Evaluation of Intensified Pharmacological Treatment with Esketamine for Major Depressive Disorder in Patients with First-Line Treatment Failure

The primary objective of this study is to evaluate the **treatment response** in subjects with major depressive disorder who experienced a first-time treatment failure on their first-line treatment. This is assessed by comparing symptom severity at baseline (visit 2) and at the end of a six-week treatment period (visit 4) using the Montgomery Åsberg Depression Rating Scale (MADRS). The study aims to determine the efficacy of an early-intensified pharmacological treatment compared to treatment as usual. This is clinically relevant as it addresses the need for effective treatment strategies in patients who do not respond to initial therapy, potentially improving outcomes and quality of life for these individuals.

Secondary objectives include:

• Comparing changes in severity and improvement in global functioning using the Clinical Global Impression Scale (CGI) between treatment arms.
• Assessing changes in levels of depression and anxiety between treatment arms.
• Evaluating changes in quality of life and functioning measures between treatment arms.
• Comparing changes in cognitive performance between treatment arms.
• Determining the proportion of participants in symptomatic remission at visit 4 between treatment arms.
• Comparing the presence of adverse events, both related and unrelated to treatment, between treatment arms.
• Assessing the use of concomitant medication between treatment arms.
• Evaluating premature treatment discontinuation, including timing and reason, between treatment arms.
• Comparing changes in suicidal ideation between treatment arms.

The clinical trial involves a total of **93 participants** diagnosed with **major depressive disorder**. The study population includes both male and female subjects, aged between 18 and 65 years. Participants were selected based on their failure to respond to first-line treatment for major depressive disorder, as confirmed by a score of 3 or higher on the Clinical Global Impression-Improvement scale. The trial includes individuals who are either inpatients or outpatients and who meet the diagnostic criteria for major depressive disorder without psychotic features, as per DSM-5, confirmed by the Mini International Neuropsychiatric Interview. Participants must exhibit a minimum symptom severity threshold, with a score of 20 or higher on the Montgomery Åsberg Depression Rating Scale and functional impairment as defined by a score of 5 or higher on the Sheehan Disability Scale. Both male and female subjects are included, with female participants of childbearing potential required to use effective contraception and have a negative pregnancy test before randomization. The trial population is characterized by a willingness and ability to provide informed consent, with the option for a legal guardian to cosign if necessary. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of a six-week intensified pharmacological treatment for **major depressive disorder** compared to standard treatment in individuals who have experienced a first-time treatment failure with their initial therapy. This study employs a randomized, controlled trial design, ensuring that participants are randomly assigned to either the experimental or control group, with both groups being blinded to the treatment allocation to minimize bias. The trial is expected to commence on January 1, 2024, and conclude by June 30, 2026, with the primary objective of assessing changes in symptom severity using the Montgomery Åsberg Depression Rating Scale (MADRS) from baseline to the end of the treatment period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit where eligibility criteria are confirmed, including age, consent, and diagnostic criteria for major depressive disorder. Following the screening, participants will be randomized and begin treatment, with follow-up visits scheduled to monitor progress and collect data on symptom severity, side effects, and overall treatment response. The end-of-study visit will occur at the six-week mark, where final assessments will be conducted to evaluate the primary and secondary endpoints, including changes in quality of life, functional measures, and cognitive tests.

The expected duration of participant involvement is approximately six weeks, aligning with the treatment period. However, certain conditions may lead to early termination from the study, such as significant adverse effects, withdrawal of consent, or non-compliance with study protocols. The trial aims to provide valuable insights into the effectiveness of intensified pharmacological interventions for individuals with major depressive disorder who have not responded to initial treatments.

The clinical trial involves the administration of **bupropion hydrochloride**, a chemical compound also known as amfebutamone hydrochloride. It is provided in an oral pharmaceutical form with a maximum daily dose of 300 mg and a total maximum dose of 12,600 mg over a treatment period of six weeks. The administration route is oral, and participant compliance is monitored throughout the trial.

**Vortioxetine** is another experimental medication used in the trial. It is administered orally with a maximum daily dose of 20 mg and a total maximum dose of 840 mg over six weeks. The pharmaceutical form is designed for oral intake, ensuring ease of administration and adherence to the dosing schedule.

**Reboxetine** is included in the study as an oral medication with a maximum daily dose of 12 mg and a total maximum dose of 504 mg over the six-week treatment period. The chemical nature of reboxetine ensures its stability and efficacy when administered orally.

**Trazodone** is administered orally with a maximum daily dose of 300 mg and a total maximum dose of 12,600 mg over six weeks. The pharmaceutical form supports oral administration, facilitating participant compliance with the dosing regimen.

**Paroxetine hydrochloride**, also known by its synonyms such as anhydrous paroxetine hydrochloride, is administered orally with a maximum daily dose of 50 mg and a total maximum dose of 2,100 mg over six weeks. The oral route of administration is chosen for its convenience and effectiveness.

**Mirtazapine** is provided in an oral form with a maximum daily dose of 45 mg and a total maximum dose of 1,890 mg over the six-week treatment period. The oral administration route is selected to ensure participant adherence to the treatment protocol.

**Agomelatine** is administered orally with a maximum daily dose of 50 mg and a total maximum dose of 2,100 mg over six weeks. The pharmaceutical form is optimized for oral intake, promoting consistent dosing and participant compliance.

**Imipramine hydrochloride** is included in the trial as an oral medication with a maximum daily dose of 200 mg and a total maximum dose of 8,400 mg over six weeks. The chemical stability of imipramine hydrochloride supports its efficacy when administered orally.

**Amitriptyline hydrochloride** is administered orally with a maximum daily dose of 150 mg and a total maximum dose of 6,300 mg over the six-week treatment period. The oral route is chosen for its practicality and participant adherence.

**Mianserin hydrochloride** is provided in an oral form with a maximum daily dose of 90 mg and a total maximum dose of 3,780 mg over six weeks. The oral administration route is selected to ensure ease of use and compliance with the dosing schedule.

**Fluoxetine hydrochloride** is administered orally with a maximum daily dose of 60 mg and a total maximum dose of 2,520 mg over six weeks. The pharmaceutical form supports oral administration, facilitating participant adherence to the treatment regimen.

**Desvenlafaxine benzoate** is included in the study as an oral medication with a maximum daily dose of 200 mg and a total maximum dose of 8,400 mg over six weeks. The chemical nature of desvenlafaxine benzoate ensures its stability and efficacy when administered orally.

**Duloxetine** is administered orally with a maximum daily dose of 120 mg and a total maximum dose of 5,040 mg over the six-week treatment period. The oral route of administration is chosen for its convenience and effectiveness.

**Clomipramine hydrochloride** is provided in an oral form with a maximum daily dose of 250 mg and a total maximum dose of 10,500 mg over six weeks. The oral administration route is selected to ensure participant adherence to the treatment protocol.

**Esketamine** is administered via infusion with a maximum daily dose of 1 mg/kg and a total maximum dose of 8 mg/kg over a four-week treatment period. The infusion route is chosen for its rapid onset of action and precise dosing control.

**Ketamine** is included in the trial as an infusion with a maximum daily dose of 1 mg/kg and a total maximum dose of 8 mg/kg over four weeks. The infusion route allows for controlled administration and monitoring of participant response.

**Tianeptine** is administered orally with a maximum daily dose of 37.5 mg and a total maximum dose of 1,575 mg over six weeks. The pharmaceutical form is optimized for oral intake, promoting consistent dosing and participant compliance.

**Venlafaxine** is provided in an oral form with a maximum daily dose of 375 mg and a total maximum dose of 15,750 mg over the six-week treatment period. The oral administration route is selected to ensure ease of use and compliance with the dosing schedule.

**Citalopram hydrobromide** is administered orally with a maximum daily dose of 40 mg and a total maximum dose of 1,680 mg over six weeks. The pharmaceutical form supports oral administration, facilitating participant adherence to the treatment regimen.

**Nortriptyline hydrochloride** is included in the study as an oral medication with a maximum daily dose of 150 mg and a total maximum dose of 6,300 mg over six weeks. The chemical stability of nortriptyline hydrochloride supports its efficacy when administered orally.

**Citalopram** is administered orally with a maximum daily dose of 20 mg and a total maximum dose of 840 mg over the six-week treatment period. The oral route is chosen for its practicality and participant adherence.

**Dosulepin hydrochloride** is provided in an oral form with a maximum daily dose of 150 mg and a total maximum dose of 6,300 mg over six weeks. The oral administration route is selected to ensure ease of use and compliance with the dosing schedule.

**Fluvoxamine** is administered orally with a maximum daily dose of 300 mg and a total maximum dose of 12,600 mg over six weeks. The pharmaceutical form supports oral administration, facilitating participant adherence to the treatment regimen.

**Atomoxetine** is included in the trial as an oral medication with a maximum daily dose of 100 mg and a total maximum dose of 4,200 mg over six weeks. The chemical nature of atomoxetine ensures its stability and efficacy when administered orally.

**Milnacipran hydrochloride** is administered orally with a maximum daily dose of 100 mg and a total maximum dose of 4,200 mg over the six-week treatment period. The oral route of administration is chosen for its convenience and effectiveness.

**Sertraline hydrochloride** is provided in an oral form with a maximum daily dose of 200 mg and a total maximum dose of 8,400 mg over six weeks. The oral administration route is selected to ensure participant adherence to the treatment protocol.

**Esketamine** is also administered as a nasal spray with a maximum daily dose of 84 mg and a total maximum dose of 672 mg over a four-week treatment period. The nasal spray route allows for rapid absorption and ease of use.

Efficacy in this clinical trial will be assessed primarily through the evaluation of symptom severity changes in patients with major depressive disorder. The primary endpoint is the mean change from baseline in symptom severity, as measured by the Montgomery Åsberg Depression Rating Scale (MADRS) total score at six weeks. This will be compared between two treatment arms: early-intensified pharmacological treatment (EIPT) and treatment as usual (TAU).

Secondary endpoints include several measures: changes from baseline in the severity and improvement sub-scores of the Clinical Global Impression Scale (CGI), changes in the total score and subscales of the Hospital Anxiety and Depression Scale (HADS), and changes in quality of life and functioning measures using tools such as the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), Life Assessment of Productivity and Satisfaction (LAPS), Quality of Life Scale (QLS-100), and Sheehan Disability Scale (SDS). Cognitive assessments will be conducted using the Trail Making Test, Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and the Perceived Deficits Questionnaire.

Additional assessments will include the presence of symptomatic remission, defined as a MADRS score of 12 or less, and the presence of reported side effects using the General Assessment of Side Effects Scale (GASE). Concomitant medication use, premature treatment discontinuation, and changes on the Columbia-Suicide Severity Rating Scale (C-SSRS) will also be evaluated. These assessments will be conducted at baseline (visit 2) and at the end of treatment (visit 4), ensuring a comprehensive evaluation of the treatment's efficacy.