Treatment Of Major Depressive Disorder Research Articles

Association of Lower Rostral Anterior Cingulate GABA+ and Dysregulated Cortisol Stress Response With Altered Functional Connectivity in Young Adults With Lifetime Depression: A Multimodal Imaging Investigation of Trait and State Effects.

Preclinical work suggests that excess glucocorticoids and reduced cortical γ-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucocorticoids and GABA in current or remitted major depressive disorder (MDD). Multimodal imaging data were collected from 130 young adults (ages 18-25), of whom 44 had current MDD, 42 had remitted MDD, and 44 were healthy comparison subjects. GABA+ (γ-aminobutyric acid and macromolecules) was assessed using magnetic resonance spectroscopy, and task-related functional MRI data were collected under acute stress and analyzed using data-driven network modeling. Across modalities, trait-related abnormalities emerged. Relative to healthy comparison subjects, both clinical groups were characterized by lower rostral anterior cingulate cortex (rACC) GABA+ and frontoparietal network amplitude but higher amplitude in salience and stress-related networks. For the remitted MDD group, differences from the healthy comparison group emerged in the context of elevated cortisol levels, whereas the MDD group had lower cortisol levels than the healthy comparison group. In the comparison group, frontoparietal and stress-related network connectivity was positively associated with cortisol level (highlighting putative top-down regulation of stress), but the opposite relationship emerged in the MDD and remitted MDD groups. Finally, rACC GABA+ was associated with stress-induced changes in connectivity between overlapping default mode and salience networks. Lifetime MDD was characterized by reduced rACC GABA+ as well as dysregulated cortisol-related interactions between top-down control (frontoparietal) and threat (task-related) networks. These findings warrant further investigation of the role of GABA in the vulnerability to and treatment of MDD.

Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n=585; placebo, n=502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. At the end of 8weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p<0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p<0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

A sirtuin 6 activator in the pipeline: New perspectives in depressive disorder treatment

Major Depressive Disorder (MDD) is among the most prevalent mental illnesses worldwide. Its symptoms include persistent feelings of sadness, loss of interest in previously enjoyed activities, and a lack of motivation for daily tasks. While FDA-approved medications are available, they often come with side effects, especially those targeting monoamine neurotransmitters like SSRIs and SNRIs. Thus, there is a need for innovative medications with different mechanisms of action. Sp-624, a derivative of griseofulvin, is currently undergoing clinical trials for MDD treatment. It acts as a sirtuin 6 (SIRT6) activator, offering a novel approach to treating this disorder. This article discusses the biochemical aspects related to the mechanism of action of sp-624, provides a brief overview of related patents, and highlights ongoing clinical trials involving this substance.

Do enteric glial cells play a role in the pathophysiology of major depression?

Major depressive disorder (MDD) is a common mental disorder associated with significant suffering and disability. Recent evidence has highlighted the role of the gut-brain axis in the pathogenesis of MDD. Enteric glial cells are a structurally and functionally diverse population that plays a key role in regulating enteric nervous function and maintaining intestinal mucosal integrity. These cells may be implicated in the origin of several digestive and extra-digestive disorders, known as enteric neuro-gliopathies (ENG). This paper reviews the evidence that MDD may also belong to the category of ENG. Animal models suggest that environmental adversity can lead to enteric glial dysfunction and depressive-like behaviors. Conditions that are highly comorbid with MDD, both intestinal and extra-intestinal, have been linked to enteric glial alterations. Peripheral blood markers linked to glial integrity and function are altered in patients with MDD, and certain treatments for MDD may have beneficial effects on enteric glial functioning. Though much of this evidence is indirect and provisional, it suggests that MDD may belong to the group of ENG. Further investigation of enteric glial functioning in MDD may yield valuable insights into the pathophysiology and treatment of this disorder.

A Review of the Influence of Personality and Temperament on Major Depressive Disorder Treatment

A Review of the Influence of Personality and Temperament on Major Depressive Disorder Treatment

A Review of the Influence of Personality and Temperament on Major Depressive Disorder Treatment

A Review of the Influence of Personality and Temperament on Major Depressive Disorder Treatment

Combining MRI, clinical data has predictive value in sertraline treatment

A secondary analysis of results from a clinical trial of predictors of response to sertraline treatment for major depressive disorder (MDD) has found that a combination of magnetic resonance imaging (MRI) and clinical data can predict treatment response. These results were specific for sertraline treatment compared with placebo treatment.

Analysis: Study design contributed to differences in ketamine‐ECT trials

Differences in study population characteristics and treatment modalities were largely responsible for the discordant findings between the two adequately powered trials that have compared ketamine treatment and electroconvulsive therapy (ECT) for major depressive disorder, an analysis has concluded. Remission rates with ECT treatment diverged significantly, at 63% in one of the studies and 22% in the other. Results of the analysis were published online Dec. 19, 2023 in the International Journal of Neuropsychopharmacology.

Association between duration of antidepressant treatment for major depressive disorder and relapse rate after discontinuation: A meta-analysis

The optimal duration of antidepressant treatment for patients with major depressive disorder to reduce the risk of relapse after discontinuation remains uncertain. Medline, Cochrane Central Register of Controlled Trials, and Embase were systematically searched for randomized controlled trials (RCTs) with a discontinuation design. A single-group summary meta-analysis was performed to calculate 6-month relapse rates after discontinuation. Meta-regression with restricted cubic splines was performed to model the non-linear relationship between treatment duration and relapse rate after discontinuation. Thirty-five RCTs were included. The relapse rate after discontinuation was approximately 34.81 % at 6 months and 45.12 % at 12 months. After controlling for covariates, the meta-analysis shows that the duration of treatment is associated with the risk of relapse after discontinuation in a non-linear curve, with a relatively higher risk of relapse observed for a duration of less than three months. There appears to be no further reduction in the risk of relapse when treatment is continued for over six months. Our results indicate the importance of at least three months of treatment to avoid the relatively high risk of relapse after discontinuation. The additional benefit of longer treatment remains to be proven.

Can the potential benefit of individualizing treatment be assessed using trial summary statistics alone?

Individualizing treatment assignment can improve outcomes for diseases with patient-to-patient variability in comparative treatment effects. When a clinical trial demonstrates that some patients improve on treatment while others do not, it is tempting to assume that treatment effect heterogeneity exists. However, if outcome variability is mainly driven by factors other than variability in the treatment effect, investigating the extent to which covariate data can predict differential treatment response is a potential waste of resources. Motivated by recent meta-analyses assessing the potential of individualizing treatment for major depressive disorder using only summary statistics, we provide a method that uses summary statistics widely available in published clinical trial results to bound the benefit of optimally assigning treatment to each patient. We also offer alternate bounds for settings in which trial results are stratified by another covariate. Our upper bounds can be especially informative when they are small, as there is then little benefit to collecting additional covariate data. We demonstrate our approach using summary statistics from a depression treatment trial. Our methods are implemented in the rct2otrbounds R package.

PBPK modeling to predict the pharmacokinetics of venlafaxine and its active metabolite in different CYP2D6 genotypes and drug-drug interactions with clarithromycin and paroxetine.

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder, social anxiety disorder, generalized anxiety disorder, and panic disorder. Venlafaxine is metabolized to the active metabolite desvenlafaxine mainly by CYP2D6. Genetic polymorphism of CYP2D6 and coadministration with other medications can significantly affect the pharmacokinetics and/or pharmacodynamics of venlafaxine and its active metabolite. This study aimed to establish the PBPK models of venlafaxine and its active metabolite related to CYP2D6 genetic polymorphism and to predict drug-drug interactions (DDIs) with clarithromycin and paroxetine in different CYP2D6 genotypes. Clinical pharmacogenomic data for venlafaxine and desvenlafaxine were collected to build the PBPK model. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) characteristics of respective compounds were obtained from previously reported data, predicted by the PK-Sim® software, or optimized to capture the plasma concentration-time profiles. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and plasma concentration-time profiles to the observed data. Predicted plasma concentration-time profiles of venlafaxine and its active metabolite were visually similar to the observed profiles and all predicted AUC and Cmax values for respective compounds were included in the twofold error range of observed values in non-genotyped populations and different CYP2D6 genotypes. When clarithromycin or clarithromycin plus paroxetine was concomitantly administered, predicted plasma concentration-time profiles of venlafaxine properly captured the observed profiles in two different CYP2D6 genotypes and all predicted DDI ratios for AUC and Cmax were included within the acceptance range. Consequently, the present model successfully captured the pharmacokinetic alterations of venlafaxine and its active metabolite according to CYP2D6 genetic polymorphism as well as the DDIs between venlafaxine and two CYP inhibitors. The present model can be used to predict the pharmacokinetics of venlafaxine and its active metabolite considering different races, ages, coadministered drugs, and CYP2D6 activity of individuals and it can contribute to individualized pharmacotherapy of venlafaxine.

Unraveling the molecular basis of cannabidiolic acid methyl Ester's anti-depressive effects in a rat model of treatment-resistant depression

Major depressive disorder (MDD) stands as a significant cause of disability globally. Cannabidiolic Acid-Methyl Ester (CBDA-ME) (EPM-301, HU-580), a derivative of Cannabidiol, demonstrates immediate antidepressant-like effects, yet it has undergone only minimal evaluation in psychopharmacology. Our goal was to investigate the behavioral and potential molecular mechanisms associated with the chronic oral administration of this compound in the Wistar Kyoto (WKY) genetic model of treatment-resistant depression. Male WKY rats were subjected to behavioral assessments before and after receiving chronic (14-day) oral doses of CBDA-ME (0.5 mg/kg), 15 mg/kg of imipramine or vehicle. At the end of the study, plasma corticosterone levels and mRNA expression of various genes in the medial Prefrontal Cortex and Hippocampus were measured. Behavioral outcomes from CBDA-ME treatment indicated an antidepressant-like effect similar to imipramine, as oral ingestion reduced immobility and increased swimming duration in the Forced Swim Test. Neither treatment influenced locomotion in the Open Field Test nor preference in the Saccharin Preference Test. The behavioral impact in WKY rats coincided with reduced corticosterone serum levels, upregulated mRNA expression of Cannabinoid receptor 1, Fatty Acid Amide Hydrolase, and Corticotropin-Releasing Hormone Receptor 1, alongside downregulation of the Serotonin Transporter in the hippocampus. Additionally, there was an upregulation of CB1 mRNA expression and downregulation of Brain-Derived Neurotrophic Factor in the mPFC. These findings contribute to our limited understanding of the antidepressant effects of CBDA-ME and shed light on its potential psychopharmacological mechanisms. This discovery opens up possibilities for utilizing cannabinoids in the treatment of major depressive disorder and related conditions.

The effectiveness of using cognitive behavioral therapy and internet-based cognitive behavioral therapy interventions on relapse prevention and severity of symptoms among patients diagnosed with major depressive disorder: a systematic review of randomized controlled trials

Purpose This study aims to evaluate and summarize the effectiveness of cognitive behavioral therapy (CBT) and internet-based CBT (ICBT) interventions on relapse prevention and severity of symptoms among individuals with major depressive disorder (MDD). CBT is one of the most used and suggested interventions to manage MDD, whereas ICBT is a novel effective proposed approach. Design/methodology/approach The review was conducted following the preferred reporting items for systematic review and meta-analysis protocol. A comprehensive and extensive search was performed to identify and evaluate the relevant studies about the effectiveness of CBT and ICBT on relapse prevention and severity of symptoms among patients with MDD. Findings A total of eight research studies met the inclusion criteria and were included in this systematic review. RCT studies were conducted to assess and evaluate the effectiveness of CBT and ICBT on relapse prevention and severity of symptoms among patients with MDD. It has been found that CBT is a well-supported and evidently based effective psychotherapy for managing depressive symptoms and reducing the relapse and readmission rate among patients diagnosed with MDD. The ICBT demonstrated greater improvements in depressive symptoms during major depressive episodes among patients with MDDS. The ICBT program had good acceptability and satisfaction among participants in different countries. Research limitations/implications Despite the significant findings from this systematic review, certain limitations should be acknowledged. First, it is important to note that all the studies included in this review were exclusively conducted in the English language, potentially limiting the generalizability of the findings to non-English speaking populations. Second, the number of research studies incorporated in this systematic review was relatively limited, which may have resulted in a narrower scope of analysis. Finally, a few studies within the selected research had small sample sizes, which could potentially impact the precision and reliability of the overall conclusions drawn from this review. The authors recommend that nurses working in psychiatric units should use CBT interventions with patients with MDD. Practical implications This paper, a review of the literature gives an overview of CBT and ICBT interventions to reduce the severity of depressive symptoms and prevent patients’ relapse and rehospitalization and shows that CBT interventions are effective on relapse prevention among patients with MDD. In addition, there is still no standardized protocol to apply the CBT intervention in the scope of reducing the severity of depressive symptoms and preventing depression relapse among patients with major depressive disorder. Further research is needed to confirm the findings of this review. Future research is also needed to find out the most effective form and contents of CBT and ICBT interventions for MDD. Social implications CBT is a psychological intervention that has been recommended by the literature for the treatment of major depressive disorder (MDD). It is a widely recognized and accepted approach that combines cognitive and behavioral techniques to assist individuals overcome their depressive symptoms and improve their overall mental well-being. This would speculate that effectiveness associated with several aspects and combinations of different approaches in CBT interventions and the impact of different delivery models are essential for clinical practice and appropriate selection of the interventional combinations. Originality/value This systematic review focuses on the various studies that explore the effectiveness of face-to-face CBT and ICBT in reducing depressive symptoms among patients with major depressive disorder. These studies were conducted in different countries such as Iran, Australia, Pennsylvania and the USA.

A Fully Remote Randomized Trial of Transcranial Alternating Current Stimulation for the Acute Treatment of Major Depressive Disorder.

A Fully Remote Randomized Trial of Transcranial Alternating Current Stimulation for the Acute Treatment of Major Depressive Disorder.

Leveraging DNA methylation to predict treatment response in major depressive disorder: A critical review.

Major depressive disorder (MDD) is a debilitating and prevalent mental disorder with a high disease burden. Despite a wide array of different treatment options, many patients do not respond to initial treatment attempts. Selection of the most appropriate treatment remains a significant clinical challenge in psychiatry, highlighting the need for the development of biomarkers with predictive utility. Recently, the epigenetic modification DNA methylation (DNAm) has emerged to be of great interest as a potential predictor of MDD treatment outcomes. Here, we review efforts to date that seek to identify DNAm signatures associated with treatment response in individuals with MDD. Searches were conducted in the databases PubMed, Scopus, and Web of Science with the concepts and keywords MDD, DNAm, antidepressants, psychotherapy, cognitive behavior therapy, electroconvulsive therapy, transcranial magnetic stimulation, and brain stimulation therapies. We identified 32 studies implicating DNAm patterns associated with MDD treatment outcomes. The majority of studies (N = 25) are focused on selected target genes exploring treatment outcomes in pharmacological treatments (N = 22) with a few studies assessing treatment response to electroconvulsive therapy (N = 3). Additionally, there are few genome-scale efforts (N = 7) to characterize DNAm patterns associated with treatment outcomes. There is a relative dearth of studies investigating DNAm patterns in relation to psychotherapy, electroconvulsive therapy, or transcranial magnetic stimulation; importantly, most existing studies have limited sample sizes. Given the heterogeneity in both methods and results of studies to date, there is a need for additional studies before existing findings can inform clinical decisions.

Telephone support vs. self-guidance in an Internet-based self-administered psychological program for the treatment of depression: Protocol for a hybrid type 1 effectiveness-implementation randomized controlled trial

BackgroundDepression is already the leading psychological disability around the world, impairing daily life, well-being, and social functioning and leading to personal and social costs. Despite the effectiveness of Evidence-Based Psychological Practices (EBPP), a significant percentage of depressive individuals remain untreated, especially in Primary Care (PC) settings in Spain. There are numerous barriers that limit access to EBPPs, including high costs, professional training, and adherence problems. Information and Communication Technologies (ICTs) offer a cost-effective way to disseminate and scale EBPPs to address these barriers. The iCBT program Smiling is Fun has been demonstrated to be a cost-effective treatment for depression in various Randomized Control Trials. However, adherence and implementation problems in real-world settings need to be addressed. Implementation research can help evaluate these challenges by identifying facilitators and barriers to the implementation process in PC. In this regard, including human support has been pointed out as a possible key factor in addressing the population's mental health needs and promoting treatment adherence. ObjectiveThe current study aims to examine the effectiveness, adherence rates, and implementation process of Smiling is Fun to address depression in a PC setting considering the influence of telephone support vs no support. MethodsThe proposed research is a Hybrid Effectiveness-Implementation Type I study, with a two-armed randomized controlled design, which will test a clinical intervention for major depressive disorder while gathering information on its implementation in a real-world setting. The study will include adult patients with mild to moderate symptoms of depression. Participants will be randomly assigned to one of two groups: self-applied psychotherapy or self-applied psychotherapy with psychotherapeutic telephone support. The trial will recruit 110 patient participants, with a loss-to-follow-up rate of 30 %. DiscussionA study protocol for a hybrid effectiveness-implementation study is presented with the aim to assess the implementation of Smiling is Fun for the treatment of depression in PC. The study evaluates the influence of telephone support during a self-administered intervention compared to unguided self-administration. The main goal is to address the barriers and facilitators of the implementation process and to promote treatment adherence. Ultimately, the results of the study could help in the uptake of sustainable resources so that the population could gain better access to psychological interventions in mental health services. RegistrationClinicalTrials.gov; NCT06230237.

Dysregulation of adipogenesis and disrupted lipid metabolism by the antidepressants citalopram and sertraline

Selective Serotonin Reuptake Inhibitors (SSRIs) are widely used medications for the treatment of major depressive disorder. However, long-term SSRI use has been associated with weight gain and altered lipid profiles. These findings suggest that SSRIs may have negative effects on metabolism. Exposure to certain chemicals called ‘obesogens’ is known to promote lipid accumulation and obesity by modulating adipogenesis. Here, we investigated whether citalopram (CIT) and sertraline (SER) interfere with the process of adipogenesis, using human mesenchymal stem cells (MSCs) in a 2D and a 3D model. Assessment of intracellular lipid accumulation by fluorescence staining was used as a measure for enhanced adipogenesis. To explore possible mechanisms behind SSRIs' effects, receptor mediated activity was studied using responsive cell lines for various nuclear receptors. Furthermore, RNA sequencing was performed in the 3D model, followed by differential gene expression and pathway analysis. A dose dependent increase in lipid accumulation was observed in both models with CIT and SER. For the 3D model, the effect was seen in a range close to reported steady-state plasma concentrations (0.065–0.65 μM for SER and 0.12–0.92 μM for CIT). Pathway analysis revealed unexpected results of downregulation in adipogenesis-related pathways and upregulation in phospholipids and lysosomal pathways. This was confirmed by an observed increase in lysosomes in the 2D model. Our findings suggest lysosomal dysfunction and disrupted lipid metabolism in mature adipocytes, leading to excessive phospholipid synthesis. Moreover, important adipogenic processes are inhibited, potentially leading to dysfunctional adipocytes, which might have implications in the maintenance of a healthy metabolic balance.

Tricyclic antidepressants: An update

Tricyclic antidepressants (TCAs) are a class of psychotropic medications primarily used in the treatment of major depressive disorders, although their indications extend to a variety of psychiatric and neurological conditions. This class of medications was one of the first to be developed for the treatment of depression, marking a revolution in the management of this condition in the mid-20th century. The aim of this study is to present a narrative review in the form of an update on the pharmacokinetic properties, pharmacodynamics, indications, and side effects of tricyclic antidepressants. For this purpose, a narrative review in the format of an update was carried out, which analyzed 42 manuscripts. TCAs have various pharmacological and therapeutic properties, low cost, but their major limitation is their side effects. Since the clinical trials for this class were conducted well before the launch of new antidepressants, new research is needed to allow comparison of these groups within the same methodology and with more up-to-date statistics.

Feasibility and preliminary efficacy of a theory-informed resistance exercise training single-arm intervention for major depression

Many adults with major depressive disorder (MDD) do not receive effective treatment. The potential benefits of resistance exercise training (RET) are understudied and may be mechanistically related to cerebral blood flow changes. PurposeTo assess feasibility, acceptability, and preliminary efficacy of a 16-week, theory-informed RET trial for the treatment of MDD and explore changes in cerebral blood flow. MethodsTen adults with DSM-5-diagnosed MDD were enrolled in a single-arm, 16-week, twice-weekly, whole-body RET intervention, consistent with US and WHO Physical Activity resistance exercise guidelines. To build intrinsic motivation and develop exercise-preparatory habits, motivators and commitment were discussed weekly. Screening, enrollment, and intervention attendance and compliance rates documented feasibility. At baseline and weeks 8, 16, and 26, current MDD diagnosis, clinician-rated, and self-reported symptom severity were evaluated along with cerebral blood flow which was assessed as middle cerebral artery (MCA) mean blood velocity, conductance, and pulsatility. ResultsNine participants completed the intervention. Strong feasibility and acceptability (98 % adherence, 93 % compliance, and 90 % retention) were found. MDD remission was reached by 8/9 participants at week 16 and persisted through week 26. There were large decreases in clinician-rated and self-reported symptoms at each assessment (Hedges’ g = 0.84–2.13). There were small-to-moderate increases in MCA velocity (g = 0.32–0.57) and conductance (g = 0.20–0.76) across time, with minimal changes in pulsatility (all g < 0.21). ConclusionsPreliminary results suggest RET for MDD treatment is feasible and plausibly efficacious, finding large antidepressant effects. A sufficiently powered randomized controlled trial to assess RET’s efficacy for treating MDD via potential cerebrovascular mechanisms is warranted.

Validation of the predictive value of BDNF -87 methylation for antidepressant treatment success in severely depressed patients—a randomized rater-blinded trial

BackgroundBrain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE).MethodsThe BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study’s main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE.Ethics and disseminationThe trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals.Trial registrationGerman Clinical Trial Register DRKS00032503. Registered on 17 August 2023.