For patients enrolled in the open-labeled extension study, the mean HAM-D17 total score for 50 patients on entry to the extension phase was 12.0 (SD=6.1). The mean HAM-D17 total score for 40 patients who completed the 44-week treatment was 5.7 (SD=6.0) and the remission rate was 75.0% (30/40). Findings from other secondary endpoints, including CGI-S, CGI-I, and QIDS16-SR-J, confirmed the sustained long-term efficacy of venlafaxine (data not shown).
During the treatment period, a comparable proportion of patients experienced AEs in all study groups: 118 (67.8%), 138 (76.7%), and 108 (59.0%) patients in the fixed-dose, flexible-dose, and placebo groups, respectively. In the tapering/follow-up periods, AEs occurred in 49 (33.8%), 50 (30.9%), and 46 (28.0%) patients in the fixed-dose, flexible-dose, and placebo groups, respectively. Treatment-related AEs during the treatment period were reported for 90 (51.7%), 122 (67.8%), and 71 (38.8%) patients in the fixed-dose, flexible-dose, and placebo groups, respectively. Frequently reported AEs in the venlafaxine groups, experienced by more than twice the number of patients than in the placebo group, were nausea, somnolence, constipation, dizziness, increased heart rate, malaise, abdominal discomfort, and hyperhidrosis (Table 3); most AEs were mild or moderate in severity.
Sustained hypertension (defined as systolic blood pressure≥140 mmHg with change from baseline≥20 mmHg, diastolic blood pressure≥90 mmHg with change from baseline≥10 mmHg, or pulse rate≥100 bpm with change from baseline≥15 bpm observed over three consecutive visits) was experienced by less than 3% patients and was comparable across all treatment groups. There were no clinically significant AEs in laboratory tests.
SAEs were rarely experienced by patients in any treatment group: however, one death was reported in each of the flexible-dose and placebo groups. The cause of both deaths was suicide; however, the relationship with the study drug could not be ruled out. Other SAEs included one case each of anemia and Ménière’s disease in the placebo and fixed-dose groups, respectively; these SAEs were considered unrelated to the study drug. Among patients who discontinued the study drug because of AEs, a causal relationship with the study drug could not be ruled out for three patients in each of the fixed-dose and placebo groups, and nine patients in the flexible-dose group.
After study treatment initiation, self-injurious behavior was reported in one patient in the fixed-dose group, who discontinued the study because of agitation, which occurred concurrently with the self-injurious behavior. Suicidal ideation was confirmed in 41 (23.6%), 47 (26.1%), and 39 (21.3%) patients in the fixed-dose, flexible-dose, and placebo groups, respectively, in the Columbia-Suicide Severity Rating Scale. The proportion of patients in whom suicidal ideation was not confirmed at baseline but occurred after study treatment initiation was 7 (4.0%), 13 (7.3%), and 21 (11.5%) patients in the fixed-dose, flexible-dose, and placebo groups, respectively.
Among the patients enrolled in the open-labeled extension study, 49 (98.0%) patients experienced AEs and SAEs were observed in 3 (6.0%) patients, but there were no deaths during the 52-week study period. Similar to the double-blinded study, frequently reported AEs were nasopharyngitis, headache, dizziness, somnolence, nausea, constipation, and increased blood pressure; most of these were mild or moderate in severity. The only severe AE, which occurred in one patient, was crime (theft and sexual abuse). No new clinically significant safety issues specific to Japanese patients emerged during the long-term study.
The present randomized double-blinded placebo-controlled study was carried out in Japan to investigate the efficacy and safety of fixed (75 mg/day) and flexible (75–225 mg/day) doses of venlafaxine ER in patients with MDD. After 8 weeks of double-blinded treatment, the difference in the mean reduction of HAM-D17 as the primary efficacy variable was statistically significant in the fixed-dose, but not the flexible-dose group compared with placebo. However, secondary efficacy parameters such as MADRS, HAM-D6, and CGI-S showed consistent and significantly greater reduction in both venlafaxine groups compared with placebo. In addition, CGI-I showed significantly greater improvement in the flexible-dose group compared with placebo. Thus, it is assumed that MADRS was more sensitive to antidepressant drug effects than HAM-D17 in this study, considering the previous reports (Galinowski and Lehert, 1995; Mulder et al., 2003; Carmody et al., 2006). As both MADRS and HAM-D are recommended as primary measures in clinical trials (Japanese guideline, 2010; EMA guideline, 2013), the treatment difference detected by MADRS in this study was clinically important.
The reason for the inconsistent result for the flexible-dose group among the scales used in the present study may possibly be the characteristics related to sensitivity to the symptoms of depression. In the characteristics of scales for sleep items, HAM-D17 consists of three separate items including early, middle, and late insomnia, whereas MADRS has just one item evaluating the same aspects of insomnia as HAM-D17. As described previously in Fig. 2b, an improving trend was observed in the sleep disturbance scores of HAM-D17 until week 4, following which the flexible-dose group deviated from the improving trend shown by the fixed-dose and placebo groups. The total HAM-D17 score for the flexible-dose group was clearly affected by less improvement in the sleep disturbance scores. Thus, it can be suggested that HAM-D17 was more sensitive in capturing sleep disturbance when the dose was titrated to 225 mg because of venlafaxine’s norepinephrine uptake inhibition. Venlafaxine is known to sequentially engage the mechanisms of serotonin 5-HT at a low dose (75 mg/day) and norepinephrine uptake inhibition at a high dose (225 mg/day) (Harvey et al., 2000; Debonnel et al., 2007). More than 80% of patients in the flexible-dose group took 225 mg/day at week 4, beyond which no improvement in the sleep disturbance score of HAM-D was observed. This could be attributed to the enhancement of norepinephrine signaling, which is a critical component of the arousal pathway (Mitchell and Weinshenker, 2010). For example, reboxetine, an SNRI, was associated with a significantly higher incidence of insomnia than placebo (Tanum, 2000). In addition, almost all patients took the study drug in the evening (data not shown), which might cause lower reduction in the sleep disturbance score of HAM-D in the flexible-dose group because of a noradrenergic effect.
The norepinephrine effect is in line with the suggestion that higher doses, as used in the flexible-dose group of our study (75–225 mg/day), could be more effective for patients with severe disease (Berney, 2005; Debonnel et al., 2007), given that the severity of depression may influence the relationship between SNRI dose and clinical response. This could potentially explain the lack of a statistically significant clinical response in the flexible-dose group compared with placebo for some of the efficacy measures in our study (Table 2). The majority of patients in the present study had moderate depression at baseline, with a mean HAM-D17 score less than 23 (Shelton et al., 2007) and a mean MADRS score less than 35 (Müller et al., 2000); therefore, the relatively lower doses used in the fixed-dose group (75 mg/day) aligned better with the treatment requirements of the patient population, producing better outcomes than in the flexible-dose group. In addition, a mild-to-moderate placebo response, as found in recent placebo-controlled studies of MDD, could have reduced the likelihood of detecting a large treatment difference associated with HAM-D17 response between the venlafaxine groups and placebo in the present study (Papakostas and Fava, 2009b; Khan et al., 2010; Khin et al., 2011). Nevertheless, the minimally effective dose of venlafaxine 75 mg/day was superior to placebo in efficacy parameters investigated in the present study.
The safety profile of venlafaxine in the present study did not identify any new drug-related risks specific to a Japanese population and the most common AEs observed were consistent with the known profile of venlafaxine (Mendels et al., 1993; Cunningham, 1997; Thase 1997; Khan et al., 1998; Rudolph et al., 1998; Rudolph and Feiger, 1999; Silverstone and Ravindran, 1999). Although venlafaxine has a safe cardiovascular profile, an increase in blood pressure/pulse rate is often observed at doses greater than 300 mg (Thase 1998). Consistent with this observation, up to 3% patients showed sustained hypertension in all treatment groups. No other clinically meaningful difference was apparent between venlafaxine and placebo in the benign safety profile, including laboratory measurements and vital signs. Although overall suicidal ideation was comparable across venlafaxine and placebo groups in this study, it should be noted that there were patients who developed suicidal ideation during the course of study treatment (4.0, 7.3, and 11.5% patients in the fixed-dose, flexible-dose, and placebo groups, respectively); therefore, patients should be informed of this risk before commencement of treatment. Nevertheless, only a small proportion of patients (5.2, 5.6, and 1.6% patients in the fixed-dose, flexible-dose, and placebo groups, respectively), comparable across treatment groups, discontinued the study because of AEs, suggesting that both dosing regimens of venlafaxine were well tolerated in Japanese patients with MDD. Furthermore, the well-tolerated safety profile was confirmed by the extension study, with no new AEs arising during this period.
According to the findings from dose–response studies (Khan et al., 1998; Rudolph et al., 1998), improvement in efficacy variables did not necessarily increase monotonically, with increasing doses greater than 75 mg/day. Nevertheless, some patients experienced greater benefit with dose escalation in the flexible-dose group (Fig. 4) without an additional increase in SAEs or discontinuation because of AEs (data not shown) in the present study. On the basis of these findings, a majority of patients could be treated with 75 mg/day venlafaxine, but increasing the dose may perhaps be beneficial for selected patients, in particular, those showing little improvement and tolerability to treatment with lower doses of venlafaxine.
It is considered that the findings of the present study will inform treatment decisions and dosing recommendations for the use of venlafaxine in Japan for treating patients with MDD. However, some limitations might have confounded the study results; the short double-blinded treatment period might not have enabled evaluation of the long-term benefits of venlafaxine and excluded patients, especially those with comorbid conditions, which cannot be considered a manifestation of the real-world practice setting. Despite these limitations, this study should be recognized as the placebo-controlled study of venlafaxine conducted in Japan. Perhaps additional subsequent analyses might be useful to identify specific populations who need not titrate up to 225 mg/day as in the flexible-dose group. The forced titration method used in this study allowed us to gather more conclusive data on efficacy and safety at higher doses, despite it being an uncommon approach in actual clinical practice because physicians adjust the dosage of antidepressants on the basis of both the disease condition and tolerability in each patient. Therefore, further investigations are needed to evaluate the antidepressant efficacy of 225 mg/day dosing of venlafaxine in real-world clinical settings in Japan, in addition to making comparisons with other antidepressant agents. Despite these limitations, this study provides strong evidence supporting the antidepressive efficacy of venlafaxine ER, especially the 75 mg fixed-dose regimen, following 8 weeks of double-blinded treatment in patients with MDD. In addition, venlafaxine ER was found to be associated with an acceptable safety profile that was similar to that established in previous studies. Therefore, venlafaxine ER was efficacious and safe for the treatment of MDD in Japan.
The authors gratefully acknowledge the contributions of trial participants, principal investigators, and all the medical personnel in this clinical study. The authors are grateful to the journal reviewers for insightful comments and suggestions that helped improve the content and presentation of this article. Medical writing services were provided by Cactus Communications. All authors retained full control of the manuscript content.
The study received funding from Pfizer, Japan Inc. Editorial support was provided by Lorraine Sweeney of Peloton Advantage and was funded by Pfizer.
Conflicts of interest
Rio Itamura, Yuko Asami, Kazuhiko Kuribayashi, and Takayuki Imaeda are employees of Pfizer Japan Inc., which funded the study. Teruhiko Higuchi received a consulting fee from Sumitomo Dainippon Pharma Co. Ltd, Takeda Pharmaceutical Co. Ltd, Kowa Company Ltd, Chugai Pharmaceutical Co. Ltd, Eli Lilly Japan K.K., Pfizer Japan Inc., Janssen Pharmaceutical K.K., Bristol-Myers Squibb, FP Pharmaceutical Corporation, Nippon Boehringer Ingelheim Co. Ltd, received support for travel to meetings from Pfizer Japan Inc., received grants from AbbVie Inc., Otsuka Pharmaceutical Co. Ltd, Chugai Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K., Meiji Seika Pharma Co. Ltd, Pfizer Japan Inc., Boehringer Ingelheim Japan Inc., GlaxoSmithKline K.K., and Abbott Japan Co. Ltd; also received payment for lectures from MSD K.K. a subsidiary of Merck & Co. Inc., Asahi Kasei Pharma Corp., Otsuka Pharmaceutical Co. Ltd, Sumitomo Dainippon Pharma Co. Ltd, Shionogi & Co. Ltd, Meiji Seika Pharma Co. Ltd, Pfizer Japan Inc., Janssen Pharmaceutical K.K., Kyowa Hakkou Kirin Co. Ltd, and Novartis Pharma K.K., received payment for manuscript preparation from Eli Lilly Japan K.K., and Kyowa Yakuhin Co Ltd. Kunitoshi Kamijima received consulting fee from Asahi Kasei Pharma Corporation, Pfizer Japan Inc., received support for travel to meetings from Pfizer Japan Inc., received payment for lectures from Pfizer Japan Inc., Astellas Pharma Inc., AbbVie Pharmaceuticals, Eli Lilly Japan, Eisai, Osuka Pharmaceuticals, Kyowa Hakko Kirin, Glaxo Smith Kline, Shionogi, Dainippon Sumitomo Pharma, Tanabe Mitsubishi, Meiji Seika Pharma, and Mochida Pharmaceutical Co. Kazuyuki Nakagome received consulting fee from Pfizer Japan Inc., Otsuka Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd, Sumitomo Dainippon Pharma Co. Ltd, Mochida Pharma, Nippon Boehringer Ingelheim Co. Ltd, and Mitsubishi Tanabe Pharma Corporation, received support for travel to meetings from Pfizer Japan Inc., received grants from Mochida Pharma, Tanabe Mitsubishi, Shionogi Pharma, Sumitomo Dainippon Pharma, Otsuka Pharma, Astellas Pharma, and Asahi Kasei Pharma, and received payment for lectures from Otsuka Pharma, Sumitomo Dainippon Pharma, Eli Lilly Pharma, Tanabe Mitsubishi Pharma, Meiji Seika Pharma, GSK, Shionogi Pharma, Janssen Pharma, MSD, and Kyowa Hakko Kirin Co.
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Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Hamilton Rating Scale For Depression; Japan; major depressive disorder; Montgomery–Åsberg Depression Rating Scale; placebo controlled; venlafaxine