamine3626.4−8.9−0.73524.9−10.0−1.84625.0−8.2
Sertraline8825.1−10.7−4.36824.8−11.3−4.96926.1−6.4
Milnacipran2727.7−6.4−1.72426.5−8.7−3.92427.0−4.8
Duloxetine1822.9−9.3−1.22327.0−12.3−4.21524.3−8.1

MADRS and HAM-D17 individual item analyses

The mean changes in the MADRS individual item scores during the 6-week double-blind treatment phase are shown in Figure 1. Adjunctive aripiprazole at either 3–15 mg/day or 3 mg/day significantly improved seven of the 10 MADRS items compared to adjunctive placebo. At week 1, aripiprazole at either 3–15 mg/day or 3 mg/day significantly improved the following items: Apparent sadness, Reported sadness, Lassitude, Inability to feel, and Suicidal thoughts. At week 2, aripiprazole showed greater improvements in Pessimistic thoughts than did placebo. At week 3, aripiprazole in both groups significantly improved Reduced appetite compared to placebo.

Figure 1.

Mean changes in Montgomery–Åsberg Depression Rating Scale (MADRS) individual items during treatment with aripiprazole or placebo. image, Aripiprazole 3–15 mg/day; image, Aripiprazole 3 mg/day; image, Placebo. *P < 0.05, **P < 0.01, ***P < 0.001 vs placebo (ancova with the score at the end of selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor treatment phase as a covariate.)

The mean changes in the HAM-D17 individual item scores during the 6-week double-blind treatment phase are shown in Figure 2. Significantly greater reductions at the end-point were observed in the following HAM-D items for both aripiprazole groups compared to the placebo group: Depressed mood, Work and activities, Somatic symptoms (gastrointestinal), Insomnia (early), Guilt, Suicide, Anxiety psychic, Anxiety somatic, Hypochondriasis and Retardation.

Figure 2.

Mean changes in Hamilton Rating Scale for Depression (HAM-D) individual items during treatment with aripiprazole or placebo. image, Aripiprazole 3–15 mg/day; image, Aripiprazole 3 mg/day; image, Placebo. *P < 0.05, **P < 0.01, ***P < 0.001 vs placebo (ancova with the score at the end of selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor treatment phase as a covariate.)

Discussion

These post-hoc analyses indicate that aripiprazole was effective for a variety of patient subgroups. There appears to be no demographic- or disease-related factors that affected the clinical responses to aripiprazole in this study. Notably, aripiprazole was effective regardless of the severity at the end of the SSRI/SNRI treatment phase. Aripiprazole improved MADRS total scores in mild, moderate, and markedly ill patients. In addition, we suggested that aripiprazole was effective regardless of the type of SSRI/SNRI. Due to the high placebo response in the paroxetine group, the treatment differences in terms of MADRS total scores appeared to be relatively small. The US trials have demonstrated that aripiprazole induces similar improvements in MADRS total scores when used with five antidepressants: escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine.[15] The results of our post-hoc analyses in Japanese MDD patients are consistent with those in the US trials.

Greater improvements in a broad range of symptoms were observed in the aripiprazole groups over the placebo group in the MADRS and HAM-D17 item analyses. Furthermore, aripiprazole significantly and rapidly improved core depressive symptoms, such as depressed mood, sadness, and guilt, as early as week 1. The pattern of improvement that resulted from aripiprazole was different than those that have been reported for olanzapine/fluoxetine combination and adjunctive extended-release quetiapine fumarate (quetiapine XR). The olanzapine/fluoxetine combination demonstrated significant improvements in apparent sadness, reported sadness, inner tension and suicidal thoughts from week 0.5 through week 7 compared to the fluoxetine group.[19] Additionally, adjunctive quetiapine XR significantly improved the symptoms of reduced sleep, pessimistic thoughts and concentration difficulties in 10 MADRS items at week 1. At week 6, adjunctive quetiapine XR at 300 mg/day significantly improved the following four of the 10 MADRS items: reduced sleep, pessimistic thoughts, suicidal thoughts, and inner tension.[20] These different patterns of improvement might contribute to the pharmacological profiles.

General patterns of improvement by antidepressant treatment alone were different from the pattern by aripiprazole. Shelton et al. revealed that duloxetine, an SNRI, improved depressed mood, feelings of guilt and psychic anxiety in the HAM-D17 within 2 weeks and depressed mood, suicidal ideation, work and activities and psychic anxiety at end-point (8 weeks) in patients with moderate and severe depression.[21] An SSRI, escitalopram at 10 and 20 mg/day, significantly improved apparent sadness, reported sadness, inner tension, concentration difficulties and suicidal thoughts at 8 weeks after the treatment.[22]

The item analysis of the HAM-D17, which is heavily weighted toward behavioral and somatic symptoms of depression, also demonstrated that aripiprazole improved the following symptoms: anxiety psychic, anxiety somatic, somatic symptoms GI and insomnia early as well as depressed mood and guilt. These results from this Japanese trial are consistent with those from the US trials.[16, 23] Core mood symptoms and anxiety are the most frequent residual symptoms and occurred in more than 70% of patients, and there is the strongest association between patient functioning and residual core mood symptoms, with an odds ratio of 8.7.[24] Therefore, it is important that aripiprazole rapidly improved the core depressive symptoms because this effect suggests that aripiprazole improved functioning. Indeed, aripiprazole has been shown to improve Sheehan Disability Scale total score and all three domains (Work/School, Social Activity and Family Life).[14]

This study had some limitations. It involved post-hoc analyses of a dataset that was not designed to examine the subpopulations and individual item changes as primary outcome measures. The selection of patients for this study may limit the generalizability of the results to clinical practice due to the comorbidity of mental and physical disorders that is commonly found in patients with MDD.

In conclusion, these post-hoc analyses indicate that aripiprazole is effective for a variety of Japanese patients with MDD who have exhibited inadequate responses to ADT. Additionally, we suggest that aripiprazole significantly and rapidly improves core depressive symptoms, including depressed mood, sadness, and guilt, in Japanese patients with MDD.

Acknowledgments

The authors thank the participants of this study and the members of the ADMIRE study group. We acknowledge Sakiko Yamada (Otsuka Pharmaceutical Co., Ltd) for editorial assistance with the manuscript. This study was supported by Otsuka Pharmaceutical Co., Ltd. Dr Ozaki has received research support or speakers' honoraria from, or has served as a consultant to, Abbvie, Asahi Kasei Pharma, Astellas, Dainippon Sumitomo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Meiji Seika Pharma, Mochida, MSD, Novartis Pharma, Ono, Otsuka, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi, Sanofi, and Yoshitomi. Dr Otsubo has received speakers' honoraria from Eli Lilly, GlaxoSmithKline, Mochida, MSD, Otsuka, Pfizer, and Tanabe Mitsubishi. Dr Kato has received speakers' honoraria from GlaxoSmithKline and Otsuka. Dr Higuchi has received research support or speakers' honoraria from, or has served as a consultant to, Abbot, Asahi Kasei Pharma, Bristol-Myers Squibb, Chugai, Dainippon Sumitomo, Eli Lilly, GlaxoSmithkline, Janssen, Kyowa-Hakko Kirin, Meiji Seika Pharma, Mochida, MSD, Otsuka, Pfizer, Shionogi, Taisho Toyama and Tanabe Mitsubishi. Mr Ono is an employee of Otsuka Pharmaceutical Co., Ltd. Dr Kamijima has served as a consultant to Asahi Kasei Pharma and has received speakers' honoraria from Pfizer, GlaxoSmithKline, Otsuka, Astellas, Eli Lilly, Shionogi, Dainihon Sumitomo, MSD, Yoshitomi, and Mochida.

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