Additional Clinical Benefit of Agomelatine Treatment for Major Depressive Disorder in Naturalistic Treatment Setting

Abstract

Objective

This study tried to observe additional benefit of agomelatine (AGO) treatment for major depressive disorder (MDD) in routine practice.

Methods

Retrospective chart review (n = 63) was conducted for additional benefit of combination with or switching to AGO in MDD patients without full remission. The primary endpoint was the mean change of Clinical Global Impression-Clinical Benefit (CGI-CB) total scores from baseline to the endpoint. Additional secondary endpoints were also collected.

Results

The changes of CGI-CB (Z = −3.073, p = 0.002) and Montgomery-Åsberg Depression Rating Scale (Z = −3.483, p < 0.001) total scores were significantly decreased from baseline to the endpoint, respectively. At the endpoint, the remission rate was 22.6% (n = 18) and 28.6% of patient had improvement in CGI-CB total scores at the endpoint. No significant adverse events were observed.

Conclusion

This study has shown additional benefit of AGO treatment as combination or switching agent for MDD patients without full remission in routine practice. However, adequately-powered and well-controlled studies are necessary for generalization of the present findings.

INTRODUCTION

The primary goal of treatment for patients with major depressive disorder (MDD) is the complete resolution of depressive symptoms and recovery of premorbid func-tion. Despite widespread pharmacotherapy, substantial proportion of MDD patients suffers inadequate symptom reduction, adverse events (AEs), and/or incomplete recovery leading to frequent relapse, recurrence, and/or functional impairment [1-4]. Most treatment guidelines suggest switching (SW) to different antidepressants (ADs), combination (COM) with different ADs, and augmentation (AUG) with another psychotropics such as atypical antipsychotics and mood stabilizers upon failure to adequate trial with current Ads [5,6]. However, none of such treatment strategies has failed to show the relative superiority over other treatment modalities yet.

Agomelatine (AGO) is a new AD presenting quite different action mechanisms including agonist and antagonist effects at melatonergic (MT1 and MT2) receptors and serotonergic 5-HT_2C receptor, respectively, which may show additional benefit in reduction of anxiety, sleep problem and weight gain in MDD patients [7]. AGO has consistently proven its short-term and long-term efficacy, and safety in numerous clinical trials [8,9]. Notably AGO was found to be the best acceptable AD for treatment of MDD as well as being one of top-tier medication in efficacy and tolerability in comparison with numerous ADs in successive large meta-analysis studies [10-12]. How-ever, there has been a dearth of data regarding AGO as combination (AGOCOM) or switching (AGOSW) for MDD patients in naturalistic treatment setting yet.

Hence, the present study aimed to observe the additional benefit of AGOCOM or AGOSW therapy in MDD patients with inadequate clinical outcomes despite of adequate current AD treatment in routine practice.

METHODS

Medical records were retrieved from those who were treated with AGOCOM or AGOSW for further clinical benefit for 8 weeks in outpatients with MDD without full remission in routine practice. AGOCOM was added on current ADs and AGOSW was changed from current AD, with flexible dose adjustment. Included subjects were MDD outpatients with inadequate clinical outcomes despite of more than 8 weeks ongoing AD treatment in routine practice at Bucheon St. Mary’s Hospital. Any subjects who had another AXIS I/II disorders were excluded, while patients with comorbid medical conditions were not excluded.

All endpoints were collected from baseline to the end of 8 weeks treatment. The primary endpoint was the mean change of total scores of Clinical Global Impression- Clinical Benefit (CGI-CB) [12]. Secondary endpoints included; the mean changes of Montgomery–Åsberg De-pression Rating Scale (MADRS) [13] total scores, proportions of responder (≥ 50% reduction of MADRS total score), remitter (≤ 11 of MADRS total score) and improvers in CGI-CB score at the endpoint of treatment. The CGI-CB score of 1 indicates the greatest benefit (effective-ness) with least burden (AEs) from treatment, whereas score of 10 indicates the least benefit with the greatest burden from the treatment. The CGI-CB improver was defined those who shown a decrease in CGI-CB total score 1 or more at the endpoint. The proportion of patients achieving total CGI-CB scores 1 through 4 at the end of treatment was also collected. Patients’ satisfaction was assessed by visual analog scale (VAS) from 1 (lowest) to 10 (highest). Any occurrence of AEs throughout the study was reported.

The power of the present sample size was 90%, with observed mean difference in MADRS at the end of treatment (effect size = 0.7, β = 0.1), under an alpha value of 0.05 with two tailed. Non-parametric analyses were done if the data distribution was not in normative range after Kolmogorov-Smirnov test, otherwise all data was analyzed by parametric analyses. Descriptive statistics, Wilcoxon Signed Rank (or paired ttest) test, chi-square test were performed where appropriate. Statistical significance was determined at p < 0.05. Statistical analysis was performed using the NCSS v07 for Windows (NCSS Inc.) program.

The present study has been thoroughly reviewed and approved by local Institutional Review Board (approval number: HC21RISE0140).

RESULTS

Sixty-three patients were enrolled and analyzed during the study. The sample included a greater proportion of female patients (n = 38, 60.3%) with mean age of 43 years. AGOCOM was 53 subjects (84.1%) and 10 (15.9%) were on AGOSW treatments in the study.

The mean onset age of MDD was 39.4 years. The baseline MADRS and CGI-CB total scores were 16.0 and 6.6, respectively. The most common antidepressant and antianxiety medication were venlafaxine and alprazolam, respectively. The mean daily AGO dose was 24.2 mg/d (± 5.4) at the end of study. Table 1 displays baseline clinical and demographical of patients in detail.

Table 1.

Clinical parameters of the sample during the study

Variable	Value
Age (yr)	43.2 ± 18.3
Sex, female	38 (60.3)
Marital status (married)	29 (46.0)
Education
High school or higher	57 (90.4)
Family history	0 (0.0)
General national health insurance	50 (79.3)
Comorbidity	11 (17.4)
Onset age (yr)	39.4 ± 16.6
History of admission	2 (3.2)
Number of previous MDD episode	2.8 ± 1.9
Duration of current treatment (mo)	6.0 ± 3.7
MADRS at baseline/endpoint	16.0 ± 4.3/14.5 ± 5.4
CGI-CB at baseline/endpoint	6.6 ± 2.8/5.9 ± 3.0
VAS at baseline/endpoint	6.4 ± 0.6/6.5 ± 1.0
Proportion of the patients on CGI-CB 1−4 at baseline/endpoint	15 (23.8)/24 (38.1)
Antidepressants
Escitalopram	16 (25.3)
Fluoxetine	3 (4.7)
Paroxetine	5 (7.9)
Sertraline	3 (4.7)
Mirtazapine	2 (3.1)
Venlafaxine	23 (36.5)
Others	11 (17.4)
Antianxiety drugsa
Alprazolam	29 (46.0)
Lorazepam	4 (6.3)
Clonazepam	16 (25.3)
Others	5 (7.9)

Values are presented as mean ± standard deviation or number (%).

MDD, major depressive disorder; MADRS, Montgomery and Asberg Depression Rating Scale; CGI-CB, Clinical Global Impression- Clinical Benefit; VAS, visual analog scale.

^aOne patient had combined benzodiazepine treatment.

The changes of CGI-CB, MADRS and VAS total scores from baseline to the endpoint were −0.8, −1.1, and 0.3, respectively (p = 0.002, p = 0.05, and p < 0.0001). At the endpoint, the responder and remitter rates were 1.6% (n = 1) and 22.6% (n = 14), respectively.

The CGI-CB improvers were 28.6% (n = 18) at the endpoint. In detail, the most frequent score at baseline on the CGI-CB was 7 (n = 25), indicating mild therapeutic effect/no side effect (SE) burden, followed by scores of 10 (n = 18), indicating no therapeutic effects/outweighs therapeutic effect in burden of AEs, 2 (n = 7), 3 (n = 5), 4 (n = 2), 5 (n = 2) and 1 (n = 1) indicating moderate to marked therapeutic effect/none to clinically significant SE burden. At the endpoint, the most frequent score on the CGI-CB was 7 (n = 19), indicating mild therapeutic effect/no SE burden, followed by scores of 10 (n = 15), indicating no therapeutic effects/outweighs therapeutic effect in burden of AEs, 3 (n = 12), 2 (n = 7), 1 (n = 3), 5 (n = 3), 4 (n = 2) and 6 (n = 1) indicating moderate to marked therapeutic effect/none to clinically significant SE burden.

The patients achieving total CGI-CB scores 1 through 4 was 38.1% (n = 24) at the endpoint, while it was 23.8% (n = 15, 95% confidence interval [CI] = 0.3810, 0.2614 to 0.5120) at baseline, indicating that 9 patients (18.7%, n = 9/48) had more benefit than baseline (McNemar test, Exact Sig = 0.022) (Fig. 1).

Fig. 1.

The number of patients achieving total CGI-CB scores 1 through 4 at baseline and endpoint, respectively. The patients achieving total CGI-CB scores 1 through 4 was 38.1% (n = 24) % at the endpoint, while it was 23.8% (n = 15, 95% confidence interval = 0.3810, 0.2614 to 0.5120) at baseline, indicating that 9 patients (18.7%, n = 9/48) had more benefit than baseline (McNemar test, Exact Sig = 0.022).

There was no serious AEs during the study. Burning sense (n = 1), headache (n = 2) and tremor (n = 1) were reported.

DISCUSSION

The unique action mechanism of agomelatine (MT1 and MT2 agonist and 5-HT_2C antagonist effects) may assume its potential synergistic effects onto commonly used antidepressants mainly involving serotonergic and noradrenergic neurotransmission, where its proven effects on depressive-like behavior, anxiety, and disrupted circadian rhythms in preclinical and clinical trial studies [13]. According to the recent systematic review and network meta-analysis including 522 trials comprising 116,477 subjects, agomelatine has shown the highest acceptability (odds ratio [OR] 0.84, 95% CI 0.72−0.97) as well as the lowest dropout rate due to AEs (OR 1.21, 95% CI 0.94−1.56) among all included antidepressants, while all other antidepressants were related to higher withdrawal rates than placebo with ORs (1.64 to 4.44) [10]. Such trend was also represented in the head-to-head comparison analyses. However, there has been a paucity of combination/switch treatment of agomelatine with other antidepressants in real world data, only a handful of uncontrolled small case series have shown potential effects for the AGOCOM/AGOSW in real world though [14,15].

Our study has shown the potential effects of AGOCOM/ AGOSW in real world, where AGOCOM/AGOSW has shown significant and modest improvements in most endpoints. The significant and marginal decrease in MADRS total scores and the number of responders might be caused by baseline effects in relation with the severity of MDD. Indeed baseline severity, symptom domain, assessment scale and gender were found to be related to differential efficacy of antidepressants [16,17]. Interestingly in our previous study using aripiprazole AUG for patients with partially remitted MDD, the additional reduction of Hamilton Depression Rating Scale-17 items (HAMD-17) was only 3 points, it was also significant improvement from the baseline (HAMD total score, 8 to 15) though [2]. In fact positive correlation between MADRS and HAMD scores in assessment or improvement of depression symptoms has been proved [18]. Various residual symptoms may also affect less improvement in MADRS total scores [2,19].

However, the increase of the patients achieving total CGI-CB scores 1 through 4 (25% increase) was impressive proposing overall clinical benefit of AGOCOM/AGOSW in terms of balanced efficacy/AEs in real world. The remission rates of 22.6% was also comparable to that of controlled trials using different class of antidepressants combination [20]. The significant mean decrease from 7 to 6 in CGI-CB total scores should be also in line with the results from Combining Medications to Enhance Depres-sion Outcomes trial led by Dr. Rush [20].

Our study has clear pitfalls in generalization of the findings. The study design was retrospective with small samples and thereby natural improvement of the illness should be considered. Treatments including existing antidepressant type and dose of agomelatine were not con-trolled. Assessment biases could not be excluded. No structured interview was used for the diagnosis of MDD, although mean previous MDD episode was 3. Finally, the 2-month study duration may be also inadequate for proper assessment of patients’ symptom changes.

In conclusion, this study has shown additional benefit of AGO treatment as combination or switching agent for MDD patients with no full remission in routine practice. However, adequately-powered and well-controlled studies are necessary for generalization of the present findings.

Funding Statement

Funding This study was supported by Whan In Pharm. Co., Ltd, Seoul, Korea; the funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.