Non response at week 4 as clinically useful indicator for antidepressant combination in major depressive disorder. A sequential RCT

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Abstract

We aimed to compare the efficacy and tolerability of mirtazapine versus SSRIs and to assess whether “non-response at week 4” may be a clinical indicator for combining mirtazapine and SSRIs for subsequent treatment. One-hundred fifty-four outpatients with MDD were randomized to receive mirtazapine or SSRIs in step I (4 weeks). Non-responders in step I were randomly assigned to either mirtazapine or SSRIs monotherapy or their combination in step IIa while responders in step I continued the same monotherapy in step IIb for 4 weeks. In step I, mirtazapine showed significantly faster improvement as shown by higher remission rate at week 2 with NNT = 8 compared to SSRIs. Somnolence rate was higher in mirtazapine and nausea rate was higher in SSRIs. In step IIa, combination therapy showed a more favorable time course than SSRIs monotherapy. For subjects taking SSRIs in step I, combination therapy showed significant better improvement in the Hamilton Depression Rating (HAM-D) score both at week 6 (p = 0.006) and 8 (p = 0.013) than SSRIs monotherapy. About 80% of responders at week 4 could reach remission at week 8 and 64% of non-responders could not reach remission at week 8 for patients who continued monotherapy. When mirtazapine was added on for SSRIs non-responders at week 4, the remission rate increased by 5% and HAM-D score improved by 4 points. While for mirtazapine non-responders, SSRIs add-on was not equally effective.

Mirtazapine may provide a faster improvement and “non-response at week 4” may be indicator to mirtazapine add-on for patients receiving SSRIs.

Introduction

According to the World Health Organization, major depressive disorder is among the most important causes of disability, accounting for around one fifth of years lived with disability among adults aged 15 years and over (World Health Organization, 2008) despite its relatively low mortality. The introduction and development of antidepressant drugs has largely contributed to the treatment of major depressive disorder, however, the efficacy of these treatments remains uncertain (Rush et al., 2006, Souery et al., 2007).

Mirtazapine and SSRIs are both first-line medication for major depressive disorder and their combination is also suggested for patient of treatment resistant to the first antidepressant medication (Bauer et al., 2013, Kennedy et al., 2016). A meta-analysis found mirtazapine having a more favorable treatment response than SSRIs at week 2, but no difference in efficacy was found at the end of the 6-weeks treatment (Watanabe et al., 2011). As for antidepressant combination therapy, there is only one RCT to assess the mirtazapine combination treatment compared to continuation of antidepressant monotherapy in 26 patients with major depression who failed to respond the first antidepressant treatment (Carpenter et al., 2002). In this study, adjunctive mirtazapine appeared more effective than monotherapy. Meanwhile discrepant findings were reported in RCTs that compared monotherapy to combination from treatment initiation (Blier et al., 2009, Blier et al., 2010, Rush et al., 2011).

Our clinical questions were as follows; 1. Which is a better treatment between mirtazapine and SSRIs for drug free patients with major depression? 2. Could “response” during the first 4 weeks of treatment be a predictor of remission at week 8? 3. Could the combination therapy of mirtazapine and SSRIs for week 4 non responders contribute to a better outcome than the monotherapies? Genotype Utility Needed for Depression Antidepressant Medication (GUNDAM) study (Kato, 2011) is the project focused on the personalized first-line treatment and subsequent combination treatment based on a series of biological and clinical factors such as genetic factors, proteomic factors, neurophysiological factors, temperament, childhood trauma and so on. This is the first report from GUNDAM study to present the result of a randomized clinical trial of SSRIs and mirtazapine in acute treatment phase (step I) and monotherapy and combination therapy for patient who could or could not reach response (step II).

Section snippets

Study design

GUNDAM is a two-step, open-label, randomized, flexible dose, 8-week study (Fig. 1). We directly compared the efficacy and tolerability of mirtazapine versus SSRIs for drug free patients with major depressive disorder in step I (4 weeks). For patients who had inadequate response to the antidepressant in step I, we compared the efficacy and tolerability of continuing mirtazapine or SSRIs monotherapy versus their combination in step IIa (4 further weeks). For patients who reached response in step

Baseline characteristics

Fig. 1 presents the study flow diagram. From September 2011 through December 2014, a total of 207 patients were screened, 154 were enrolled and 141 took at least one post baseline HAM-D assessment during the step I study. Out of 126 patients who completed step I, 58 patient failed to reach response and were randomly assigned again and 45 patients (mirtazapine; n = 13, SSRIs; n = 12 and combination; n = 20) had at least one post 4-week HAM-D assessment during the step IIa. On the other hand, 68

Discussion

We reported the results of a sequential RCT of mirtazapine and SSRIs and this is the first study to investigate “response at week 4” as a predictor of remission at week 8 and as an indicator for the superiority of subsequent antidepressant combination. Overall, both antidepressants improved the depressive symptoms in subjects with untreated depression in step I, 4-week treatment.

In our Japanese subjects, mirtazapine showed significantly faster improvement as shown by higher remission rate at

Role of funding source

This study was supported by Grant-in-Aid for Scientific Research (No. 23591684) to Masaki Kato.

Conflict of interest

Dr. Kato has received grant funding from Grant-in-Aid for Scientific Research (C) (KAKEN 23591684) from Japan Society for the Promotion of Science (JSPS) and speaker's honoraria from Dainippon-Sumitomo Pharma, Otsuka, Meiji-Seika Pharma, Eli Lilly, MSD K.K., GlaxoSmithkline, Pfizer, Janssen Pharmaceutical, Shionogi, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical and Ono Pharmaceutical within the past 3 years.

Dr. Takekita has received speaker's honoraria from Dainippon-Sumitomo Pharma, Otsuka,

Acknowledgments

The authors thank Drs. Sumiko Takahasi, Satoshi Irisawa and Yoshiki Ohashi for help of data collection.

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