Efficacy In Major Depressive Disorder Research Articles

Temporal binding and sense of agency in major depression.

Alterations in the experience of controlling oneself and one's environment are of high relevance to understanding the psychopathology of depression. This study investigated the relationship between Temporal Binding for action-event sequences, sense of agency, self-efficacy and symptom severity in Major Depressive Disorder. We employed the Sense of Agency Scale (SoAS) and the General Self-Efficacy Scale (GSE) to assess explicit Sense of Agency and self-efficacy in a group of 42 persons diagnosed with Major Depressive Disorder (MDD) [20 identifying as female, 19 as male; mean age 37.8 years (± 13.3)] and 40 control persons without a psychiatric diagnosis (CG) [22 identifying as female, 20 as male; mean age 38.0 years ( ± 13.3)]. Depressive symptom severity was measured using the BDI-II. We additionally performed a temporal binding paradigm as a potential correlate to Sense of Agency. Participants partook in a time estimation task judging three intervals (250ms, 450ms, 650ms) while either observing or causing stimulus presentations. The underestimation of intervals following intentional actions causing stimulus presentations (compared to merely observing the stimulus presentation) is interpreted as temporal binding. SoAS scores demonstrated an inverse correlation with depressive symptoms (CG: p=.032, R2=.113; MDD: p<.001, R2=.260) and a positive correlation with GSE scores (CG: p<.001, R2=.379; MDD: p<.001, R2=.254). We found distinct differences in temporal binding between healthy participants and the Major Depressive Disorder group without significant correlation between temporal binding and the SoAS or GSE scores. The data suggest group differences in time estimation particular pertaining to time intervals involving intentional action and increasingly complex multisensory stimuli. We investigated parameters of subjective control, namely Sense of Agency and Self Efficacy. Here, we were able to reveal their inverse relationship with depressive symptoms in patients with major depressive disorder, highlighting a profound experience of loss of control with increasing symptom load. Deficits in experiencing control, particularly involving intentional motor actions (and more complex multisensory stimuli), appear to be more pronounced in Major Depressive Disorder, involving not only negative self-efficacy expectations but also an altered Sense of Agency and temporal binding. Temporal binding and SoAS scores did not correlate, adding to the growing evidence that the two measures may not be directly related. We propose that future research be directed at this contiguous relationship between Sense of Agency and Self Efficacy in Major Depressive Disorder.

The efficacy of zuranolone versus placebo in postpartum depression and major depressive disorder: a systematic review and meta-analysis.

Zuranolone, an oral version of allopregnanolone and neurosteroid, is a novel drug for the treatment of major depressive disorder (MDD) and postpartum depression (PPD). The purpose of this systematic review and meta-analysis was to assess the efficacy of zuranolone in the treatment of MDD and PPD. A systematic search was conducted using EBSCOhost to simultaneously search Academic Search Premier, APA PsycArticles, APA PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL Ultimate, and MEDLINE with Full Text. Two independent reviewers screened the articles and completed a full-text review using Covidence. The quality of each study was assessed using the Cochrane Risk of Bias tool for randomized trials (RoB 2). A meta-analysis was then conducted using Review Manager (RevMan v5.4) software. The initial search yielded 127 results, with 6 articles fitting our inclusion and exclusion criteria. All 6 studies, comprising 1707 participants, had an overall low risk of bias. There was a significant decrease in HAM-D scores for MDD at 15days versus placebo (MD - 2.40, 95% CI - 3.07 to - 1.63; p < .001). When pooling data for PDD, there was an overall significant decrease in HAM-D scores at 15days versus placebo (MD - 4.06, 95% CI - 4.25 to - 3.87; p < .001). The results suggest that zuranolone can improve symptoms of PPD at 15days; however, results were not clinically significant for MDD. Future research is needed to evaluate the long-term efficacy of zuranolone in PPD and the treatment efficacy in MDD.

Identification of the antidepressant effect of electroconvulsive stimulation-related genes in hippocampal astrocyte

Major depressive disorder (MDD) remains a significant global health concern, with limited and slow efficacy of existing antidepressants. Electroconvulsive therapy (ECT) has superior and immediate efficacy for MDD, but its action mechanism remains elusive. Therefore, the elucidation of the action mechanism of ECT is expected to lead to the development of novel antidepressants with superior and immediate efficacy. Recent studies suggest a potential role of hippocampal astrocyte in MDD and ECT. Hence, we investigated antidepressant effect of electroconvulsive stimulation (ECS), an animal model of ECT, -related genes in hippocampal astrocyte with a mouse model of MDD, in which corticosterone (CORT)-induced depression-like behaviors were recovered by ECS. In this model, both of CORT-induced depression-like behaviors and the reduction of hippocampal astrocyte were recovered by ECS. Following it, astrocytes were isolated from the hippocampus of this model and RNA-seq was performed with these isolated astrocytes. Interestingly, gene expression patterns altered by CORT were reversed by ECS. Additionally, cell proliferation-related signaling pathways were inhibited by CORT and recovered by ECS. Finally, serum and glucocorticoid kinase-1 (SGK1), a multi-functional protein kinase, was identified as a candidate gene reciprocally regulated by CORT and ECS in hippocampal astrocyte. Our findings suggest a potential role of SGK1 in the antidepressant effect of ECS via the regulation of the proliferation of astrocyte and provide new insights into the involvement of hippocampal astrocyte in MDD and ECT. Targeting SGK1 may offer a novel approach to the development of new antidepressants which can replicate superior and immediate efficacy of ECT.

Prediction of Early Antidepressant Efficacy in Patients with Major Depressive Disorder Based on Multidimensional Features of rs-fMRI and P11 Gene DNA Methylation: Prédiction de l'efficacité précoce d'un antidépresseur chez des patients souffrant du trouble dépressif majeur d'après les caractéristiques multidimensionnelles de la méthylation de l'ADN du gène P11 et de la IRMf-rs.

This study established a machine learning model based on the multidimensional data of resting-state functional activity of the brain and P11 gene DNA methylation to predict the early efficacy of antidepressant treatment in patients with major depressive disorder (MDD). A total of 98 Han Chinese MDD were analysed in this study. Patients were divided into 51 responders and 47 nonresponders according to whether the Hamilton Depression Rating Scale-17 items (HAMD-17) reduction rate was ≥50% after 2 weeks of antidepressant treatment. At baseline, the Illumina HiSeq Platform was used to detect the methylation of 74 CpG sites of the P11 gene in peripheral blood samples. Resting-state functional magnetic resonance imaging (rs-fMRI) scan detected the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and functional connectivity (FC) in 116 brain regions. The least absolute shrinkage and selection operator analysis method was used to perform feature reduction and feature selection. Four typical machine learning methods were used to establish support vector machine (SVM), random forest (RF), Naïve Bayes (NB), and logistic regression (LR) prediction models based on different combinations of functional activity of the brain, P11 gene DNA methylation and clinical/demographic features after screening. The SVM model based on ALFF, ReHo, FC, P11 methylation, and clinical/demographic features showed the best performance, with 95.92% predictive accuracy and 0.9967 area under the receiver operating characteristic curve, which was better than RF, NB, and LR models. The multidimensional data features combining rs-fMRI, DNA methylation, and clinical/demographic features can predict the early antidepressant efficacy in MDD.

Predicting acupuncture efficacy for major depressive disorder using baseline clinical variables: A machine learning study

Acupuncture is a viable treatment option for major depressive disorder (MDD). However, its effectiveness varies among patients. This study aimed to develop a model to predict the efficacy of acupuncture therapy for MDD using machine learning and baseline clinical variables. A total of 124 patients with MDD from five research centers were included in our machine learning study. All patients underwent acupuncture treatment for 6 weeks and the efficacy of the treatment was evaluated using the Hamilton Depression Scale-17 (HAMD-17). The max-relevance and min-redundancy (mRMR) algorithm and Pearson correlation analysis were used for selecting 11 significant features from 26 baseline clinical variables for model training. We compared the performance of five machine learning models, including logistic regression, support vector machine, K-nearest neighbor, random forest, and XgBoost, in predicting the effect of acupuncture in relieving major depression. Among the five models, XgBoost performed the best with an area under the receiver operating characteristic curve (AUC) of 0.835, an accuracy of 0.730, a sensitivity of 0.670, a specificity of 0.774, and an F1 score of 0.751. The key predictive variables identified were anxiety score in the self-rating depression scale (SDS), the traditional Chinese medicine syndrome of deficiency in both heart and spleen, and body mass index (BMI). The study demonstrates that the developed model can help physicians predict the patients who will benefit from acupuncture treatment, which is of positive significance for improving the clinical efficacy of acupuncture on MDD.

Esmethadone-HCl (REL-1017): a promising rapid antidepressant.

This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders.

Choice of Outcome Measure Predicts Anti-Inflammatory Treatment Efficacy in Major Depressive Disorder [Letter

Choice of Outcome Measure Predicts Anti-Inflammatory Treatment Efficacy in Major Depressive Disorder [Letter

Anti-Inflammatory Treatment Efficacy in Major Depressive Disorder: A Systematic Review of Meta-Analyses.

Immune imbalances in major depressive disorder (MDD) have been targeted by anti-inflammatory treatment approaches in clinical trials to increase responsiveness to therapy. However, even after several meta-analyses, no translation of evidence into clinical practice has taken place. We performed a systematic review to evaluate meta-analytic evidence of randomized controlled trials on the use of anti-inflammatory agents for MDD to summarize efficacy estimates and elucidate shortcomings. Pooled effect estimates and heterogeneity indices were primary outcomes. Characteristics of the included meta-analyses were extracted. Scientific quality of meta-analyses was assessed using the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR). N=20 meta-analyses met the eligibility criteria. Study characteristics like outcome scales, composition of patient populations, and add-on or monotherapy regimen varied very little for celecoxib studies, varied little for minocycline studies, and were rather variable for omega 3 fatty acids studies. R-AMSTAR scores ranged from 26 to 39 out of 44 points indicating variable quality, where a comprehensive literature search was the strongest and the consideration of scientific quality in the conclusions was the weakest domain across all meta-analyses. For minocycline and celecoxib, superiority was demonstrated with medium to large effect size with substantial heterogeneity and with large to very large effect size with negligible heterogeneity, respectively. For omega 3 fatty acids, superiority was also demonstrated with mainly small and medium effect sizes with substantial heterogeneity. However, for minocycline and omega 3 fatty acids, non-significant meta-analyses were found also. Even in our synthesized approach, no clear recommendations could be derived on the use of anti-inflammatory treatment for MDD due to several critical aspects like heterogeneity, diversity of patient populations, treatment regimen, and outcomes, and limited scientific quality. However, we observed clear inter-substance differences with meta-analytic evidence being strongest for celecoxib and weakest for omega 3 fatty acids.

Dosing Transcranial Magnetic Stimulation: Efficacy in Major Depressive Disorder as a function of number of treatment sessions

Dosing Transcranial Magnetic Stimulation: Efficacy in Major Depressive Disorder as a function of number of treatment sessions

Abnormal Dynamic Functional Connectivity of the Left Rostral Hippocampus in Predicting Antidepressant Efficacy in Major Depressive Disorder.

Objective Some pharmacological treatments are ineffective in parts of patients with major depressive disorder (MDD), hence this needs prediction of effective treatment responses. The study aims to examine the relationship between dynamic functional connectivity (dFC) of the hippocampal subregion and antidepressant improvement of MDD patients and to estimate the capability of dFC to predict antidepressant efficacy. Methods The data were from 70 MDD patients and 43 healthy controls (HC); the dFC of hippocampal subregions was estimated by sliding-window approach based on resting-state functional magnetic resonance imaging (R-fMRI). After 3 months treatment, 36 patients underwent second R-fMRI scan and were then divided into the response group and non-response group according to clinical responses. Results The result manifested that MDD patients exhibited lower mean dFC of the left rostral hippocampus (rHipp.l) compared with HC. After 3 months therapy, the response group showed lower dFC of rHipp.l compared with the non-response group. The dFC of rHipp.l was also negatively correlated with the reduction rate of Hamilton Depression Rating Scale. Conclusion These findings highlighted the importance of rHipp in MDD from the dFC perspective. Detection and estimation of these changes might demonstrate helpful for comprehending the pathophysiological mechanism and for assessment of treatment reaction of MDD.

Adjunctive home-based transcranial direct current stimulation treatment for major depression with real-time remote supervision: An open-label, single-arm feasibility study with long term outcomes

Current treatments for major depressive disorder (MDD) have limited effectiveness and acceptability. Transcranial direct current stimulation (tDCS) is a novel non-invasive brain stimulation method that has demonstrated treatment efficacy in MDD. tDCS requires daily sessions, however clinical trials have been conducted in research centers requiring repeated visits. As tDCS is portable and safe, it could be provided at home. We developed a home-based protocol with real-time supervision, and we examined the clinical outcomes, acceptability and feasibility. Participants were 26 MDD (19 women), mean age 40.9 ± 14.2 years, in current depressive episode of moderate to severe severity (mean 17-item Hamilton Rating Scale for Depression (HAMD) score 19.12 ± 2.12). tDCS was provided in a bilateral frontal montage, F3 anode, F4 cathode, 2 mA, each session 30 min, in a 6-week trial, for a total 21 sessions. Participants maintained their current treatment (antidepressant medication, psychotherapy, or were enrolled in online CBT). Two tDCS device brands were used, and a research team member was present in person or by real-time video call at each session. 92.3% MDD participants (n = 24) completed the 6-week treatment. Attrition rate was 7.7%. There was a significant improvement in depressive symptoms following treatment (mean HAMD 5.33 ± 2.33), which was maintained at 6 months (mean HAMD 5.43 ± 2.73). Acceptability was endorsed as “very acceptable” or “quite acceptable” by all participants. Due to the open-label feasibility design, efficacy findings are preliminary. In summary, home-based tDCS with real-time supervision was associated with significant clinical improvements and high acceptability which were maintained in the long term.

Methylenedioxymethamphetamine (MDMA)-Assisted Therapy in Hawaii: A Brief Review

The Food and Drug Administration (FDA) granted breakthrough therapy status to 3,4-methyl​enedioxy​methamphetamine-assisted therapy (MDMA-AT) in 2017 due to preliminary evidence supporting its efficacy and safety in treating post-traumatic stress disorder (PTSD). A series of six phase-II clinical trials studying MDMA-AT for treatment-resistant PTSD found that 54% of MDMA-AT full-dose participants no longer met the diagnosis of PTSD after two MDMA sessions, compared to 23% in the control group. In the first phase-III clinical trial, 67% no longer met the criteria for PTSD after three sessions. The effects are durable, with 67% no longer diagnosable after one year and 74% at nearly four years. The MDMA-AT is being fast-tracked for potential FDA approval by 2023. In 2021, Hawaii’s Senate Bill 738 unsuccessfully proposed that psilocybin be removed from the Schedule I controlled substances list due to its clinical efficacy for major depressive disorder. Methyl​enedioxy​methamphetamine is also a Schedule I controlled substance and has proven to be a treatment option that could potentially benefit the people of Hawaii.

Adjunctive D-Cycloserine with Intermittent Theta-Burst Stimulation: A Randomized Placebo-Controlled Trial in Major Depressive Disorder

Intermittent theta-bust stimulation (iTBS) is emerging as a first-choice transcranial magnetic stimulation (TMS) protocol in the treatment of refractory Major Depressive Disorder (MDD). While the mechanisms for antidepressant efficacy remain unclear, physiological studies suggest that N-Methyl-D-Aspartate (NMDA) receptor activation is required for iTBS related synaptic plasticity. No study to date has directly targeted the NMDA receptor as a means of enhancing clinical efficacy in MDD.

P387. PRAX-114, An Extrasynaptic-Preferring GABAA Receptor Positive Allosteric Modulator: A Phase 2 Trial Evaluating Multiple Dose Safety, Tolerability, and Preliminary Efficacy in Major Depressive Disorder

PRAX-114 is an extrasynaptic-preferring GABAA receptor positive allosteric modulator in development for treatment of major depressive disorder (MDD). Extrasynaptic preference was hypothesized to explain preclinical findings demonstrating >20-fold separation between antidepressant- and sedative-like doses in rodents, and the lack of dose-limiting sedation in a Phase 1 trial assessing PRAX-114 safety and tolerability in healthy participants. Here we report results from an open-label Phase 2 trial assessing safety, tolerability and preliminary efficacy in MDD.

Comparative effectiveness of repeated ketamine infusions in treating anhedonia in bipolar and unipolar depression

ObjectivesAnhedonia is a common, persistent, and disabling phenomenon in patients with major depressive disorder (MDD) and bipolar depression (BD). This study was conducted to investigate the comparative effectiveness of repeated ketamine infusions in treating anhedonia in Chinese individuals suffering from MDD and BD. MethodsNinety-seven individuals suffering from MDD (n = 77) or BD (n = 20) were treated with six intravenous infusions of ketamine (0.5 mg/kg) administered over 40 min. Anhedonia was measured through the Montgomery–Åsberg Depression Rating Scale (MADRS). The antianhedonic response and remission were defined as ≥ 50% and ≥ 75% reduction in MADRS anhedonia subscale score one day after the sixth infusion, respectively. ResultsAnti-anhedonic response and remission rates after the sixth ketamine infusion were 48.5% (95% confidence interval = 38.3%–58.6%) and 30.9% (95% confidence interval = 21.6%–40.3%), respectively. When compared to baseline, a significant reduction in the MADRS anhedonia subscale score was observed at 4 h after the first infusion and was maintained with repeated infusions at any time point (all Ps < 0.05). The anti-anhedonic effect of ketamine did not differ between the MDD and BD groups. ConclusionThis preliminary study found that repeated ketamine infusions appeared to be effective at rapidly ameliorating anhedonia, with similar efficacy in MDD and BD.

White matter markers and predictors for subject-specific rTMS response in major depressive disorder

Repetitive transcranial magnetic stimulation (rTMS) has established therapeutic efficacy for major depressive disorder (MDD). While translational research has focused primarily on understanding the mechanism of action of TMS on functional activation and connectivity, the effects on structural connectivity remain largely unknown especially when rTMS is applied using subject-specific brain targets. This study aims to use novel diffusion magnetic resonance imaging (dMRI) analysis to examine microstructural changes related to rTMS treatment response using a unique cohort of 21 patients with MDD treated using rTMS with subject-specific targets. White matter dMRI microstructural measures and clinical scores were captured before and after the full course of treatment. We defined disease-relevant fiber bundles connected to different subregions of the left prefrontal cortex and analyzed changes in diffusion properties as well as correlations between the changes of dMRI measures and the changes in Hamilton Depression Rating Scale (HAMD). No significant changes were observed in tracts connected to the TMS targets. rTMS significantly increased the extra-axonal free-water volume, fractional anisotropy and decreased the radial diffusivity in anterior-medial prefrontal fiber bundles but did not lead to raw changes in lateral prefrontal tracts. That said, the microstructural changes in the lateral prefrontal white matter were significantly correlated with treatment response. Moreover, pre-rTMS dMRI measures of the dorsal anterior cingulate cortex and lateral prefrontal cortex connections are correlated with changes in HAMD scores. Microstructural changes in the anterior-medial and lateral prefrontal white matter are potentially involved in treatment response to TMS, though further investigation is needed using larger datasets.

Childhood trauma mediates repetitive transcranial magnetic stimulation efficacy in major depressive disorder

Childhood trauma is one of the most prominent risk factors in developing major depressive disorder (MDD) and may lead to unfavorable outcomes of pharmacotherapy and psychotherapy in MDD. While how it modulates the treatment outcome of the repetitive transcranial magnetic stimulation (rTMS) and how sex difference may play a role in mediating this relationship remain unknown. To evaluate this question, 51 (37 women) MDD patients were treated with 10Hz rTMS to the left dorsolateral prefrontal cortex (lDLPFC). The experience of childhood trauma was quantified by the Childhood Traumatic Questionnaire (CTQ). The depressive severity was assessed by Hamilton Depression Scale (HAMD) and Beck Depression Inventory (BDI) as the primary and secondary assessments. Beck Hopelessness Scale (BHS) and Hamilton Anxiety Scale (HAMA) were also assessed for further confirmation. Thirty-six (70.6%) participants showed a response including 17 (33.3%) achieving remission to the rTMS treatment. The alleviation of depressive symptoms was negatively correlated with the CTQ scores, specifically in women but not men, in subjective BDI and BHS, but not objective HAMD or HAMA. We demonstrate that childhood trauma negatively affects the subjective perception of rTMS-lDLPFC treatment outcomes in female MDD patients. This highlights the importance of measuring childhood trauma-related symptoms in routine clinical rTMS treatment, as they may impact perceived efficacy.

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation.

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.

Association of the TLR4 gene with depressive symptoms and antidepressant efficacy in major depressive disorder

At present, the etiology and pathogenesis of major depressive disorder(MDD) are still unclear. Some studies have shown that toll-like receptor 4 may play an important role in MDD. However, little is currently known about the association between TLR4 single gene polymorphisms (SNPs) and depressive symptoms and antidepressant efficacy.The aim of this study is to analyze whether TLR4 SNPs are associated with depressive symptoms and antidepressant efficacy. The study consisted of 438 patients with first-episode depression. We analyzed three TLR4 SNPs (rs1927911, rs11536889, and rs7873784) and obtained the baseline and 6-week scores using the 17-item Hamilton Depression Rating Scale (HAMD17) and its five-factor model. Allelic and genotypic association tests between TLR4 SNPs and HAMD17 total and cluster scores were performed with UNPHASED, while chi-square tests to analyze the association between TLR4 SNPs and response to antidepressants were performed with SPSS. Patients with the rs1927911-GG genotype exhibited higher scores of anxiety (physical symptoms) and anxiety (somatic). Patients with rs1927911-G also exhibited higher anxiety (physical symptoms) and anxiety (somatic) scores. Patients with rs11536889-GG had significantly lower suicide scores and higher psychomotor retardation scores. Patients with rs11536889-G also had significantly lower suicide scores and higher psychomotor retardation scores. Patients with rs7873784-G had higher anxiety (physical symptoms) and anxiety (psychological) scores. There was no significant difference between antidepressant efficacy and TLR4 gene polymorphisms. These findings provide evidence that TLR4 plays an important role in anxiety, suicide, and other symptoms in patients with MDD. No relationship was found between TLR4 gene polymorphisms and antidepressant efficacy in this study. Further research is needed on gene polymorphisms and the expression of TLR4 in patients with MDD.

The preclinical discovery and development of agomelatine for the treatment of depression

ABSTRACT Introduction Under the treatment of commonly used antidepressants, many patients with major depressive disorder (MDD) do not achieve remission. All previous first-line treatments for depression have focused on the enhancement of monoaminergic activity. Agomelatine was the first antidepressant with a mechanism of action extending beyond monoaminergic neurotransmission. Areas covered The aim of this case history is to describe the discovery strategy and development of agomelatine. The pharmacodynamic profile of the drug is briefly presented. The article summarizes (a) the preclinical behavioral data on agomelatine’s effects on depressive-like behavior, anxiety, and circadian rhythmicity disruptions, and (b) the results of early preclinical studies on safety, efficacy in MDD, and the risk-benefit pharmacological profile. Furthermore, the article examines findings of post-marketing research on safety, efficacy, and cost-effectiveness of the drug. Expert opinion There is now evidence supporting the clinical efficacy and safety profile of agomelatine in the acute-phase treatment of MDD. Agomelatine may be more effective in specific subgroups of MDD patients, those with severe anxiety symptoms or disturbed circadian profiles. Its antidepressant and anxiolytic activities are due to synergy between its melatonergic and 5-hydroxytryptaminergic effects. Since its discovery, novel compounds acting on the melatonergic system have been under investigation for the treatment of MDD.