Agomelatine's effects on loss of pleasure, physical symptoms, and sexual problems in major depression

Major depressive disorder (MDD) is one of the most prevalent, burdensome, and costly psychiatric disorders in adults globally (1). MDD is associated with significant functional impairment and high morbidity and mortality (2). The World Health Organization (WHO) has reported that MDD is the leading cause of disability in the world (3). Although both pharmacological and non-pharmacological interventions are available for MDD treatment, antidepressants with different mechanisms are a milestone in treatment progress (4). Fully functional recovery, which is the ultimate treatment goal for patients with MDD, may be unsuccessful in some patients. The Sequenced Treatment Alternatives to Relieve Depression (STAR^*D) study reported that up to 30% of patients with MDD fail to achieve adequate remission (5). Different subtypes or presented symptoms of MDD partly account for discrepant treatment outcomes, functioning, and quality of life (QOL) (6, 7). Similarly, somatic and residual symptoms are also the most common risk factors for therapeutic inefficiency (8) in MDD patients.

Anhedonia is a predictor of poor treatment response in patients with MDD (9, 10). Anhedonia, the diminished interest and ability to experience pleasure, is conceptualized as a core feature of MDD (11). Anhedonia is difficult to treat, as accumulated evidence has shown that current first-line antidepressant treatments [such as selective serotonin reuptake inhibitors (SSRIs)] have limited effectiveness in treating defects in motivation and reward processing (12–14).

In clinical practice, somatic symptoms usually present as the major complaints of MDD (15–17). Anxiety/somatic symptoms are characterized by anxiety and worries that are difficult to control and by accompanying psychic and somatic symptoms, including sleep disturbance (18). Previous literature has shown that patients with MDD in Asian countries, especially in China, are more likely to emphasize their somatic symptoms instead of other depressive symptoms than their counterparts in Western countries (19, 20). In addition to somatic complaints, sexual dysfunction is also commonly associated with poor medication adherence (21), a higher incidence of relapse (22), and a negative impact on quality of life (23). Therefore, the therapeutic care of this population with an anhedonic state, somatic symptoms, and sexual dysfunction raises particular clinical concerns.

Agomelatine is an antagonist targeting the postsynaptic serotonin receptor 5-HT2c and melatonergic receptor agonist (MT1/MT2). Agomelatine has been approved for the treatment of MDD (24, 25). As the first approved drug targeting the melatoninergic system rather than the monoaminergic system (26), the efficacy and safety of agomelatine in treating MDD have been established in several randomized controlled trials with placebo or active controls (18, 27, 28). In a 12-week double-blind comparison study, favorable effects of agomelatine were shown in many psychopathological conditions, extending beyond emotional symptoms (29). Published articles have shown that agomelatine is beneficial for sleep structure; it resynchronizes the sleep–wake cycle by acting on melatonin receptors. Additionally, agomelatine has anti-anxiety effects along with antidepressant properties (30).

Previous RCTs have shown that agomelatine seems to be an efficacious antidepressant for treatment-resistant depression or residual symptoms of depression. However, there are limited studies about agomelatine on the issues stated above for treatment in the Chinese population (31, 32). Therefore, a prospective, multicenter, and interventional study was conducted to confirm the effectiveness and safety of agomelatine in treating anhedonia, depression-related somatic symptoms, and sexual dysfunction in patients with MDD.

A total of 93 patients participated in this study. Eighty-five patients (25 men and 60 women) with a mean age of 40.11 years [standard deviation (SD) = 13.71] met the inclusion criteria and accepted agomelatine monotherapy (Figure 1). Seventeen patients dropped out of the trial, 15 of whom were lost to follow-up, one discontinued agomelatine, and one withdrew informed consent. Ultimately, 68 patients completed the 9-week trial and were included in the analysis. The baseline demographics and clinical characteristics of the subjects are summarized in Table 1. The average doses of agomelatine at weeks 3, 6, and 9 were 35.47 (SD = 12.42) mg, 40.14 (SD = 12.30) mg, and 41.04 (SD = 12.07) mg, respectively.

The HAMD-17 total score significantly decreased as early as the third week of treatment (p < 0.001). The response rate was 73.5%; 39.7% of the patients achieved remission.

The total score of the HAMD-17 anxiety/somatic symptoms subscale significantly decreased as early as the third week of treatment (p < 0.001) and significantly decreased from 6.95 (SD = 2.12) at baseline to 2.16 (SD = 2.03) at the endpoint of the trial (p < 0.001). The mixed-effect model revealed that there was no significant difference in the change in the anxiety/somatic symptoms subscale score among the three study sites. Temporal and multicenter interactions were significant (F = 11.81, p < 0.001).

The scores of anhedonia were 2.58 (SD = 0.06), 1.68 (SD = 0.09), 1.07 (SD = 0.09), and 0.93 (SD = 0.09) at baseline and weeks 3, 6, and 9 of treatment, respectively. A significant reduction in the severity of anhedonia was observed from the second follow-up (p < 0.001) until the endpoint of the trial. About effectiveness outcomes, the Q-LES-Q-SF total score significantly increased from 41.02 (SD = 5.99) at baseline to 46.27 (SD = 8.11) at week 3 (p < 0.001) and 50.49 (SD = 8.57) at week 9 (p < 0.001) (Figure 2). There were no significant differences in the change in the Q-LES-Q-SF total score across the three study sites. Temporal and multicenter interactions were significant (F = 7.36, p < 0.001). Both the total scores of the ASEX and SDS significantly decreased from the baseline [ASEX: 21.89 (SD = 4.06); SDS: 15.52 (SD = 4.7), p < 0.001] to the week 3 treatment [ASEX: 20.03 (SD = 3.04); SDS: 11.26 (SD = 5.07), p < 0.001] and to the week 9 treatment [ASEX: 16.19 (SD = 4.79); SDS: 7.09 (SD = 5.62), p < 0.001, Figure 2]. Temporal and multicenter are significant in the mixed-effect model (ASEX: F = 25.64, p < 0.001; SDS: F = 15.65, p < 0.001). A total of 17 adverse events were spontaneously reported. The most frequently reported adverse events were insomnia (10.29%) and agitation (8.82%). After 6 weeks of treatment, one case (1.47%) reported elevation of serum concentration of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) but recovered at week 9 without any additional liver protection treatment. Three events, including influenza (1.47%), nasopharyngitis (1.47%), and constipation (1.47%), were determined to be unrelated to agomelatine. Another 14 patients showed abnormalities in clinical tests and vital signs after treatment, such as elevated total bilirubin (TBil), elevated uric acid (UA), and abnormal blood pressure, but none were serious or related to the laboratory test values.

To the best of our knowledge, this was the first prospective, multicenter study to examine the effectiveness outcomes of agomelatine on anxiety/somatic symptoms, anhedonia, and sexual dysfunction in patients with MDD in China. After 9 weeks of treatment, the response rate was 73.5%, and the remission rate was 39.7%. Gargoloff et al. (44) defined remission as a score of ≤ 5 on the QIDS-SR-16. They reported that the remission rate of agomelatine was 49.6% when treating MDD outpatients. The corresponding response rate was 65.7%. The daily dose of agomelatine in Gargoloff's study was 25–50 mg, which was comparable to the average daily dose of agomelatine in our study (41.04 mg, SD = 12.07 mg). Meanwhile, a network meta-analysis showed that MDD patients treated with agomelatine and venlafaxine had higher remission rates (RR = 1.36; 95% CI = 1.05–1.76) than those treated with fluoxetine and sertraline (27).

This study found that agomelatine produced a significant improvement in anxiety/somatic symptoms as early as the third week of treatment. This positive effect on anxiety/somatic symptoms is consistent with a previous report on agomelatine (25–50 mg/day) vs. escitalopram (10–20 mg/day) in outpatient treatments. The psychic and somatic anxiety scores clinically significantly decreased, alertness and sleep parameters improved, and ability to experience pleasure increased, using the HAMA scale (18). Another narrative review investigating the efficacy of agomelatine on individual HAMD items found that agomelatine significantly outperformed placebo in 10 items, including psychic and somatic anxiety, as well as somatic symptoms, suggesting that agomelatine is effective for a broad spectrum of depressive symptoms (45). In an 8-week trial comparing the efficacy of agomelatine and fluoxetine when treating MDD, both of these antidepressants were effective in reducing the HAMA somatic anxiety subscale score; however, the change in this subscale score had no significant difference between the two treatment groups (46). Previous studies have suggested that fluoxetine has beneficial effects on specific anxiety disorders (e.g., generalized anxiety disorder, social anxiety disorder, and panic disorder) (47–49). More head-to-head studies with comparable conditions are needed to provide more convincing evidence. However, agomelatine has more rapid action on dendritic maturation than selective serotonin reuptake inhibitors (SSRIs) and any other monoaminergic antidepressant (50), which has also been demonstrated in animal models of depression/anxiety (51). The actions of agomelatine on dendritic maturation are thought to be mediated through both MT and 5-HT_2C receptors present in the ventral hippocampus, which are involved in the emotional circuitry controlling depressive/anxiety states (52, 53).

As a core symptom of MDD, anhedonia is considered crucial in treatment and as a potential trait marker related to vulnerability to illness relapse (54, 55). In this study, agomelatine significantly improved anhedonia from the third week of treatment (P < 0.001). This finding is consistent with previous research that agomelatine produced, as early as the first week following treatment initiation, a significant improvement in anhedonia measured by the Snaith–Hamilton Pleasure Scale (SHAPS) (56). A pilot 8-week trial reported that agomelatine showed significantly better effectiveness when treating anhedonia in MDD compared to venlafaxine as assessed by the SHAPS (57). The pharmacological effects of enhancing dopamine and noradrenaline transmission, as well as agonist actions at melatonin receptors in the prefrontal cortex, were thought to be responsible for the effect of agomelatine in treating anhedonia (25, 58).

Moreover, due to the function of agomelatine in specifically limbic areas without influencing extracellular serotonin (5-HT) levels (56, 59), agomelatine is well tolerated and associated with lower levels of sexual dysfunction, gastrointestinal reactions, headaches, weight gain, daytime somnolence, and serotonin syndrome, which would have important advantages. These characteristics are important advantages that are different from SSRIs. Our results support previous findings that agomelatine is associated with a low incidence of sexual dysfunction. In several randomized, placebo/active control trials, agomelatine appeared to consistently have a lower propensity to cause sexual dysfunction (60–63). Agomelatine was associated with less decreased desire (agomelatine 6% vs. venlafaxine 16.4%; p < 0.0001), less orgasmic disorder (agomelatine 9.1% vs. venlafaxine 18.5%; p = 0.001), and better overall sexual function (agomelatine 8.2% vs. venlafaxine 15.2%; p < 0.0001) in both genders (60).

Agomelatine monotherapy has satisfactory effectiveness and tolerance, especially for improving somatic symptoms, sexual dysfunction, and insomnia in previous studies (64–66), which is helpful for the comprehensive rehabilitation of patients with MDD. A network meta-analysis on the acceptability of 21 antidepressants for the treatment of patients with MDD at an acute illness stage found that agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more acceptable than other antidepressants (range of ORs = 0.43–0.77) (31). In this study, 17 cases of mild-to-moderate adverse events were reported, and 14 cases of abnormal laboratory results with no clinical significance were reported. The incidence of adverse events was consistent with a previous study, which found that in a 6-month extension trial, compared to venlafaxine and sertraline, the percentage of patients who discontinued treatment due to adverse events was lower in those treated with agomelatine (agomelatine 4.2% vs. venlafaxine 14.9%, p = 0.001; agomelatine 6.7% vs. 12.5% for sertraline 12.5%, p = 0.09) (67).

Several limitations should be noted. First, the effectiveness results are strictly exploratory and thus should be interpreted with caution due to a lack of placebo control. Second, due to logistical reasons, relevant factors related to the effectiveness of agomelatine, such as the duration of illness or the number (and duration) of previous depressive episodes, lifestyle, family support, and medication adherence, which may influence the current response to antidepressants, were not obtained. Third, our data on sexual dysfunction were collected from self-report questionnaires, and different results might have been obtained with diagnostic interviews. Fourth, because this was a study in the real world, convenience sampling was used, and gender biases were inevitable; therefore, the number of participants should be increased in the future. Finally, the number of participants was limited, so a large number of participants along with random controlled studies are needed in the future.

To summarize, current evidence indicates that MDD patients treated with agomelatine at a daily dose of 25–50 mg had satisfactory treatment outcomes regarding remission rate, response rate, and the severity of anhedonia, somatic symptoms, and sexual dysfunction. This study also provides further evidence that a daily dose of 25–50 mg of agomelatine is safe and tolerable. These findings are important to improve the treatment strategy for MDD to provide broad symptom relief and achieve complete functional recovery. Agomelatine not only improves anhedonia and sexual dysfunction but also relieves somatic symptoms. More clinical trials on the global effectiveness of agomelatine are warranted to confirm the present findings.

There are stringent restrictions in making the research dataset of the clinical studies publicly available. Readers and all interested researchers may contact LZ (Email address:) to apply for exemptions from the participating institutions if appropriate. zhangling@ccmu.edu.cn

The studies involving human participants were reviewed and approved by Anding hospitals' Ethics Committee. The patients/participants provided their written informed consent to participate in this study.

GW and LZ: study design. JH, X-MX, and NL: collection, analyses, and interpretation of data. JH, X-MX, B-BF, and QZ: drafting of the manuscript. GW: critical revision of the manuscript. All authors approved the final version for publication.

We would like to thank all the participants and staff involved in this study. The clinical trial had been registered in a public trials registry to be considered for publication (ID: ChiCTR2200066866) and the authors were compliant with the Consolidated Standards of Reporting Trials (CONSORT).

The study was supported by the Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (XMLX202128) and the Research and Cultivation Program of Beijing Municipal Hospitals (PX2022076).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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