The DEXA-PSYCH Study: Dexamethasone Repurposing for Moderate to Severe Depression - A Double-Blind, Randomized, Parallel-Group, Placebo-Controlled Trial

The primary objective of the DEXA-PSYCH study is to evaluate the **efficacy** and **safety** of **dexamethasone**, a glucocorticoid, as an adjunct to treatment as usual (TAU) in patients with moderate to severe **depression**. This investigation is clinically relevant as it explores the potential repurposing of dexamethasone, which is traditionally used for its anti-inflammatory properties, in the management of depression, a condition with significant morbidity and a need for novel therapeutic strategies.

The clinical trial involves participants diagnosed with **depression**, specifically non-psychotic, moderate to severe depressive disorder, as defined by ICD-10 criteria. The study population includes both male and female subjects, aged between 18 and 64 years, who are currently receiving pharmacological treatment for depression. Participants are required to have a score of 22 or above on the MADRS10 scale at the start of the trial. The trial does not include a vulnerable population, and all participants must be able to provide informed consent and speak Danish fluently. The sponsor has not provided information regarding the total number of participants in the trial. The selection criteria ensure that the study population is representative of individuals with moderate to severe depression, without any specific lifestyle considerations being highlighted.

The clinical trial is designed to evaluate the efficacy and safety of **dexamethasone** as an adjunctive treatment for moderate to severe **depression**. This study is a double-blind, randomized, parallel-group, placebo-controlled trial. The trial is expected to run from October 17, 2022, to November 30, 2026. Participants will be randomly assigned to receive either dexamethasone or a placebo, with both groups continuing their usual pharmacological treatment for depression. The trial will include several study visits to monitor the participants' progress and collect data on the primary and secondary endpoints.

The sequence of study visits begins with an inclusion (screening) visit, where participants will be assessed for eligibility based on criteria such as a diagnosis of non-psychotic, moderate to severe depressive disorder according to ICD-10 criteria, a score of 22 or above on the MADRS10 scale, and other inclusion criteria. Following the screening, eligible participants will be enrolled in the study. The primary endpoint is the change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS-10) at day 7. Secondary endpoints include remission rates, changes in quality of life, safety outcomes, and other measures of depression and functioning at various time points, including day 7, day 28, and a 6-month follow-up.

Participants are expected to be involved in the study for a period that includes the initial treatment phase and follow-up assessments, with the possibility of early termination if they experience adverse reactions or if they withdraw consent. The trial will also assess the relative risk of unemployment, psychiatric admissions, and suicide attempts, as well as all-cause mortality, through patient interviews and national registers. The study aims to provide comprehensive data on the potential repurposing of dexamethasone for treating depression, contributing valuable insights into its efficacy and safety profile in this context.

The clinical trial involves the administration of **dexamethasone**, a glucocorticoid, as the primary experimental medication. Dexamethasone is provided in an oral pharmaceutical form with a maximum daily dose of 4 mg and a total dose of 22 mg over a treatment period of 7 days. The administration route is oral, and the medication is intended to be used as an add-on to treatment as usual (TAU) for moderate to severe depression.

In addition to dexamethasone, several auxiliary medications are included in the study. **Mirtazapine** is administered orally with a maximum daily dose of 45 mg. **Citalopram** is also administered orally, with a maximum daily dose of 40 mg. **Nortriptyline** is provided in an oral form with a maximum daily dose of 150 mg. **Escitalopram** is administered orally with a maximum daily dose of 20 mg. **Lithium** is included with a maximum daily dose of 40 mg, administered orally. **Sertraline** is provided with a maximum daily dose of 200 mg, administered orally. **Venlafaxine** is administered orally with a maximum daily dose of 375 mg. **Quetiapine** is included with a maximum daily dose of 600 mg, administered orally. All auxiliary medications have a maximum treatment period of 999 days.

The study also includes a placebo group. The placebo consists of pills containing lactose monohydrate, starch, gelatine, talc, and magnesium stearate, encapsulated in gelatin. The placebo is used to maintain the double-blind nature of the trial and is administered in a manner consistent with the active treatments.

Participant compliance with the medication regimen is monitored throughout the trial to ensure adherence to the dosing schedules. The trial is designed to evaluate the efficacy and safety of dexamethasone as an adjunctive treatment for depression, with all medications administered orally to participants.

The efficacy of the DEXA-PSYCH trial will be assessed using several parameters. The primary endpoint is the change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS-10) at day 7. Secondary endpoints include the number of participants achieving **remission** (MADRS-10 score ≤ 11) on day 7, changes in quality of life as measured by the EQ-5D-5L, and various safety outcomes. These safety outcomes encompass adverse reactions, all-cause discontinuation, vital signs, suicidal ideation, laboratory tests, ECG, toxicity, side effects of antidepressants, positive psychotic symptoms, manic symptoms, admissions, suicide attempts, completed suicides, and all-cause mortality. Additional secondary endpoints include changes from baseline on the MADRS-10 at days 4, 14, and 28, and at 6-month follow-up, as well as changes on the Hamilton Depression Rating Scale (HAM-D6 and HAM-D17), Columbia-Suicide Severity Rating Scale (C-SSRS), Hamilton Anxiety Rating Scale (HAM-A), Global Assessment of Functioning (GAF) scale, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale at specified time points.

Data collection will occur at multiple time points, including days 4, 7, 14, 28, and at 6-month follow-up. The trial will utilize validated scales and patient-reported outcomes to measure these parameters. The Monsenso app will be used to collect self-rated MADRS scores and assess physical and social activity levels from day 1 to 28. Baseline levels of CRP, leucocytes, and other biochemical markers will be assayed in biological samples to differentiate responders from non-responders. The trial will also assess the relative risk of unemployment, psychiatric admissions, and suicide attempts through patient interviews and national Danish registers. The efficacy assessments are designed to provide a comprehensive evaluation of the impact of dexamethasone as an add-on treatment for moderate to severe depression.