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. 2023 Nov 10;102(45):e35871. doi: 10.1097/MD.0000000000035871

Efficacy and safety of agomelatine in the treatment of patients with depressive disorder: A meta-analysis

Yue-Han Guo a, Le Zhou b, Zi-Ang Cui c, Jian Wang d, Lei Zhang e, Ting Xu f, Yi-Dan Xie g, Hui Chen a,*
PMCID: PMC10637518  PMID: 37960759

Abstract

Objective:

To systematically assess the efficacy and safety of agomelatine in the treatment of patients with depressive disorder.

Methods:

Randomized controlled trials (RCTs) related to agomelatine in the treatment of patients with depressive disorder published in PubMed, Web of Science, CNKI, VIP, and Wangfang were retrieved. Extracted data on the efficacy and safety of agomelatine and placebo in the treatment of depressive disorder, and the collected data were processed by RevMan5.4 software.

Results:

A total of 10 RCTs were included. Meta-analysis showed that the HAMD-17 total scores of agomelatine group were statistically different from those of placebo group (odds ratio [OR]: 2.04, 95% confidence intervals [CIs]: 1.71–2.43, P < .001). High heterogeneity was found between agomelatine groups and placebo groups (P < .0001, and I2 = 78%), so a subgroup analysis was further performed, and the heterogeneity became insignificant (P = .33, and I2 = 14%) after excluding the studies, of which course of treatment was 24 weeks or the sample size was relatively small. The adverse events between agomelatine and placebo groups were not statistically significant (OR: 1.15, 95% CIs: 0.69–1.92; P = .05).

Conclusion:

Agomelatine was superior comparable to placebo in the treatment of patients with depressive disorder, and has fewer adverse events.

Keywords: adverse events, agomelatine, depressive disorder, meta analysis

1. Introduction

Depressive disorder is a kind of affective psychiatric illness and the main symptoms are characterized by persistent sadness, loss of interest, lack of energy, and disturbed sleep, and there is a strong suicidal tendency.[1] Moreover, Major depressive disorder is estimated by the World Health Organization to affect more than 264 million people globally, making the disorder one of the leading causes of disability worldwide.[2,3] Currently, the types and mechanisms of antidepressant drugs on the market are limited, and only ~50% of patients respond to frontline antidepressants, and < 33% obtain remission [Hou et al, 2016]. In recent years, the pathogenesis of depressive disorder with some non-monoamine neurotransmitters has been introduced to clinical practice, such as hypothalamus-pituitary-adrenal axis (HPA) hyperactivity, brain-derived neurotrophic factor deficiency, etc.

Agomelatine is an innovative antidepressant drug, which has pharmacological effects by stimulating the melatonin MT1/MT2 receptor and selectively antagonizing the 5-HT2C receptor but the traditional monoamine transmitter system, and has no significant effect on the monoamine transmitter system.[4] Agomelatine also has the function of regulating biological rhythm.[5–7] Therefore, in this paper, the relevant literatures were screened to objectively explore the efficacy and safety of agomelatine in the treatment of depressive disorder through a meta-analysis.

2. Materials and methods

2.1. Literature inclusion and exclusion/inclusion criteria

The search strategy uses “agomelatine” as the key word to search Wanfang database, CNKI, PubMed, and other databases; the search time is from January 1, 2000 to December 30, 2022, and the reference of the final included study is thoroughly screened. The randomized controlled trials (RCT) are included regardless of whether they are age, gender, and race. The subjects of the study were patients with major depressive disorder, who met the fourth edition of the American Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) or met the diagnostic criteria for depressive disorder in the 10th edition of the International Classification of Diseases (ICD-10),[8] none for other serious mental or physical diseases, patients aged 18 years or older, regardless of gender. Patients in the experimental group were treated with agomelatine, and patients in the control group were treated with placebo or other antidepressants. Outcome indicators include total effective rate, cure rate and so on. The safety outcome indicators include the occurrence of adverse reactions. The literature exclusion criteria are that full text is not available; animal experiments; and documents with no data to extract.

2.2. Data extraction

Two review authors independently screened the titles and abstracts of the documents, and retrieved the publications that meet the standards; discrepancies in the publications were determined by the third review author for inclusion in the study. Two authors extracted the data information of the publications, and disagreement was solved by discussion.

2.3. Evaluation of included literature quality using Cochrane Handbook

The evaluation criteria were performed with the Cochrane Handbook for Systematic Reviews of Interventions to evaluate the quality of the literature from 5 aspects: selection bias, scheme bias, measurement bias, follow-up bias, and scoring bias. If these 5 indicators are consistent, the quality of the literature is high; otherwise, corresponding bias may occur.[9]

2.4. Statistical analysis

The measurement data uses the mean difference (MD) and its 95% confidence interval (CI) as the result indicators, and the count data uses the OR and its 95% CI is used as an indicator of the result. When the heterogeneity between studies is small (P > .1, and I2 ≤ 50%), use the fixed-effects model for meta-analysis; if the heterogeneity between studies is too large (P ≤ .1, I2 > 50%), we used random-effects model for meta-analysis. Difference was considered as statistically significant if P < .05.

2.5. Ethics and dissemination

Ethical approval was not required because this study only involved published data.

3. Results

3.1. Study characteristics

The literature screening process is illustrated in Figure 1. Electronic searches yielded a total of 342 publications which were published in 2000 to 2021. After a preliminary review, there were 34 full-text publications were retrieved for a more detailed evaluation, and 10 publications were finally included for the meta-analysis since they were randomized, placebo-controlled clinical trials. Among them, there were 2 Chinese publications and 8 English publications. All of the 10 included publications mentioned the term of random. There were 8 trials that were short-term clinical trials with 6–8 weeks of study duration,[10–17] and 2 trials involved were 24-weeks double-blinded, placebo-controlled trial in patients who showed optimal remission with agomelatine.[18,19] A total of 2146 participants were included, and number of patients included in placebo group and agomelatine groups were 1071 and 1075 respectively. There were 7 publications that used identical dose of agomelatine, 25–50 mg/day,[10,11,14,15,17–19] and 2 publications that used identical dose of agomelatine, 25 mg/day.[12,13] However, in one study, the agomelatine group was further randomized into agomelatine 25 mg/day or 50 mg/day.[16] The basic characteristics of each included publications are shown in Table 1.

Figure 1.

Figure 1.

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A flowchart of the meta-analysis.

Table 1.

Basic characteristics of included publications.

Authors Number (Agomelatine Group Placebo Group) The dose of agomelatine (mg/d) Course of treatment (wk)
Liang et al, 2020 62 (31 31) 25~50 mg/d 6
Lv et al, 2018 60 (30 30) 25~50 mg/d 8
Lôo et al, 2002 276 (139 137) 25 mg/d 8
Yao et al, 2021 68 (48 20) 25 mg/d 6
Kennedy et al, 2006 201 (106 105) 25~50 mg/d 6
Kennedy et al, 2014 277 (136 141) 25~50 mg/d 6
Kennedy et al, 2016 277 (136 141) 25~50 mg/d 24
Zajecka et al, 2010 343 (170 173) 25 mg/d 8
Zajecka et al, 2010 341 (168 173) 50 mg/d 8
Olié et al, 2007 235 (116 119) 25~50 mg/d 6
Goodwin et al, 2009 339 (165 174) 25~50 mg/d 24
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3.2. Efficacy

3.2.1. Primary outcomes: change of HAM-D.

Nine of the included publications provided the mean difference of the HAM-D total score from baseline to study endpoint. The result of the meta-analysis of the HAM-D total score were presented as forest plots in fixed-effect model (Fig. 2A), that suggest they were significantly heterogeneous (P = .02, and I2 = 55%) and we re-analyzed with random-effect model instead of fixed-effect model by default (Fig. 2B).

Figure 2.

Figure 2.

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Changes of HAM-D total score from baseline to end point between 2 groups. (A) fixed-effect model; (B) random-effect model; (C) HAM-D total score after excluding the 2 studies. 95% CI = 95% confidence interval, IV = inverse variance, SD = standard deviation, std = standardized.

Next, we conducted a subgroup analysis to explain the heterogeneity in HAM-D total score from baseline to study endpoint in the included publications in fixed effect model by default. We hypothesized that the heterogeneity occurred due to the study by Kennedy et al,[18] of which course of treatment was 24 weeks and the study by Yao et al,[13] with a small sample size. After excluding the 2 studies, the heterogeneity became insignificant (P = .33, and I2 = 14%).

Moreover, Figure 2A to C indicated that agomelatine groups were more significantly improved in HAM-D total scores than placebo group, and the difference between agomelatine groups and placebo groups were statistically significant in both fixed effect model [MD = −3.50, 95%CI: (−4.02 to −2.98), P < .001, I2 = 55%] and random effect model [MD = −3.66, 95%CI: (−4.57 to −2.74), P < .001, I2 = 55%]. After excluding the studies by Kennedy et al,[18] the superiority in agomelatine groups compared with placebo groups remained statistically significant (MD = −3.28, 95%CI: (−3.82 to −2.75), P < .001, I2 = 0%).

3.2.2. Secondary endpoint: proportion change of response rate.

The secondary endpoint in 8 included publications was clinical response defined as a HAM-D17 total score reduction 50% from baseline,[10–12,14–18] and the result of the meta-analysis of the clinical response rate were presented as forest plots in fixed-effect model (Fig. 3A), that suggest they were moderately heterogeneous (P = .003, and I2 = 65%) and we re-analyzed with random-effect model instead of fixed effect model by default (Fig. 3B).

Figure 3.

Figure 3.

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Changes of clinical response from baseline to end point between agomelatine and placebo treatment groups. (A) fixed-effect model; (B) random-effect model; (C) clinical response after excluding the 2 studies. 95% CI = 95% confidence interval, IV = inverse variance, SD = standard deviation, std = standardized.

Then, a subgroup analysis to explain the heterogeneity in clinical response from baseline was conducted. We hypothesized that the heterogeneity occurred due to the study by Kennedy et al,[18] of which course of treatment was 24 weeks and the study by Zajecka et al,[16] in which the dose of agomelatine was 25 mg/d. After excluding the 2 studies, the heterogeneity became insignificant (P = .27, and I2 = 21%).

The OR of agomelatine over placebo for clinical response rates were, 2.04 (95% CIs, 1.71 to 2.43; P < .001), 2.11 (95% CIs, 1.54 to 2.91; P < .001) and 2.00 (95% CIs, 1.62 to 2.47; P < .001), respectively in fixed-effect model (Fig. 3A) and random-effect model (Fig. 3B), and in fixed-effect model after excluding the 2 studies (Fig. 3C).

3.2.3. Secondary endpoint: proportion change of remission rate.

There were 6 included publications in which the clinical remission rate was the secondary endpoint,[10–12,15,16,18] and clinical remission was defined as HAM-D17 total score < 7 or < 6. The meta-analysis of the clinical response rate that presented as forest plots in fixed-effect model (Fig. 4A), demonstrated that the 6 included publications were moderately heterogeneous (P = .005, and I2 = 68%) and we re-analyzed with random-effect model instead of fixed-effect model by default (Fig. 4B).

Figure 4.

Figure 4.

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Changes of clinical remission from baseline to end point between agomelatine and placebo treatment groups. (A) fixed-effect model; (B) random-effect model; (C) clinical remission after excluding 1 study. 95% CI = 95% confidence interval, IV = inverse variance, SD = standard deviation, std = standardized.

Then, we performed the subgroup analysis to explain the heterogeneity in clinical remission rate from baseline in the 6 included publications. We hypothesized that the heterogeneity occurred also due to the study by Kennedy et al,[18] of which course of treatment was 24 weeks. After excluding the study, the heterogeneity in clinical remission rate became insignificant (P = .39, and I2 = 5%).

The OR of agomelatine over placebo for clinical remission rates were, 2.03 (95% CIs, 1.59 to 2.59; P < .001), 1.99 (95% CIs, 1.24 to 3.19; P = .004) and 1.57 (95% CIs, 1.19 to 2.08; P = .002), respectively in fixed-effect model (Fig. 4A) and random-effect model (Fig. 4B), and in fixed-effect model after excluding the study by Kennedy et al,[18] (Fig. 4C). The percentage of patients who achieved clinical remission were statistically significant in agomelatine group compared with the placebo groups.

3.2.4. Improvement based on the CGI-S and CGI-I scores.

We found that depressive disorder patients in 5 publications were measured from baseline to study endpoint with the clinical global impression-severity scale (CGI-S),[11,12,14,15,17] which had also been used to define severity, and had the advantage of capturing the clinical judgement of an investigator but was subject to substantial variability. The result of the meta-analysis of the CGI-S score were presented as forest plots in fixed-effect model (Fig. 5A), that suggest the 5 studies were significantly homogeneous (P = .74, and I2 = 0%), and CGI-S score of agomelatine groups were more significantly decreased than placebo groups, and the difference between agomelatine groups and placebo groups were statistically significant in fixed-effect model [MD = −0.52, 95%CI: (−0.67 to −0.36), P < .00001, I2 = 0%].

Figure 5.

Figure 5.

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Changes of CGI-S and CGI-I score from baseline to end point between agomelatine and placebo treatment groups. (A) CGI-S in fixed-effect model; (B) CGI-I in fixed-effect model. 95% CI = 95% confidence interval, IV = inverse variance, SD = standard deviation, std = standardized.

In addition, it found that there were 3 publications in which the clinical global impression-improvement scale (CGI-I) was used to the depressive disorder patients’ global improvement.[14,15,17] The result of the meta-analysis of the CGI-I score were presented as forest plots in fixed effect model (Fig. 5B), that suggest the 3 studies were mildly homogeneous (P = .11, and I2 = 54%), and CGI-I score of agomelatine groups were more significantly decreased than placebo groups, and the difference between agomelatine groups and placebo groups were statistically significant in fixed effect model [MD = −0.51, 95%CI: (−0.75 to −0.28), P < .001, I2 = 54%].

3.3. Safety and tolerability

In the included placebo-controlled studies with adverse events information,[12,14–16] a similar percentage of depression patients reported at least one adverse event in the placebo group (20.1%) and in the agomelatine group (22.3%). The most frequent adverse events in agomelatine groups were headache, abdominal pain, diarrhea, nausea, somnolence, insomnia and dry mouth. The meta-analysis of the adverse events that presented as forest plots in fixed-effect model (Fig. 6A), demonstrated that the 3 included publications were moderately heterogeneous (P = .05, and I2 = 58%) and we re-analyzed with random-effect model instead of fixed-effect model by default (Fig. 6B).

Figure 6.

Figure 6.

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Adverse events from baseline to end point between agomelatine and placebo treatment groups. (A) fixed-effect model; (B) random-effect model; (C) adverse events after excluding 1 study. 95% CI = 95% confidence interval, IV = inverse variance, SD = standard deviation, std = standardized.

Then, we performed the subgroup analysis to explain the heterogeneity in adverse events from baseline in the 6 included publications. We hypothesized that the heterogeneity occurred also due to the study by Kennedy et al[18] of which course of treatment was 24 weeks. After excluding the study, the heterogeneity in adverse events became insignificant (P = .83, and I2 = 0%).

The OR of the adverse events rates between agomelatine and placebo groups were, 1.22 (95% CIs, 0.90 to 1.66; P = .20), 1.15 (95% CIs, 0.69 to 1.92; P = .59) and 0.88 (95% CIs, 0.60 to 1.28; P = .50), respectively in fixed-effect model (Fig. 6A) and random-effect model (Fig. 6B), and in fixed-effect model after excluding the study by Kennedy et al[18] (Fig. 6C). The adverse events between agomelatine and placebo groups were not statistically significant.

4. Discussion

In present study, a meta-analysis of the RCTs of agomelatine in the treatment of patients with depressive disorder was performed to compare the therapeutic effect of agomelatine compared with placebo. Patients with depressive disorder did not take any antidepressants before enrollment, avoiding the effects of drugs and recurrent episodes. There was no significant difference in baseline data between agomelatine groups and placebo groups, to ensure a better comparison of their treatment effectiveness, safety and tolerability.

In the ten included publications, overall analysis or subgroup analysis showed that agomelatine was significantly better than placebo in treatment of patients with depression. Agomelatine is the innovative melatonergic antidepressant, approved for the treatment of in both the acute phase and the continuation phase of treatment of depression.[20–22] Agomelatine has pharmacological effects by stimulating the melatonin MT1/MT2 receptor and selectively antagonizing the 5-HT2C receptor, and has no significant effect on the monoamine transmitter system.[4] In the treatment of depressive disorder, the activation of melatonin receptors is mainly relevance to the regulation of biological rhythms with low levels during the day and elevated levels at night.[5–7] The 5-HT2C receptor can inhibit the release of dopamine and norepinephrine. Antagonizing the 5-HT2C receptor blocks the original inhibitory function, causing the release of dopamine and norepinephrine, and increasing its extracellular level. Increase the antidepressant effect.[20,23] Simultaneously, damage to neuroplasticity and cell compliance is considered to be one of the main biological theories for the onset of depressive disorder, while the clinical studies have also shown that agomelatine can promote nerve formation and increase brain-derived neurotrophic factor in the hippocampus and reduce the release of glutamate in the prefrontal cortex caused by acute stress.[24,25]

In summary, agomelatine can regulate the secretion and release of dopamine, norepinephrine and glutamate, thereby improving depressive symptoms, which is consistent with the results of our present study that agomelatine improved depressive symptoms. Moreover, agomelatine has fewer adverse events than SSRIs/SNRIs antidepressants,[25,26] and the most frequent adverse events with agomelatine treatment were headache, abdominal pain, diarrhea, nausea, somnolence, insomnia and dry mouth, that may have correlation with the pharmacological mechanism of agomelatine.

Agomelatine mainly acts by stimulating the melatonin MT1/MT2 receptor and selectively antagonizing the 5-HT2C receptor, without significantly increasing the levels of 5-HT. However, the current clinical evidence is still insufficient, and more RCTs are necessary to comprehensively analyze the effect and safety of agomelatine in antidepressant treatment.

Author contributions

Conceptualization: Yue-Han Guo, Le Zhou, Zi-Ang Cui, Jian Wang, Lei Zhang, Ting Xu.

Formal analysis: Le Zhou.

Funding acquisition: Le Zhou, Lei Zhang, Hui Chen.

Methodology: Ting Xu, Yi-Dan Xie, Hui Chen.

Project administration: Ting Xu, Yi-Dan Xie.

Resources: Ting Xu, Yi-Dan Xie.

Software: Hui Chen.

Abbreviation:

RCT
randomized controlled trials

Y-HG and LZ contributed equally to this work.

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Guo Y-H, Zhou L, Cui Z-A, Wang J, Zhang L, Xu T, Xie Y-D, Chen H. Efficacy and safety of agomelatine in the treatment of patients with depressive disorder: A meta-analysis. Medicine 2023;102:45(e35871).

Contributor Information

Yue-Han Guo, Email: 8547025@qq.com.

Le Zhou, Email: 257896078@qq.com.

Zi-Ang Cui, Email: 732764130@qq.com.

Jian Wang, Email: yswj0211@163.com.

Lei Zhang, Email: zhanglei19821025@hotmail.com.

Ting Xu, Email: xieandgan@163.com.

Yi-Dan Xie, Email: 2438078543@qq.com.

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