A multicenter, randomized controlled study on the efficacy of agomelatine in ameliorating anhedonia, reduced motivation, and circadian rhythm disruptions in patients with major depressive disorder (MDD)
Annals of General Psychiatry volume 22, Article number: 46 (2023)
To evaluate the clinical efficacy and safety of Agomelatine in improving symptoms in patients with major depressive disorder (MDD), providing more scientific evidence for the treatment of depression, and offering more effective therapeutic options for patients.
A total of 180 MDD patients in acute phase from 10 psychiatric hospitals of Grade three in Zhejiang Province were enrolled in this 12-week study with the competitive and consecutive pattern, and they were randomized into two different groups treated with flexible-dosage antidepressants of selective serotonin reuptake inhibitors (SSRI) or agomelatine, respectively. The subjects were evaluated with psychological scales of HAMD-17, HAMA, SHAPS for anhedonia, MFI-20 for fatigue, PQSI for sleep quality and MEQ for disturbances in chronobiologic rhythms at baseline, 2, 4, 8 and 12-weekend points, and TESS was used for side-effect. The results were analyzed with repeated measurement analysis of variance.
The two groups each had 90 participants, and there were no significant differences at baseline. The scores of various assessment scales showed statistically significant time main effects during the visits (P < 0.01). The Agomelatine group demonstrated faster efficacy within 2 weeks, with better improvement in SHAPS, MEQ, and PSQI compared to the SSRIs group. However, the remission rate at 12 weeks was lower in the Agomelatine group than in the SSRIs group (63.3% and 72.2%), but the difference between the groups was not statistically significant. The Agomelatine group had fewer adverse reactions (14.4% and 16.7%), but there was a slightly higher incidence of liver function impairment (6.7% and 4.4%), with no statistically significant difference between the groups.
Agomelatine, as a novel antidepressant, shows certain advantages in improving depression and anxiety symptoms and is comparable to SSRIs in terms of safety. However, its long-term efficacy and safety on MDD or other depressive subtypes still require further observation and research.
Major depressive disorder (MDD) is a severe psychiatric disorder characterized by high incidence, relapse rate, and disability rate . More than 264 million people worldwide suffer from depression, which has become a leading cause of disability-adjusted life years . Currently, even with optimal antidepressant treatments, the remission rate for MDD patients is only between 60 and 70% . This suboptimal remission rate can be attributed not only to residual psychiatric  or somatic symptoms  after acute phase treatment but also to a lack of effective treatments for specific symptoms such as anhedonia and reduced motivation .
Anhedonia refers to the inability or diminished capacity to experience pleasure or enjoy pleasurable activities, clinically manifesting as reduced interest, joy, and emotional experience; Reduced motivation denotes decreased energy leading to heightened fatigue, diminished speech, and an overwhelming sense of exhaustion even after minimal activity. Both anhedonia and reduced motivation are core symptoms of MDD  and are frequently observed as residual symptoms . Studies indicate that approximately 75% of MDD patients experience anhedonia , while 79.7% of patients suffer from diminished energy . These residual symptoms not only exacerbate the severity of depression in patients [10, 11] but also negatively influence prognosis, functional recovery and treatment resistance [12, 13].
Specially, anhedonia has been reported as a linkage between the negative outcome of major depression and inflammatory markers, such as the suicidal behavior regardless of the presence or absence of psychiatric conditions. Hyperactivity hypothalamic–pituitary–adrenal (HPA) axis abnormalities, the systemic regulating factor for anhedonia, are also found to contribute the neuroinflammation and neurodegeneration and to exert an important influence on suicide . Moreover, a specific focus has been proposed on a higher risk to develop antidepressant treatment resistance in subjects with enhanced neuroinflammation. Conversely, abnormally higher mean concentrations of inflammatory mediators have been found in both the periphery and brain of individuals with treatment resistance .
Agomelatine is a novel antidepressant with distinctive pharmacological properties and mechanisms of action, offering a departure from the conventional monoaminergic neurotransmitter theories. While it antagonizes the 5-HT2C receptor, it also exerts its antidepressant effects by activating melatonin (MT) receptors MT1 and MT2 . It is currently a first-line medication for the treatment of depression [17, 18]. Recent studies have found that, in addition to effectively alleviating depressive moods in patients, agomelatine shows significant efficacy in addressing specific symptoms such as anhedonia, reduced motivation, and sleep and circadian rhythm disturbances by enhancing noradrenaline and dopamine neurotransmission in the frontal cortex . Chronic administration of agomelatine has been indicated to enhance neuroplasticity and neurogenesis with elevated Brain-Derived Neurotrophic Factor (BDNF) levels, particularly in the hippocampal region, which exerts a favorable efficacy in preventing relapse in patients with MDD without evidence of a discontinuation syndrome . Agomelatine has also been studied for its potential effects in modulating inflammatory processes within the central nervous system, which can be implicated in the pathophysiology of depression. By agonizing melatonin receptors, agomelatine can contribute to reducing oxidative stress and protecting neural cells . Given agomelatine’s action on the stress axis and circadian rhythms, it may modulate stress-induced neuroinflammation and the associated depression and cognitive dysfunction.
To compare the efficacy and safety of agomelatine and selective serotonin reuptake inhibitors (SSRIs, the standard care of MDD) in improving symptoms of anhedonia and reduced motivation in patients with MDD, various scales and measures were used to assess the remission rate and adverse reactions in patients who received different antidepressants, such as the 17-item Hamilton Depression Rating Scale (HAMD-17) for depression severity, the Hamilton Anxiety Scale (HAMA) for anxiety severity, the Snaith-Hamilton Pleasure Scale (SHAPS) for anhedonia level, the Multidimensional Fatigue Inventory-20 (MFI-20) for fatigue level, the Morningness–Eveningness Questionnaire (MEQ) for chronotype preference, the Pittsburgh Sleep Quality Index (PSQI) for sleep quality, and the Treatment Emergent Symptom Scale (TESS) for side effects. Finally, we found that agomelatine showed faster and better improvement in MDD symptoms through enhancing the neuroplasticity and adult neurogenesis, with fewer adverse reactions than SSRIs.
Research subjects and methods
Research subjects and procedure
Between March 1, 2019, and June 30, 2019, at ten tertiary psychiatric specialty hospitals in Zhejiang Province, based on the number of depression patient visits and referring to inclusion/exclusion criteria, a fixed quota, competitive continuous enrollment method was employed, culminating in the inclusion of 180 patients with active depression. Utilizing a computer-generated random numbering system, 180 sequences ranging from 1 to 180 were produced. Odd numbers were assigned to the agomelatine group, while even numbers were allocated to the SSRIs group. Based on the random sequence outcomes, the 180 patients were divided into the agomelatine group and the SSRIs group, with 90 patients in each group. No specific medication was prescribed for the SSRIs group, and dosages did not exceed the recommended maximum dosage outlined in the drug manuals. At baseline, demographic data such as age, gender, and Body Mass Index (BMI) were collected from enrolled patients, along with the administration of related scales for assessment. For a detailed research procedure, refer to Fig. 1.
Inclusion and exclusion criteria, and criteria for withdrawal
Inclusion Criteria: (1) Patients diagnosed with a depressive episode based on the International Classification of Diseases 10th Revision (ICD-10); (2) Diagnosis conducted using the Chinese version of the Mini-International Neuropsychiatric Interview (MINI); (3) Patients in the acute phase of a depressive episode with a total score of ≥ 17 on the HAMD-17 and a score of ≥ 3 on the Clinical Global Impression-Severity (CGI-S). Patients can be either first-episode or recurrent cases, and they should not have received antidepressant treatment or undergone Modified Electroconvulsive Therapy (MECT) or other physical therapies within the 2 weeks prior to inclusion. (4) Of Han ethnicity, both genders are acceptable, aged between 18 and 65 years; (5) Patients who have signed an informed consent form.
Exclusion Criteria: (1) Patients diagnosed with schizoaffective disorder, dysthymia, or bipolar depression; those primarily diagnosed with any other anxiety disorder within the last year; individuals with substance dependence; or those with personality disorders. (2) Carriers/patients of hepatitis B or C viruses; those with liver function abnormalities, cirrhosis, or active liver disease; (3) Patients with serious cardiac, cerebral, renal, or endocrine organ diseases or any other significant physical ailment. (4) Patients for whom previous standardized treatment with agomelatine was ineffective, or those who have been unsuccessfully treated with a full dose and full course of ≥ 2 antidepressants during the current episode. (5) Patients whose current depressive episode has lasted for more than 2 years. (6) Those with evident suicidal intentions or behaviors, with a score of ≥ 3 on the third item (suicidal thoughts) of HAMD. (7) Lactating or pregnant women, or those planning to conceive during the trial period, or those unable to employ safe and effective contraceptive measures.
Withdrawal Criteria: (1) Patient revokes their informed consent; (2) Non-compliance with study medication or therapeutic interventions during the research; (3) Persistent elevation of alanine aminotransferase (ALT) levels exceeding three times the upper limit of normal that cannot be ameliorated by hepatoprotective medications; (4) Emergence of manic shift, psychotic symptoms such as hallucinations or delusions, or disorders of consciousness; (5) Pregnancy.
This study was approved by the Ethics Committee of Huzhou City's Third People's Hospital (Ethical Approval Number: 2019 Ethics Review No. 028). All research participants or guardians are required to sign an informed consent form before participating in the study.
Patients in both groups were administered variable doses of agomelatine tablets (Jiangsu Hansoh Pharmaceutical Co., Ltd., National Medicine Approval No. H20143375, Batch No.: 160901. Specification: 25 mg/tablet) or SSRIs (including: Citalopram, Escitalopram, Paroxetine, Fluoxetine, Sertraline).
The study group received agomelatine tablets with an initial dose of 25 mg/day, taken once daily before bedtime. Two weeks later, based on the patient's therapeutic response and tolerance, the dosage may be adjusted to 50 mg/day, taken once daily before bedtime. The control group was treated with SSRIs. The specific choice of medication was not mandated, with all doses based on the recommended starting doses in the drug's package insert, taken once daily after breakfast. Subsequently, depending on the patient's individual response to the medication and the drug's half-life, the drug dosage can be titrated every 1–2 weeks, but the maximum daily dose should not exceed the recommended limit mentioned in the package insert.
During the study, symptomatic treatment can be administered for adverse reactions caused by the medication. Medications that were being used to treat existing somatic diseases before study inclusion can continue to be co-administered. However, during the study period, concomitant use of other antidepressants, anti-anxiety medications, antipsychotics, mood stabilizers, thyroid hormones, etc., is prohibited. The use of any systemic psychotherapy other than supportive psychotherapy is not allowed, nor is the use of MECT or other physical therapies. If necessary, short-term combined use of low-dose benzodiazepines or zopiclone is permitted but not for more than a week, to avoid affecting the observation and analysis of the patient's inherent circadian rhythm.
Primary research tools
In addition to employing scales such as HAMD-17, HAMA, and PSQI, the following instruments were also utilized:
The SHAPS  is a tool for assessing anhedonia, encompassing domains of interest/entertainment, social interaction, sensory experience, and eating. It comprises 14 items, with a total score ranging from 14 to 56. A higher score indicates a greater degree of anhedonia.
The MFI-20  consists of five dimensions: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. It encompasses 20 items, with scores ranging from 20 to 100. A higher score signifies a higher level of fatigue.
The MEQ [24, 25] is an instrument for categorizing the natural inclination of sleep/wake circadian rhythms. The questionnaire contains 19 items, with scores ranging from 16 to 86. Scores of 16–41 indicate evening-type, 42–58 intermediate-type, and 59–86 morning-type. A higher score indicates a higher degree of morningness, while a lower score indicates a higher degree of eveningness.
Efficacy and safety assessment
At baseline and at the ends of weeks 2, 4, 8, and 12, patients were assessed using HAMD-17 and HAMA; simultaneously, patients conducted self-evaluations using SHAPS, MFI-20, MEQ, and PSQI. Among these, the SHAPS, MFI-20, PSQI, and MEQ scales were designated as primary efficacy indicators, while the HAMD-17 and HAMA scales were set as secondary indicators.
Throughout the treatment, descriptive records of various patient complaints and observed adverse reactions were maintained and evaluated using the TESS, a tool for assessing the frequency and severity of adverse reactions caused by the medication. TESS consists of 24 items that ranging from 0 to 4 scores, with a higher score indicating a more severe adverse reaction. At baseline and at the ends of weeks 4, 8, and 12, routine blood tests, urinalysis, liver and kidney functions, thyroid function, a complete set of sex hormones, and electrocardiograms were conducted.
Psychological scale assessments were carried out by two physicians from each center with intermediate or higher professional titles in psychiatry. Unaware of the patients' group allocations, they conducted cross-over blind assessments, achieving a consistency test Kappa value of 0.89.
A reduction rate of > 50% in the HAMD-17 total score pre- and post-treatment was deemed effective, and a HAMD-17 total score ≤ 7 was considered clinical recovery. An increase in serum ALT or AST levels beyond the upper limit of the normal range indicated liver function abnormality, while an elevation of serum ALT or Aspartate Aminotransferase (AST) greater than three times the upper limit of the normal range was considered a significant liver function abnormality.
Statistical analysis was performed using SPSS 22.0 software. The study employed a full analysis set (FAS) for data analysis, using the last observation carried forward (LOCF) method to supplement missing data, such as scores from HAMD-17, HAMA, SHAPS, etc. Quantitative data were expressed as mean ± standard deviation (x ± s). Inter-group mean differences were analyzed using the t-test. Count data and remission rates were expressed in frequencies (percentages) with inter-group rate comparisons made using the χ2 test. As baseline scores and center-specific effects could influence subsequent score changes and inter-group differences, and considering that baseline scores were assessed before the intervention, the baseline values of HAMD-17, HAMA, SHAPS, MFI-20, MEQ, PSQI scales, and individual center effects were treated as covariates. Repeated measures analysis of variance was conducted to compare group effects on the scores from these scales at various visitation points. If the sphericity assumption wasn't met, a Greenhouse–Geisser test was conducted after adjusting degrees of freedom. The test level α was set at 0.05.
Inclusion of participants from various centers and general information and clinical assessments of depressed patients
This study involved ten qualified tertiary psychiatric specialty hospitals. A total of 180 patients with depression were planned to be included, with 90 in the Agomelatine group and 90 in the SSRIs group. During the study implementation, 26 participants dropped out after randomization at different visit points (14.45%), with 6, 11, 7, and 2 dropping out at the end of weeks 2, 4, 8, and 12, respectively. Of the dropouts, 10 were due to intolerable side effects, 6 due to inadequate therapeutic effects, 4 due to manic shifts, 4 due to prohibited medication use against the study protocol, and 2 due to relocation or school transfer. In total, 154 participants (85.55%) completed all scheduled visits. The demographic and clinical data of participants treated with different types of antidepressants are presented in Table 1.
The results demonstrate that among the Full Analysis Set (FAS), comprised of all enrolled patients, and the Per-Protocol Set (PPS), made up of those who met the protocol criteria, the depressive patients enrolled from various centers exhibited significant homogeneity. The demographic compositions and outcomes from clinical assessment scales presented by these two datasets were consistent. At baseline, there was no statistically significant difference in terms of age, gender, and other demographic data as well as various clinical psychological evaluation indices between the two groups of depressive patients receiving different antidepressant treatments (P > 0.05).
Analysis of changes in symptoms of anhedonia and reduced motivation in depressed patients treated with different medications
As the treatment duration extended, the scores of the two groups of depressive patients treated with different medications showed a declining trend at five consecutive visit points for HAMD-17, HAMA, SHAPS, MFI-20, and PSQI, with the exception of MEQ which showed an increasing trend. Using the baseline scores of these scales as covariates, a repeated measures ANOVA was conducted, as shown in Table 2.
The results indicated that the main effect of time on changes in scale scores across different treatment groups was significant (P < 0.01). The intergroup main effect of changes in PSQI scale scores was significant (FI = 3.169, P = 0.016). Further simple effect tests revealed that the intergroup effect of PSQI scores at the end of the 4th week was statistically significant (P < 0.05). However, for scales other than PSQI, the intergroup main effect of score changes was not statistically significant (P > 0.05). The interaction of time × group for changes in all scale scores was not statistically significant (P > 0.05). The variations in scale scores for patients receiving different categories of antidepressant treatments across five successive visit points are illustrated in Fig. 2.
Remission rates of both groups at the study endpoint
Using a HAMD-17 total score of ≤ 7 as the criterion for remission, the remission rates of both groups at different visit points were compared. The findings suggested that the remission rates for depressive symptoms in both groups exhibited an incremental trend across the four post-baseline visit points. Specifically, only at the end of week 2 did the Agomelatine group display a higher remission rate (20.0%) than the SSRIs group (13.3%). Nonetheless, the intergroup differences in recovery rates at each visit point were not statistically significant (P > 0.05), as presented in Table 3.
During the study, the incidence of drug-related adverse reactions in the SSRI group and the Agomelatine group was 16.7% (15/90) and 14.4% (13/90) respectively, primarily mild to moderate in nature. Both groups had 1 notable case of ALT abnormality (1.1%). Adverse reactions improved following symptomatic treatment, and there was no significant difference in the overall incidence of adverse reactions between the two groups (χ2 = 0.169, P = 0.681). See Table 4.
In this multicenter randomized controlled trial, we compared the efficacy and safety of agomelatine and SSRIs in improving symptoms of anhedonia, reduced motivation, and circadian rhythm disturbances in patients with MDD. We found that agomelatine showed faster and better improvement in these symptoms than SSRIs, especially in the first two weeks of treatment. However, agomelatine had a slightly lower remission rate than SSRIs at the end of 12 weeks, and a slightly higher incidence of liver function impairment. Both antidepressants were generally well tolerated and safe.
In terms of therapeutic efficacy for symptoms of anhedonia and diminished motivation, patients in this study receiving different pharmacological treatments exhibited marked decreasing trends in their SHAPS and MFI-20 scores at each subsequent visit. The main effect of score reductions over time was pronounced. However, there were no statistically significant intergroup differences at each visit, indicating that both medications effectively ameliorated symptoms of anhedonia and lack of motivation in patients with depression, consistent with some previous studies [26, 27]. Past research has suggested that Agomelatine's efficacy in treating anhedonia is superior to Venlafaxine  and Bupropion . Similar findings were reflected in our study, with Agomelatine showing greater reductions in SHAPS scores at all visit points within 12 weeks compared to SSRIs, particularly pronounced in the initial 2 weeks. This suggests that for persistent anhedonia in patients with depression, Agomelatine can be the preferred therapeutic choice.
Regarding the onset of action in treating anhedonia and reduced motivation, the trajectory of score changes over time differed between the two groups. The pattern of MFI-20 scores aligned generally with changes in HAMD-17 and HAMA scores, indicating that symptoms of diminished motivation improved concurrently with the alleviation of depression and anxiety symptoms. In contrast, SHAPS scores showed a more gradual change during the initial 8 weeks and only began to rapidly improve thereafter. This suggests that the resolution of anhedonia symptoms is notably delayed compared to anxiety and depressive symptoms. Similar observations have been previously reported , further confirming that as a prevalent residual symptom during the acute phase of depression, the remission of anhedonia relies on continued treatment during the consolidation phase of depression. Nevertheless, compared to SSRIs, Agomelatine was able to improve anhedonia symptoms within 2 weeks, aligning with some earlier studies. Boyer et al.  found that Escitalopram only became effective between the 4th and 8th weeks of treatment, whereas di Giannantonio et al.  observed, without setting a control group, that Agomelatine improved symptoms of anhedonia in patients with depression by the second week, as identified through intra-individual pre-post comparisons.
In the realms of circadian rhythms and sleep quality, prior research has indicated that circadian rhythm disturbances are among the pivotal etiological factors for depression, with evening chronotypes facing heightened susceptibility to depressive disorders [32, 33]. Correcting these rhythms can significantly ameliorate depressive symptoms [34, 35]. This study reveals that for patients with depression undergoing varied pharmacological treatments, their PSQI scores consistently declined across successive visits. Notably, the rate of reduction was more rapid in the Agomelatine cohort, with significant inter-group score disparities emerging by the end of the 4th week. Correspondingly, MEQ scores steadily increased with each subsequent visit. While the differences between groups at each visit were not statistically significant, the elevation was more pronounced for patients in the Agomelatine group. This suggests that post-antidepressant treatment, while the sleep quality of patients with depression improves, the circadian preference of some patients’ transitions from an unhealthy evening chronotype to a healthier morning chronotype. The simultaneous modulation of circadian rhythms and enhancement of sleep quality constitutes a vital pharmacological mechanism and unique therapeutic feature of Agomelatine, as echoed by numerous prior studies [28, 36]. Additionally, the study discerned that Agomelatine’s regulation of circadian rhythms surpasses that of SSRIs and can manifest marked improvements within the initial four weeks of treatment.
In terms of drug tolerability and safety, both categories of medications exhibited commendable profiles, devoid of severe adverse reactions. Aligning with previous findings , the overall adverse reaction incidence in the Agomelatine cohort was lower than in the SSRI cohort (16.7% and 14.4% respectively). Significant disparities between the groups in terms of sexual dysfunction and weight implications have been documented in past reports [38, 39]. Regarding hepatic impairment, the incidence in the Agomelatine group was higher than the SSRI group (6.7% versus 4.4%), consistent with the results of a 2016 meta-analysis . Hepatic impairments in both groups normalized following standard hepatoprotective interventions, without necessitating treatment discontinuation. The onset of functional impairment in the Agomelatine group was variable, with two instances emerging within each of the 1st, 2nd, and 3rd months in this study.
In terms of overall therapeutic efficacy, the Agomelatine group demonstrated a consistent decline in both HAMD-17 and HAMA aggregate scores across the five observational points during the study period, showcasing a pronounced time effect of score reduction. Nevertheless, inter-group differences between the two patient groups at each observational point were not statistically significant. This implies that both Agomelatine and SSRIs can effectively mitigate symptoms of depression and anxiety, yet their overarching efficacy did not exhibit discernible statistical disparities, aligning with previous findings [41,42,43]. However, a slight deviation from earlier studies was noted. By the conclusion of the 2nd week, the remission rate for depressive symptoms in the Agomelatine cohort (20.0%) surpassed that of the SSRI group (13.3%). Subsequent remission rates at later observation points for Agomelatine were lower than SSRIs, culminating in rates of 63.3% and 72.2%, respectively, by the 12th week. This indicates that Agomelatine demonstrates efficacy as early as within two weeks, yet its prolonged therapeutic efficacy might be slightly inferior to SSRIs. Such findings resonate with the network meta-analysis by Cipriani et al. , suggesting that when juxtaposed with SSRIs, Agomelatine's acute-phase efficacy for depression is subpar to Paroxetine, Fluvoxamine, Escitalopram, and Sertraline, but superior to Fluoxetine and Citalopram.
Our study has some limitations that need to be acknowledged. First, our sample size was modest and may not have enough power to detect significant differences between agomelatine and SSRIs in some outcomes. Second, we did not include a placebo group as a control group, which may introduce bias in the assessment of efficacy and safety. Third, we used a heterogeneous group of SSRIs as a comparison group, which may obscure the specific effects of each SSRI on different aspects of depression. Fourth, we followed up the patients for only 12 weeks, which may not be sufficient to evaluate the long-term effects of agomelatine and SSRIs on depression and its related symptoms. Fifth, we excluded other depressive subtypes such as dysthymia or bipolar depression from our study, which may limit the generalizability of our findings to other populations.
Agomelatine is an intriguing option for patients with MDD who suffer from anhedonia, low motivation, and circadian rhythm disturbances, with generally well tolerability and safety. For clinical practice, our findings support that agomelatine can be considered as a first-line treatment for MDD or an alternative treatment for patients who are concerned about the sexual dysfunction and weight gain caused by SSRIs. Nonetheless, the long-term efficacy and safety profile of agomelatine are warranted and further evaluation for the effects of agomelatine on other depressive subtypes are needed.
Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Major depressive disorder
Body Mass Index
Selective serotonin reuptake inhibitor
The 17-item Hamilton Depression Rating Scale
Hamilton anxiety scale
Snaith-Hamilton Pleasure Scale
Multidimensional fatigue inventory-20
Pittsburgh sleep quality index
International Classification of Diseases 10th Revision
Mini-international neuropsychiatric interview
Clinical Global Impression-Severity
Modified electroconvulsive therapy
Treatment Emergent Symptom Scale
Last observation carried forward
Full Analysis Set
Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF. Major depressive disorder. Nat Rev Dis Primers. 2016;2:16065. https://doi.org/10.1038/nrdp.2016.65.
Abate KH, Abebe Z, Abil OZ, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789–858. https://doi.org/10.1016/S0140-6736(18)32279-7.
Sinyor M, Schaffer A, Levitt A. The sequenced treatment alternatives to relieve depression (STAR*D) trial: a review. Can J Psychiatry. 2010;55(3):126–35. https://doi.org/10.1177/070674371005500303.
Le X, Lei F, Xuequan Z, et al. A national survey of residual symptoms in Chinese depressive patients after acute phase treatment. Chin J Psychiatry. 2017;50(03):175–81. https://doi.org/10.3760/cma.j.issn.1006-7884.2017.03.005.
Zhang Xu, Wei F, Gang W, et al. A survey on residual somatic symptoms post-acute treatment in Chinese patients with depression. Chin J Psychiatry. 2019;01:76–81. https://doi.org/10.3760/cma.j.issn.1006-7884.2019.01.007.
Argyropoulos SV, Nutt DJ. Anhedonia revisited: is there a role for dopamine-targeting drugs for depression? J Psychopharmacol. 2013;27(10):869–77. https://doi.org/10.1177/0269881113494104.
Edition F. Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th ed. Washington: America Psychiatric Association; 2013.
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41(6):1165–74. https://doi.org/10.1017/S0033291710001911.
Nierenberg AA. Residual symptoms in depression: prevalence and impact. J Clin Psychiatry. 2015;76(11): e1480. https://doi.org/10.4088/JCP.13097TX1C.
McIntyre RS, Woldeyohannes HO, Soczynska JK, et al. Anhedonia and cognitive function in adults with MDD: results from the International Mood Disorders Collaborative Project. CNS Spectr. 2016;21(5):362–6. https://doi.org/10.1017/S1092852915000747.
Winer ES, Nadorff MR, Ellis TE, et al. Anhedonia predicts suicidal ideation in a large psychiatric inpatient sample. Psychiatry Res. 2014;218(1–2):124–8. https://doi.org/10.1016/j.psychres.2014.04.016.
Uher R, Perlis RH, Henigsberg N, et al. Depression symptom dimensions as predictors of antidepressant treatment outcome: replicable evidence for interest-activity symptoms. Psychol Med. 2012;42(5):967–80. https://doi.org/10.1017/S0033291711001905.
Nierenberg AA, Husain MM, Trivedi MH, et al. Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report. Psychol Med. 2010;40(1):41–50. https://doi.org/10.1017/S0033291709006011.
Berardelli I, Serafini G, Cortese N, Fiaschè F, O’Connor RC, Pompili M. The Involvement of Hypothalamus-Pituitary-Adrenal (HPA) Axis in Suicide Risk. Brain Sci. 2020;10(9):653. https://doi.org/10.3390/brainsci10090653.
Serafini G, Adavastro G, Canepa G, et al. Abnormalities in kynurenine pathway metabolism in treatment-resistant depression and suicidality: a systematic review. CNS Neurol Disord Drug Targets. 2017;16(4):440–53. https://doi.org/10.2174/1871527316666170413110605.
Stahl SM. Mechanism of action of agomelatine: a novel antidepressant exploiting synergy between monoaminergic and melatonergic properties. CNS Spectr. 2014;19(3):207–12. https://doi.org/10.1017/S1092852914000248.
Lam RW, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: introduction and methods. Can J Psychiatry. 2016;61(9):506–9. https://doi.org/10.1177/0706743716659061.
Malhi GS, Outhred T, Hamilton A, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders: major depression summary. Med J Aust. 2018;208(4):175–80.
Hong Wu, Tianmei Si, Lingjiang Li, et al. Expert recommendations on the clinical application of Agomelatine in treating depression. Chin J New Drugs Clin Remedies. 2018;37(11):601–7. https://doi.org/10.14109/j.cnki.xyylc.2018.11.001.
Pompili M, Serafini G, Innamorati M, Venturini P, Fusar-Poli P, Sher L, Amore M, Girardi P. Agomelatine, a novel intriguing antidepressant option enhancing neuroplasticity: a critical review. World J Biol Psychiatry. 2013;14(6):412–31. https://doi.org/10.3109/15622975.2013.765593.
Rebai R, Jasmin L, Boudah A. Agomelatine effects on fat-enriched diet induced neuroinflammation and depression-like behavior in rats. Biomed Pharmacother. 2021;135: 111246. https://doi.org/10.1016/j.biopha.2021.111246.
Snaith RP, Hamilton M, Morley S, et al. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;167(1):99–103. https://doi.org/10.1192/bjp.167.1.99.
Schneider RA. Concurrent validity of the Beck Depression Inventory and the multidimensional fatigue inventory-20 in assessing fatigue among cancer patients. Psychol Rep. 1998;82(31):883–6. https://doi.org/10.2466/pr0.19126.96.36.1993.
Horne JA, Östberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol. 1976;4(2):97–110.
Bin Z, Yanli H, Runguo R. Reliability and validity of the Morningness-Eveningness Assessment Scale. Chin J Behav Med Brain Sci. 2006;15(9):856–8. https://doi.org/10.3760/cma.j.issn.1674-6554.2006.09.044.
Di Giannantonio M, Martinotti G. Anhedonia and major depression: the role of agomelatine. Eur Neuropsychopharmacol. 2012;22(3):S505–10. https://doi.org/10.1016/j.euroneuro.2012.07.004.
Gargoloff PD, Corral R, Herbst L, et al. Effectiveness of agomelatine on anhedonia in depressed patients: an outpatient, open-label, real-world study[J]. Hum Psychopharmacol. 2016;31:412–8. https://doi.org/10.1002/hup.2557.
Martinotti G, Sepede G, Gambi F, et al. Agomelatine Versus Venlafaxine XR in the treatment of anhedonia in major depressive disorder a pilot study. J Clin Psychopharmacol. 2012;32(4):487–91. https://doi.org/10.1097/JCP.0b013e31825d6c25.
Guillena SLR, De Diego BOPG, Saenz BOM. Agomelatine versus desvenlafaxine versus bupropion XR in the treatment of anhedonia in major depressive disorder. Eur Neuropsychopharmacol. 2014;24:S461–2. https://doi.org/10.1016/S0924-977X(14)70738-2.
Boyer P, Tassin JP, Falissart B, et al. Sequential improvement of anxiety, depression and anhedonia with sertraline treatment in patients with major depression. J Clin Pharm Ther. 2000;25(5):363–71. https://doi.org/10.1046/j.1365-2710.2000.00302.x.
Di Giannantonio M, Di Iorio G, Guglielmo R, et al. Major depressive disorder, anhedonia and agomelatine: an open-label study. J Biol Regul Homeost Agents. 2011;25(1):109–14.
Kitamura S, Hida A, Watanabe M, et al. Evening preference is related to the incidence of depressive states independent of sleep-wake conditions. Chronobiol Int. 2010;27(9–10):1797–812. https://doi.org/10.3109/07420528.2010.516705.
Antypa N, Vogelzangs N, Meesters Y, et al. Chronotype associations with depression and anxiety disorders in a large cohort study. Depress Anxiety. 2016;33(1):75–83. https://doi.org/10.1002/da.22422.
Dalton EJ, Rotondi D, Levitan RD, et al. Use of slow-release melatonin in treatment-resistant depression. J Psychiatry Neurosci. 2000;25(1):48–52. https://doi.org/10.1016/S0022-3956(99)00038-2.
Valdés-Tovar M, Estrada-Reyes R, Solís-Chagoyán H, et al. Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression. Br J Pharmacol. 2018;175(16):3200–8. https://doi.org/10.1111/bph.14197.
Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. J Clin Psychiatry. 2007;68(11):1723–32. https://doi.org/10.4088/jcp.v68n1112.
Kasper S, Corruble E, Hale A, et al. Antidepressant efficacy of agomelatine versus SSRI/SNRI: results from a pooled analysis of head-to-head studies without a placebo control. Int Clin Psychopharmacol. 2013;28(1):12–9. https://doi.org/10.1097/YIC.0b013e328359768e.
Demyttenaere K, Corruble E, Hale A, et al. A pooled analysis of six-month comparative efficacy and tolerability in four randomized clinical trials: agomelatine versus escitalopram, fluoxetine, and sertraline. CNS Spectr. 2013;18(3):163–70. https://doi.org/10.1017/S1092852913000060.
Fornaro M, Prestia D, Colicchio S, et al. A systematic, updated review on the antidepressant agomelatine focusing on its melatonergic modulation. Curr Neuropharmacol. 2010;8(3):287–304. https://doi.org/10.2174/157015910792246227.
Perlemuter G, Cacoub P, Valla D, et al. Characterisation of agomelatine-induced increase in liver enzymes: frequency and risk factors determined from a pooled analysis of 7605 treated patients. CNS Drugs. 2016;30(9):877–88. https://doi.org/10.1007/s40263-016-0351-6.
Kasper S, Hajak G, Wulff K, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized, double-blind comparison with sertraline. J Clin Psychiatry. 2010;71(2):109–20. https://doi.org/10.4088/JCP.09m05347blu.
Hale A, Corral RM, Mencacci C, et al. Superior antidepressant efficacy results of agomelatine versus fluoxetine in severe MDD patients: a randomized, double-blind study. Int Clin Psychopharmacol. 2010;25(6):305–14. https://doi.org/10.1097/YIC.0b013e32833a86aa.
Huang KL, Lu WC, Wang YY, et al. Comparison of agomelatine and selective serotonin reuptake inhibitors/serotonin norepinephrine reuptake inhibitors in major depressive disorder: a meta-analysis of head-to-head randomized clinical trials. Aust N Z J Psychiatry. 2014;48(7):663–71. https://doi.org/10.1177/0004867414525837.
Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357–66. https://doi.org/10.1016/S0140-6736(17)32802-7.
There is no one who has contributed to the manuscript but does not qualify as a collaborator.
Science and Technology Project of Zhejiang Provincial (GF22H093655); Nonprofit Applied Research Project of Huzhou Science and Technology Bureau (2017GY50, 2021GYB16); Project of Huzhou the Third Hospital (2022SY2022112, 2022SY067)rs.
Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of Huzhou Third Municipal Hospital Affiliated to Huzhou University (ethical batch number: 2019LS028), and informed consent was obtained from all participants. All methods were carried out in accordance with relevant guidelines and regulations.
Consent for publication
All authors final approval of the version to be published.
All of the authors had no any personal, financial, commercial, or academic conflicts of interest separately.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Guo, P., Xu, Y., Lv, L. et al. A multicenter, randomized controlled study on the efficacy of agomelatine in ameliorating anhedonia, reduced motivation, and circadian rhythm disruptions in patients with major depressive disorder (MDD). Ann Gen Psychiatry 22, 46 (2023). https://doi.org/10.1186/s12991-023-00473-y