The DEXA-PSYCH Study—dexamethasone for moderate-to-severe depression: study protocol for a double-blind, randomized, parallel-group, placebo-controlled trial

Abstract

Background

Globally, depression represents one of the leading causes of years lived with disability. The effects of current pharmacological treatments are small-to-moderate and often delayed by weeks. Immunological disturbances have been associated with depression and meta-analyses have suggested that anti-inflammatory agents have moderate-to-large anti-depressant effects. The largest effects were reported for glucocorticoids. However, previous trials were too small to legitimize standard use of glucocorticoids as add-on treatment in depression. The purpose of the DEXA-PSYCH study is to investigate the effect and safety of short-term, oral dexamethasone compared to placebo as add-on therapy in moderate-to-severe depression.

Methods

The DEXA-PSYCH trial is an investigator-initiated, double-blind, randomized, placebo-controlled, parallel-group superiority trial. Three-hundred participants meeting criteria for moderate-to-severe depression will be randomized in a 1:1 ratio to 1 week of either dexamethasone (4 mg/day for 4 days, subsequently 2 mg/day for 3 days) or placebo as add-on treatment to treatment as usual. Both in- and out-patients are eligible. Exclusion criteria include, but are not limited to, psychotic disorders, bipolar disorder, and diabetes. The primary outcome is change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score on day 7 and will be analyzed through a Mixed Model for Repeated Measurements (MMRM) in an intention-to-treat analysis. Key secondary outcomes include response and remission rates, efficacy 3 weeks after the intervention, effects on quality of life, and safety outcomes. Other secondary outcomes include overall functioning, fatigue, anxiety, labor-market affiliation, and associations between inflammatory biomarkers and treatment response.

Discussion

The DEXA-PSYCH trial represents the largest trial of its kind globally. If the trial confirms findings from previous, smaller studies, short-term oral dexamethasone could become an attractive augmentation strategy if acute anti-depressant effects are warranted. Dexamethasone is an off-patent, well-known drug readily repurposed for new indications.

Trial registration

EU Clinical Trials Number 2022–501428-45–00, Registered 25th of July 2022 in the EU Clinical Trials Information System (https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2022-501428-45-00). WHO Universal Trial Identifier U1111-1280–7614.

Administrative information

Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

Title {1}	The DEXA-PSYCH Study: Dexamethasone Repurposing for Moderate-to-Severe Depression—A Double-Blind, Randomized, Parallel-Group, Placebo-Controlled Trial
Trial registration {2a and 2b}.	EU Clinical Trials Number 2022–501428-45–00. WHO Universal Trial Identifier U1111-1280–7614.
Protocol version {3}	Protocol version 1.3. (Amendment approved November 20th, 2024)
Funding {4}	Funded by an unrestricted research grant for investigator-initiated trials with a non-commercial focus awarded by the Novo Nordisk Foundation (grant number NNF21OC0072020). Additional support from the Mental Health Services in the Capital Region of Denmark.
Author details {5a}	Michael Eriksen Benros, MD/PhD (Sponsor/Principal Investigator) Professor, Chief Physician, MD, PhD Board Certified Consultant in Psychiatry Copenhagen Research Center for Biological and Precision Psychiatry Mental Health Centre Copenhagen Gentofte Hospitalsvej 19, Ground floor DK-2900 Hellerup Denmark Tel: + 45 26 25 52 39 Michael.Eriksen.Benros@regionh.dk Troels Boldt Rømer (Sub-Investigator) Medical Doctor (MD), PhD-Student Copenhagen Research Center for Biological and Precision Psychiatry Mental Health Centre Copenhagen Gentofte Hospitalsvej 19, Ground floor DK-2900 Hellerup Denmark Tel: + 45 31 47 43 45 Troels.Boldt.Roemer@regionh.dk Camilla Gøtzsche Frederiksen (Sub-Investigator) Medical Doctor (MD), PhD-Student Copenhagen Research Center for Biological and Precision Psychiatry Mental Health Centre Copenhagen Gentofte Hospitalsvej 19, Ground floor DK-2900 Hellerup Denmark Tel: + 45 26 23 38 90 camilla.goetzsche.frederiksen.02@regionh.dk Pernille Bølling Hansen (Sub-Investigator) Medical Doctor (MD) Copenhagen Research Center for Biological and Precision Psychiatry Mental Health Centre Copenhagen Gentofte Hospitalsvej 19, Ground floor DK-2900 Hellerup Denmark Tel: + 45 29 33 60 89 Pernille.hansen.16@regionh.dk Rune Haubo Bojesen Christensen, PhD (Statistician) Senior statistician Copenhagen Research Center for Biological and Precision Psychiatry Mental Health Centre Copenhagen Gentofte Hospitalsvej 19, Ground floor DK-2900 Hellerup Denmark Tel: + 45 30 26 45 54 Rune.Haubo.Christensen@regionh.dk
Name and contact information for the trial sponsor {5b}	Michael Eriksen Benros, MD/PhD Professor, Chief Physician, MD, PhD Board Certified Consultant in Psychiatry Mental Health Services in the Capital Region of Denmark (MHSC) Mental Health Center Copenhagen (MHCC) Copenhagen Research Center for Biological and Precision Psychiatry Gentofte Hospitalsvej 19, Ground floor DK-2900 Hellerup Denmark Tel: + 45 26 25 52 39 Michael.Eriksen.Benros@regionh.dk
Role of sponsor {5c}	The sponsor/principal investigator (Michael Eriksen Benros, Mental Health Services in the Capital Region of Denmark) is fully responsible for study design and management. The funding body (Novo Nordisk Foundation) does not have any role in study design; collection, management, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication.

Introduction

Background and rationale {6a}

Globally, depression represents one of the leading causes of years lived with disability [1, 2]. Depression is associated with a marked reduction in quality of life and life expectancy as well as a substantially increased risk of suicide [3, 4].

Current treatment options include (a) pharmacological therapy using anti-depressants, which is recommended for moderate-to-severe depression in Danish and international guidelines and (b) psychotherapy for mild to severe depression. The current state-of-the-art within pharmacological therapy of moderate-to-severe depression is the use of anti-depressants, primarily of the selective serotonin reuptake inhibitor (SSRI) class or the selective noradrenaline reuptake inhibitor (SNRI) class. A recent, large meta-analysis demonstrated small-to-moderate effect sizes of current anti-depressant compounds in treating depression. Of all anti-depressant agents, tricyclic anti-depressant agents (TCAs) yielded the largest effect sizes, with a maximum standardized mean difference (SMD) of 0.48 compared to placebo [5]. However, clinical effects are often delayed until 3 to 6 weeks after treatment initiation, meanwhile leaving the patients at increased risk of, e.g., suicide [6]. In addition, reports have suggested that one-third of patients do not achieve remission after treatment with at least two of the currently used anti-depressant drugs [7, 8]. Furthermore, antidepressants have non-neglectable side-effects, including weight gain, sexual dysfunction, and sleep disturbances [9]. On average, patients who achieve remission upon treatment with anti-depressants still face a substantially lower quality of life compared to the general population [10]. Non-pharmacological treatment strategies, such as psychological interventions, show some effect; however, meta-analyses estimate that only a third of patients undergoing psychotherapy achieve remission and more than half do not respond [11]. Electroconvulsive treatment (ECT), an alternative non-pharmacological treatment for severe depression, show better remission rates of 50 to 60%, but is considered an invasive procedure with limited accessibility [12]. Despite these unsatisfactory clinical outcomes, there has been a shortage of new treatment options for people affected by depression, with the recent approval of esketamine being the only introduction of a purposedly anti-depressive drug with a new mode of action for several decades [13]. Safe, effective, and fast-acting treatment options are needed and should be a focus of clinical research.

Glucocorticoids are steroid hormones that are naturally produced by the zona fasiculata of the adrenal gland and are regulated in a circadian and stress-associated manner. Glucocorticoid signaling is an integral part of the hypothalamic–pituitary–adrenal (HPA) axis and disturbances of the HPA-axis have been detected in depression [14]. Glucocorticoids assert their pleiotropic effects primarily through the glucocorticoid receptor, of which there are several isoforms with both genomic and non-genomic downstream effects. Synthetic glucocorticoids are drugs that resemble natural glucocorticoids, of which different types have been used clinically for over seven decades [15]. Dexamethasone is a widely used synthetic glucocorticoid and an off-patent and easily accessible drug with well-known dosing regiments and side-effects. Dexamethasone and other glucocorticoids are used in the treatment of a range of disorders, including rheumatological diseases, where their anti-inflammatory properties are harnessed [16]. In addition, glucocorticoids are occasionally used in the palliative care setting, specifically for the treatment of “low mood” [17], and can be used to treat fatigue among oncological patients [18]. Furthermore, dexamethasone has recently been successfully used in the treatment of COVID-19 and thereby shown its potential for repurposing in a clinical setting [19].

Both epidemiological, clinical, and experimental studies have linked immunological mechanisms to psychiatric disorders in general and depression specifically [20]. Epidemiological research has shown that infections [21] as well as auto-immune disorders [22] increase the risk of depression and that inflammatory markers such as interleukin-6 are elevated in the cerebrospinal fluid (CSF) of patients with depression [23]. A recent meta-analysis on the effect of anti-inflammatory agents in the treatment of depression [24] suggested that anti-inflammatory agents have larger effect sizes (SMD = 0.64) than anti-depressants (SMD = 0.48), while also improving response (rate ratio (RR) = 1.76) and remission rates (RR = 2.14) compared to placebo. Of all anti-inflammatory agents investigated, glucocorticoids displayed the largest effect sizes, exceeding the effect sizes in reduction of depressive symptoms of the currently most effective anti-depressives by more than twofold (SMD = 0.90; 95% CI 0.36 to 1.44). The effect on depressive symptoms was rapid and occurred in as little as 1 to 14 days [25, 26]. However, the two studies on the effect of glucocorticoids included in the meta-analysis had notable shortcomings. First, they only included a limited number of patients (n_Total = 59) of which 25 received glucocorticoid treatment. Secondly, patients were only followed for up to 14 days. Thirdly, no studies investigated if subgroups of patients with increased inflammatory markers showed improved response to glucocorticoid therapy. Furthermore, they investigated two different glucocorticoids: hydrocortisone administered intravenously and dexamethasone administered orally. Finally, reporting of adverse reactions and events in the previous studies was inadequate, detailing only that no participants were eliminated from the studies due to side effects or toxicity. Further evidence is therefore needed before glucocorticoids can be considered as a viable, evidence-based treatment option in moderate-to-severe depression.

Objectives {7}

The objective of the DEXA-PSYCH trial is to investigate the acute effect and safety of oral dexamethasone compared to placebo as augmentation in treatment of moderate-to-severe depression. The trial is based upon the hypothesis that dexamethasone as add-on to treatment as usual (TAU) is superior to placebo as add-on to TAU in reducing depression symptoms among patients with moderate-to-severe depression.

Trial design {8}

The trial is an investigator-initiated, double-blind, parallel-group, superiority, randomized, placebo-controlled clinical trial. The allocation ratio is 1:1 between intervention and placebo. For overall trial design, please refer to Fig. 1.

Fig. 1.

Trial design. All participants will undergo treatment as usual (TAU) throughout the entire study. Dexamethasone dose in the intervention group will be reduced from 4 to 2 mg on day 4. Physical visits will occur on days 0 and 7. Telephonic visits will occur on days 4, 14, and 28 and at 6 months. Primary endpoint is MADRS₁₀score assessed at a physical visit on day 7. Patients will rate their depressive symptoms on the self-reported MADRS₁₀scale daily from days 1 to 28

Methods: participants, interventions and outcomes

Study setting {9}

All trial-related physical meetings, participant interviews, and treatment visits will be conducted at the MHSC-affiliated research unit: Copenhagen Research Center for Biological and Precision Psychiatry, Mental Health Center Copenhagen (MHCC), Gentofte Hospitalsvej 19, 2900 Hellerup.

For in-patients at MHSC, for whom it is not feasible to leave their in-patient facility, trial-related physical meetings, participant interviews, and treatment visits can also be conducted at the psychiatric department to which they are admitted.

Eligibility criteria {10}

Participants are eligible for the trial if they:

1. Are diagnosed with non-psychotic, moderate-to-severe depressive disorder (single episode or recurrent) by a medical doctor according to ICD-10 criteria (ICD-10 codes: F32.1, F32.2, F33.1, F33.2) as operationalized in the Schedule for Clinical Assessment in Neuropsychiatry (SCAN), Sect. 6–8 AND

2. Score 22 or above on the 10-item Montgomery–Asberg Depression Rating Scale (MADRS₁₀) scale at day 0 AND

3. Are currently receiving pharmacological treatment for depression AND

4. Are between 18 and 64 years of age (both included) at the date of enrollment AND

5. Are habile (i.e., able to give informed consent) AND

6. Speak Danish fluently

Participants are not eligible for the trial if they:

1. Have a known hypersensitivity to glucocorticoid treatment (including any drug in the glucocorticoid class) either explicitly stated in the patient journal or known to the patient from prior glucocorticoid treatment

2. Are undergoing or have undergone systemic (oral or intravenous) treatment with any drug in the glucocorticoid class within the last 14 days

3. Have previously been diagnosed with a psychotic disorder (including depression with psychotic symptoms), personality disorder, eating disorder, or bipolar disorder

4. Are currently using psychoactive substances and fulfill ICD-10 criteria for harmful use (F1X.1) or dependence syndrome (F1X.2.)

5. Have suicidal plans

6. Have undergone electroconvulsive treatment (ECT) or transcranial magnetic stimulation (TMS) within the last 2 weeks

7. Have experienced or are experiencing manic and/or hypomanic episodes as uncovered according to Sect. 10 of the SCAN assessment

8. Have a known 1^st degree family history of bipolar disorder (i.e., among parents, siblings, and children)

9. Are diagnosed with disorders that are listed as contra-indications for glucocorticoid treatment in Danish guidelines including immunodeficiencies, systemic fungal infections, active tuberculosis, hematological malignancies, epilepsy, myasthenia gravis, ocular herpes simplex, pheochromocytoma, systemic sclerosis, or acute coronary syndrome (within the last 6 months)

10. Have prolonged QTc-interval (> 480 ms)

11. Have clinically significant reduction in liver function (ALT > 2.5 × upper limit of normal range, ULN: men > 70 U/l, women > 45 U/l)

12. Have diagnosed diabetes mellitus or suspected diabetes mellitus (as measured by HbA1c of > 45 mmol/mol)

13. Have been vaccinated within 14 days before intervention initiation or is planning on being vaccinated during the intervention or within 14 days after the vaccination

14. Are currently undergoing treatment with potassium-depleting diuretics.

15. Are currently undergoing immunosuppressive treatments or treatments affecting the CYP3A4 system (i.e., erythromycin, itraconazole, ritonavir, lopinavir, phenobarbital, phenytoin, rifampicin)

16. Have undergone treatment with monoamine oxidase (MAO) inhibitors in the last 14 days

17. Are pregnant (i.e., fertile woman below 60 with a positive urine or plasma human gonadotropin test), currently breast-feeding or not adherent to a sufficient anticontraceptive plan

We will not exclude participants enrolled in other interventional trials, but co-enrollment will be registered in the participant electronic Care Record Form (eCRF).

Assessment of eligibility will be done by a sub-investigator (medical doctor). This will be done using the SCAN interview and a structured questionnaire corresponding to the in- and exclusion criteria programmed in the eCRF.

Who will take informed consent? {26a}

Potential participants who give consent to their clinician will receive information about the study from a medical doctor (sub-investigator). They will be invited to an information meeting where detailed oral information about all relevant aspects of the study will be given by the sub-investigator. This will be done in a confidential and calm setting. The potential participant will be given ample time to ask questions. Written information will also be provided in advance of the information meeting or at the information meeting.

The potential participant will be offered 24 h reflection time from the information meeting to written consent will be obtained, but more if the patient wishes so. If the patient decides to participate, they will be invited for a screening, enrollment, and randomization consultation (day 0) conducted by the sub-investigator. Here, the patient will sign The National Committee on Health Research Ethics’ statement of consent (“Den Videnskabsetiske Komités Samtykkeerklæring”).

Additional consent provisions for collection and use of participant data and biological specimens {26b}

In addition to accessing the stored data collected during the trial (through physical meetings, phone calls, electronic health records and app-based monitoring), the consent allows the research team to follow the patients in the Danish registers. The registers will be used to follow participants (both before and after the last visit at 6 months) for outcomes coded in the registers, e.g., admissions, mortality, suicide attempts, and labor-market affiliation. The research group already holds a broad approval for register-based studies related to psychiatric illness.

Upon enrollment, the participants will furthermore be asked if they wish to contribute biological material to an already established biobank at the Copenhagen Research Center for Biological and Precision Psychiatry. The biological material will be defined as “extra” material in the DEXA-PSYCH project, in accordance with the definitions stipulated by the National Center for Ethics (https://nationaltcenterforetik.dk/anmeld-forsoeg/vejledninger/biobanker#5).

The biobank is established under the PSYCH-FLAME project and covered by a separate protocol under which the research group holds approval for collection, storage, and future analysis on immune-related biomarkers in patients with depression, psychotic disorders, and healthy controls [27]. The prospective participants will be presented with a separate subject information letter and consent form detailing the conditions under which contribute to the PSYCH-FLAME project. If the participants do not consent to contribution of extra biological material, they can still participate in the DEXA-PSYCH study.

Interventions

Explanation for the choice of comparators {6b}

As there is currently no standard, add-on treatment recommended in Danish guidelines for initial treatment of moderate-to-severe depression, we consider placebo the most relevant comparator.

Intervention description {11a}

The intervention group will receive encapsulated, orally administered dexamethasone at 4 mg/day for 4 days and 2 mg/day for 3 days before discontinuation as add-on treatment to treatment as usual (TAU). The total length of the intervention is thus 1 week. The intervention will not be extended past 1 week. Participants will be instructed to administer trial medication at 9 AM every morning, as circadian rhythms influence endogenous glucocorticoid production.

Dexamethasone is approved by the Danish Medicines Agency for clinical use in humans for anti-inflammatory purposes. The gradual dose decrease is consistent with Danish guidelines, which recommend that dexamethasone administration should be tapered by 1–2 mg/day over the course of 3 days before discontinuation.

Criteria for discontinuing or modifying allocated interventions {11b}

The sponsor/principal investigator, sub-investigator, or clinical staff caring for the patient outside the clinical trial setting may at any time violate the protocol if they find it to be in the best interest of the participant.

A trial hotline will enable discussion between clinicians caring for trial participants and the DEXA-PSYCH sub-investigator regarding protocol-related issues. Contact information for the trial hotline will be registered in the electronic health record of the participant. Protocol violations will be registered in the eCRF for the individual patient and reported by the sub-investigator to the sponsor/PI without unnecessary delay. Repeated and/or serious protocol violations will be reported to the Danish Medicines Agency and Ethics Committee no later than 7 days after protocol violation. Violations will furthermore be documented in the final reporting of the trial.

Strategies to improve adherence to interventions {11c}

Adherence will be encouraged during the first trial visit (day 0) and telephonic contact on day 2 and 4. Adherence will be monitored through daily app-based reporting using the Monsenso app on days 1–7. This enables the sub-investigator to contact the participant by phone if non-adherence should be reported on the Monsenso app and encourage adherence. Adherence will furthermore be monitored through tablet return on day 7.

Relevant concomitant care permitted or prohibited during the trial {11d}

Participants are required to receive pharmacological treatment for depression at the onset of the intervention. This could include anti-depressive medication (e.g., SSRIs, SNRIs, and TCAs) as well as treatment with antipsychotics (e.g., quetiapine and aripiprazole) and lithium for anti-depressive purposes. However, patients who have received ECT or TMS therapy or have been treated with MAO-inhibitors within the last 2 weeks are not eligible for participation. Other interventions administered in accordance with Danish guidelines will be allowed, including psychotherapy.

Any current or previous anti-depressive treatment will be registered in the eCRF of the individual patient.

We will recommend against the use of additional glucocorticoids and other anti-inflammatory agents in all trial participants during the study intervention (days 1–7) and wash-out period (day 8). This will be stated explicitly to the patient upon enrollment and be noted in the electronic health record of the participants.

Provisions for post-trial care {30}

All participants will be receiving TAU alongside the intervention and will thus be followed for post-trial care independent of the intervention. Anti-depressant treatment (including non-pharmacological interventions) before, during, and after the trial will be administered by the treating physician of the participants (general practitioner or physician at MHSC) independent of the trial personnel.

Outcomes {12}

The primary outcome of the trial will be change from baseline (day 0) on the 10-item Montgomery-Asberg Depression Rating Scale (MADRS₁₀) at day 7 as measured on a continuous scale. The primary outcome, key secondary outcomes, and safety outcomes will be reported in the primary study publication. For a complete list of primary, key secondary, secondary, and safety outcomes, please refer to Table 1.

Table 1.

Outcomes

Objective	Endpoint/outcome
Primary efficacy outcome
• To assess the efficacy of dexamethasone as add-on therapy to TAU compared to placebo in improving depressive symptoms	1. Change from baseline (day 0) on the Montgomery-Asberg Depression Rating Scale (MADRS10) at day 7. Assessment will be done in accordance with the Structured Interview Guide for MADRS (SIGMA).43
Key secondary efficacy outcomes
To assess the efficacy of dexamethasone as add-on therapy to TAU compared to placebo on:
• Depressive symptoms before day 28	1. Change from baseline (day 0) on the MADRS10 at days 4, 14, and 28
• Remission rates	2. Number of participants with remission (MADRS10 score less than or equal to 11) on day 7
• Response rates	3. Number of participants with response (MADRS10 score < 50% of the score at day 0) on day 7
• Quality of life	4. Change in quality of life as measured by change from baseline (day 0) on the EQ-5D-5L on day 7
Safety outcomes
• To assess the safety and tolerability of dexamethasone as add-on therapy to TAU compared to placebo	1. ARs (including SARs) occurring on or before day 10 2. All-cause discontinuation of the intervention 3. Vital signs 4. Suicidal ideation (C-SSRS) on day 7 5. Laboratory tests and electrocardiograms (ECG) 6. Score on the Glucocorticoid Toxicity Index (GTI) on day 7 7. Score on UKU-SSRI on day 7 8. Change in positive psychotic symptoms as measured by change from baseline (day 0) the Scale for Assessment of Positive Symptoms (SAPS) on day 7 9. Change in manic symptoms as measured by change from baseline (day 0) on the Young Mania Rating Scale (YMRS) on day 7 10. Admissions due to somatic or psychiatric illness before day 28 11. Suicide attempts and completed suicides before day 28 12. All-cause mortality before day 28
Secondary outcomes
To assess the efficacy of dexamethasone as add-on therapy to TAU compared to placebo on:
• Suicidal ideation (long-term)	1. Change in suicidal ideation as measured by change from baseline (day 0) on the Columbia-Suicide Severity Rating Scale (C-SSRS) on day 28 and at 6 months follow-up
• Anxiety	2. Change in anxiety symptoms as measured by change from baseline (day 0) on the Hamilton Anxiety Rating Scale (HAM-A) on days 7 and 28 and at 6 months follow-up
• Functioning	3. Change in functioning as measured by change from baseline (day 0) on the Global Assessment of Functioning (GAF) scale on days 7 and 28 and at 6 months follow-up
• Fatigue	4. Change in fatigue as measured by change from baseline (day 0) on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale on days 7 and 28 and at 6 months follow up
• Psychiatric hospitalization (long-term)	5. Relative risk of admissions due to psychiatric illness before 6 months follow-up (as assessed through patient interview and electronic health records) as well as beyond (as assessed through national Danish registers)
• Suicide attempts (long-term)	6. Relative risk of suicide attempts before 6-months follow-up (as assessed through patient interview and electronic health records) as well as beyond (as assessed through national Danish registers)
• Depressive symptoms (long-term)	7. Change from baseline (day 0) on the MADRS10 at 6 months follow up
• Depressive symptoms on the MADRS6 subscale	8. Change from baseline (day 0) on the MADRS6 at days 4, 7, 14, and 28 and at 6-months follow up
• Depressive symptoms measured on the HAM-D scale	9. Change from baseline (day 0) on the Hamilton Depression Rating Scale (HAM-D6 and HAM-D17) on days 7 and 28 and at 6 months follow-up
• Depressive symptoms measured on the MDI scale	10. Change from baseline (day 0) on MDI on days 7 and 28 and at 6 months follow-up
• Quality of life (long-term)	11. Change in quality of life as measured by change from baseline (day 0) on the EQ-5D-5L on day 28 and at 6 months follow-up
• Physical and social activity	12. General level of physical and social activity as measured in the Monsenso app day 1–28
• Self-rated depressive symptoms	13. Self-rated MADRS scores on days 1–28 based on data collection in the Monsenso app
• Remission rates (long-term)	14. Number of participants with remission (MADRS10 score less than or equal to 11) at 6 months follow-up
• Labor market affiliation	15. Relative risk of being unemployed or on sick leave at day 7, day 28, and at 6 months follow-up (as assessed through patient interviews) as well as beyond (as assessed through national Danish registers)
• Mortality (long-term)	16. All-cause mortality at 6 months follow-up (as assessed through electronic health records) as well as beyond (as assessed through national Danish registers)
Additional secondary outcomes
• To assess longitudinal changes in inflammatory biomarkers and to examine if baseline levels of inflammatory biomarkers predicts or moderate changes in depressive symptoms following dexamethasone treatment	17. Baseline levels of CRP and leucocytes in responders and non-responders as well as other biochemical markers assayed in biological samples

Participant timeline {13}

Upon provision of informed consent, the patient will be screened to ensure that the patient meets all inclusion criteria and does not meet one or more exclusion criteria. If the patient is found eligible for the trial, the patient will be enrolled, baseline variables will be recorded (including blood tests and ECG), and randomization will occur during an in-person meeting (day 0). The intervention will be administered on days 1–7. An in-person meeting on day 7 will be used to access outcome measures. During the intervention phase, the participants will receive phone calls on day 2 (to access adverse events) and day 4 (MADRS-rating and adverse events). After the termination of the intervention, the patients will receive phone calls on day 14, day 28, and after 6 months to access secondary outcomes. For more information and full list of tests and psychometric ratings, please refer to Schedule of Activities (SoA) (Table 2).

Table 2.

SPIRIT figure/Schedule of Activities (SoA)

Phase	Pre-screening	Information meeting	Informed consent, screening, enrolment and randomization	Intervention							Wash-out	Follow-up
Study day			0	1	2	3	4	5	6	7	10	14	28
Study month			1	1	1	1	1	1	1	1	1	1	1	6
Visit (bold = physical)		1	2		3		4			5		6	7	8
Visit window1					+/− 2		+/− 2			+/− 2		+/− 2	+/− 4	+/− 28
Trial procedures
Randomization			X
Study drug hand-out			X
Intervention				X	X	X	X	X	X	X
Pill return										X
Adherence				Xa	Xa	Xa	Xa	Xa	Xa	X
Assessment of blinding										X
Screening/administrative data
Demographic data			X
In- and exclusion criteria			X
Medical history			X
Psychiatric history			X
Family medical and psychiatric history			X
Current- and pre-study therapy			X
Employment status			X							X			X		X
Educational qualifications			X
Smoking status			X
Monsenso2				X	X	X	X	X	X	X	X	X	X
Psychopathological assessment, psychometric testing, and social activity
SCAN			X
MADRS (ex. Monsenso)			X				X			X		X	X		X
MDI			X							X			X		X
HAM-D			X							X			X		X
HAM-A			X							X			X		X
C-SSRS			X							X			X		X
EQ-5D-5L			X							X			X		X
FACIT			X							X			X		X
GAF			X							X			X		X
YMRS			X							X
SAPS			X							X
BACS			X
UKU-SSRI										X
GTI										X
Social activitya				X	X	X	X	X	X	X	X	X	X
Physiological measurements
Physical examination			X							X
ECG			X							X
Blood tests3			X							X
Vital signs			X							X
Height			X							X
Weight			X							X
Physical activitya				X	X	X	X	X	X	X	X	X	X
Safety measures
SAR and AR				X	X	X	X	X	X	X	Xb
SAE and AE				X	X	X	X	X	X	X	Xb
SUSAR				X	X	X	X	X	X	X	Xb
Admissions to somatic care										X			X
Admissions to psychiatric care										X		X	X		X
Suicide-attempts										X		X	X		X

¹Visit window allowed as measured in days

²Data will be registered continuously in the Monsenso app from days 1 to 28 (both days included). Through the app, data will be registered on adherence (days 1–7), MADRS (days 1–28) as well as physical and social activity (days 1–28). The self-rated MADRS score is modified, such that participants are asked to evaluate symptoms within the last 24 h as opposed to 3 days in order to facilitate day-to-day scoring

³For details on biochemical parameters analyzed in the blood samples, please refer to Sect. 5.9.1. and 11 of the trial protocol

Sample size {14}

Two studies have previously compared glucocorticoids to placebo for treatment of depression. DeBattista et al. compared 6 subjects treated with glucocorticoids to 10 subjects treated with placebo observing a mean difference of 7.8 favoring glucocorticoids on the Hamilton Depression Rating Scale (HAM-D₂₁) after 1 day of treatment with a pooled standard deviation of 4.8. Arana et al. compared 19 subjects treated with glucocorticoids for 4 days to 18 subjects treated with placebo for 4 days observing a mean difference of 6.2 favoring glucocorticoids on the HAM-D₂₁ scale 14 days after treatment initiation with a pooled standard deviation of 6.3. Based on these results, the required sample sizes to detect the observed differences are 10 and 23 subjects in each treatment arm with a power of 90% and 5% significance level.

However, the previous studies were rather limited in sample size and have not been replicated. We therefore assume that the effect in this larger and much more thorough trial will be substantially smaller. Our meta-analysis based on the previous studies yielded an SMD of 0.93 for dexamethasone [24]. If the DEXA-PSYCH study finds an effect size approximately half or that (SMD = 0.42), this would make dexamethasone comparable to the effect sizes of the most effective current antidepressants, the TCAs (SMD = 0.48). We find this assumption reasonable, as it both takes the larger effect sizes of the previous studies into account, while considering that more thoroughly tested anti-depressants have not been shown to yield greater effects than approximately 0.4.

Our ongoing PSYCH-FLAME study includes subjects with new-onset depression from the same geographical area in a case–control study. Here the mean (standard deviation) HAM-D₁₇ score among 106 of the first subjects was 20.6(6.3). Conservatively assuming 20% drop-out of patients the following table illustrates the relation between power and the mean difference (“delta”) that a trial with 150 subjects randomized to each treatment arm can detect. The standardized mean difference (SMD) is the detectable difference (delta) divided by the standard deviation:

Power	delta	SMD
80%	2.29	0.36
85%	2.45	0.39
90%	2.65	0.42
95%	2.94	0.47
99%	3.50	0.56

Assuming an effect size for dexamethasone of 0.42, this would yield a power of 90% for a study with a total of 300 participants assuming 20% drop-out for the primary endpoint. For this reason, we are aiming to include 300 participants in the trial, with 150 in the intervention arm and 150 in the control arm.

Recruitment {15}

Participants will primarily be recruited through in- and out-patient services at the sponsor institution, the Mental Health Services in the Capital Region of Denmark (MHSC). The MHSC is a public, free-of-charge academic hospital and outpatient service, covering secondary-level psychiatric care in The Capital Region of Denmark. In addition, we will allow recruitment from the Mental Health Services in Region Zealand and private practitioners.

Treating clinicians will be informed of the trial through presentations at clinical conferences, by posters describing the trial and recruitment procedures, and trough the trial as well as hospital website. Treating physicians will be informed of the trial and will not be involved in trial-related procedures.

Assignment of interventions: allocation

Sequence generation {16a}

The randomization will be based on a computer-generated random-number allocation sequence generated at The Hospital Pharmacy of The Capital Region of Denmark (Marielundvej 25, 2730 Herlev). The randomization will be an individual level randomization with an allocation ratio of 1:1 to dexamethasone or placebo. Randomization will occur in blocks of randomly selected sizes of 6, 8, 10, or 12 participants to reduce the risk of unblinding. The randomization process will not be stratified.

Concealment mechanism {16b}

Trial medication or placebo will be prepared in sealed pill containers and further packaged in envelopes with tamper-proof seals, numbered with a randomization number linking the containers to the allocation sequence.

Implementation {16c}

The Hospital Pharmacy of The Capital Region of Denmark will coordinate the randomization process and allocation concealment. The allocation sequence will be stored at the pharmacy. The participants will be randomly assigned to the intervention or control group through the hand-out of sealed pill containers by the sub-investigator/medical doctor upon trial enrollment. Their individual randomization number (linking participant to allocation status) will be recorded in their respective eCRF.

Assignment of interventions: blinding

Who will be blinded {17a}

Trial participants, investigators, outcome assessors, trial staff, and data analysts are all blinded to the allocation. The quality of the blinding will be tested by having the sub-investigators and the participant independently reporting which allocation group they think the individual patient belong to on day 7 (date of assessment of primary outcome).

Procedure for unblinding if needed {17b}

For a specific individual, the intervention may be unblinded if deemed necessary by the sub-investigator or the sponsor/PI for safety reasons. The sponsor/PI or the sub-investigator will break the blind for a participant if there is clinical suspicion of an unexpected serious adverse reaction (SUSAR).

It will be noted in the participant’s electronic health record (accessible to all hospital staff) that the patient participates in the trial and therefore might have been allocated to glucocorticoid treatment and that telephonic contact can be made to the trial hotline if treating clinicians consider unblinding needed.

Codes for unblinding of individual participants are stored at the trial site. The sponsor/PI or sub-investigator will be able to access the unblinding code for the individual participant by opening the code envelopes. The integrity of the unblinding envelopes will be monitored by the independent trial monitors (The Good Clinical Practice Unit at Copenhagen University Hospital) during and after the trial. Unblinding will be recorded in the eCRF and reported in the final trial report.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Baseline (day 0) assessment and assessment at primary endpoint (day 7) of MADRS, HAM-D, Major Depression Inventory (MDI), Hamilton Anxiety Rating Scale (HAM-A), Youngs Mania Rating Scale (YMRS), Scale for the Assessment of Positive Symptoms (SAPS), Columbia Suicide Severity Rating Scale (C-SSRS), and Global Assessment of Functioning (GAF) as well as SCAN-interview and Brief Assessment of Cognition in Schizophrenia (BACS) test at baseline, Glucocorticoid Toxicity Index (GTI) scoring at day 7 and additional MADRS assessment at day 4 will be carried out by a medical doctor (sub-investigator) adequately trained and under the supervision of the principal investigator (chief physician and consultant psychiatrist). Assessment of outcomes at day 14, 28, and at 6 months follow-up will be carried out by a trained research nurse, a sub-investigator/medical doctor or a medical student under the supervision of the principal investigator. All trial personnel will be trained in uniform data entry into the eCRF.

If the participants sign the informed consent form pertaining to the PSYCH-FLAME study, video recording of the interviews at day 0 and 7 will be carried out and ratings will be validated by the principal investigator on an ad hoc basis.

Data on social and physical activity, adherence, adverse events, and self-rated MADRS scores will be collected on day 1–28 through app-based monitoring (Monsenso). The Monsenso product is a CE marked, Class I, Medical Device, and is thus approved for use in the treatment of patients and ISO 13485 certified according to the requirements of medical devices. Patients will be instructed in the installation and use of the app at baseline. If the patient (a) does not have a smartphone compatible with the app and/or (b) do not wish to use the app, the patient will still be eligible for the study.

Plans to promote participant retention and complete follow-up {18b}

Participants will be encouraged to adhere to the protocol during phone calls on days 2 and 4 of the intervention and additionally if participants report non-adherence through the app-based monitoring.

If a participant no longer wishes to participate in the trial, he/she can withdraw consent at any time without need of further explanation, and without consequences for further treatment.

To ensure maximum data collection, the participant will be asked if they—despite discontinuation—will allow continued data registration through electronic health records and national registers as well as physical follow-up at day 7 and close-out follow-up at days 14, 28, and 6 months.

Data management {19}

The eCRF will be programmed in REDCap, a secure survey database approved by The Capital Region of Denmark. The REDCap project database will contain all trial related data (except national register data and app-collected data) and any changes in the database will be logged automatically. The database will be regularly managed, including routine range checks, data validation, and data extraction. The database will set up with pre-programmed range limits to maximize data accuracy. The data will be saved until 25 years after the end of the trials.

A detailed list of variables and source documents can be found in the extended protocol uploaded to the EU Clinical Trials Information System (CTIS) for authority approval.

Confidentiality {27}

All participant data will be handled according to the General Data Protection Regulation (GDPR), the Danish Data Protection Act (Databeskyttelsesloven) and the Danish Health Act (Sundhedsloven). Data will be pseudonymized, such that patient names and CPR numbers are not included in the database. Instead, the patient randomization ID/trial-ID will be used to identify the patient. This ID will also be used to mark blood samples and relevant source document pertaining to the participant. A participant identity log containing the trial ID, inclusion and randomization date, participant name, and CPR-number will be store in the Trial Master File as well as in a password-protected folder on The Capital Region of Denmark network, which is protected in accordance with GDPR regulations. Only trial personnel will have access to the identity log.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Blood samples will be drawn at day 0 (prior to treatment initiation) and at day 7 (last day of treatment). Blood samples (5–10 mL) will be drawn according to standard procedures and analyzed immediately at the Copenhagen University Hospital, by technicians blinded to the randomization status of the participants. The samples will be analyzed for hemoglobin, erythrocytes, leukocytes, lymphocytes, thrombocytes, blood glucose, HbA1c, sodium, potassium, creatinine, cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), ALT, phosphatase, thyroid-stimulating hormone (TSH), human chorionic gonadotropin (HCG), and C-reactive protein (CRP). If participants consent, additional blood (6 × 6 mL) will be drawn and stored in the biobank pertaining to the PSYCH-FLAME project for later genetic and molecular analyses.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

The primary estimand is an efficacy estimand aiming to quantify the average treatment effect of dexamethasone as compared to placebo if taken according to the schedule described in the protocol. Effect endpoints will be reported with an effect estimate, a 95% two-sided confidence interval (CI) and two-sided p-values. Superiority of the primary endpoint can be claimed if the effect favors dexamethasone and the p-value is less than 0.05.

The primary statistical analysis of the primary outcome will address the primary estimand. The intermediate assessments used in the primary analysis are the assessments of the primary outcome at the day 4 visit. The primary analysis model is a Mixed Model for Repeated Measurements (MMRM) for the post-baseline assessments of the primary outcome variable. The model includes the covariates treatment arm and baseline assessment of the outcome variable all nested in visit. Other covariates may be included as appropriate. An unstructured variance–covariance for measurements within the same subject will be used.

The MMRM will all use on-treatment assessments; assessments from subjects who are not on-treatment will not contribute to the model. Subjects who have no on-treatment post-baseline assessments will not contribute to the model. If the measurements of all subjects who contribute to the MMRM are all on-treatment and non-missing, the MMRM mathematically reduce to an analysis of covariance (ANCOVA) for the primary outcome with treatment arm and baseline assessment of the outcome variable as a covariate.

The primary outcome, key secondary outcomes, and safety outcomes will be reported in the primary study publication. Secondary outcomes will be reported in subsequent publications. Pre-specified analyses pertaining to the secondary outcomes will be described prior to unblinding of the study.

For secondary outcomes, all continuous outcomes measured as concentrations or ratios will be log-transformed prior to analysis and estimated effects, means, and confidence intervals will be back-transformed and presented on the original scale. Binary outcomes will be analyzed using logistic regression models. Time-to-event outcomes will be analyzed using Cox proportional hazard models. For secondary outcomes, p-values will be reported both crude and after adjustment for multiple testing.

Pre-specified analyses, tables, and figures will be programmed with a fake group-ID before unblinding to ensure blinding in the analyses. Primary analyses will furthermore be conducted using independent parallel programming by at least two separate statisticians/analysts. Prior to initiation of any data analysis on actual trial data, we will conduct a database lock ensuring that data cannot be changed.

If necessary, a statistical analysis plan (SAP) will be written and finalized before unblinding of the trial. The SAP may contain further details on the statistical analyses, models, and methods as well as pre-specified, secondary analyses. Any deviations from the protocol or the published SAP will be documented in the final trial report.

Interim analyses {21b}

No interim analysis will be conducted.

Methods for additional analyses (e.g., subgroup analyses) {20b}

Pre-specified subgroup variables:

• Severity of depression: moderate (MADRS10 score 22–29) vs. severe depression (MADRS10 score 30 or above)

• Treatment-resistance: Treatment-resistant depression defined as patient treated with ≥ 2 different anti-depressants in the current depressive episode with no remission prior to enrollment vs. non-treatment-resistant depression.

• BMI: Body Mass Index (BMI) of ≥ 30 vs. < 30 at baseline (might be changed within a span of +/− 5 BMI points, depending on BMI distribution in the participants).

• Age: < 40 year vs. ≥ 40 years of age (might be changed within a span of +/− 10 years, depending on age distribution in the participant groups)

• Sex: male vs. female

Subgroup analyses are performed using primary analysis model but also includes the subgroup variables as covariates and the interaction between the subgroup variable both nested within visit (if present). The p-value for the interaction at the primary endpoint quantifies the evidence of effect modification by the subgroup variable.

In addition, a sensitivity analysis excluding patients receiving diagnoses of psychiatric disorders listed as exclusion criteria (including personality disorders) within a year after randomization will be reported in a secondary, pre-specified analysis based on patient records in the Danish registers and/or electronic health records.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Two analysis sets will be used for analyses of trial data:

• The full analysis set (FAS) includes all randomized subjects with at least one post-baseline measurement of the outcome. Subjects contribute to the analyses “as randomized” following the intention-to-treat (ITT) principle.

• The safety analysis set (SAS) includes all randomized subjects who took at least one dose of randomized treatment. Subjects contribute to evaluation “as treated.”

Observe that the number of subjects in the FAS may differ across outcomes.

Outcomes pertaining to the effect of dexamethasone will be analyzed using the FAS. Outcomes pertaining to the safety of dexamethasone will be analyzed using the SAS. Assessments are considered on-treatment if randomized treatment was taken on the day, or the day before, the assessment is made.

Baseline values are obtained at the baseline visit. If baseline values are missing the last available measurement before randomization is used. If no such measurements exist, missing baseline values are imputed (single imputation) with the mean baseline value of all subjects with non-missing baseline values. The MMRM handles missing values of the primary outcome variable under missing at random (MAR) assumptions.

Plans to give access to the full protocol, participant-leveldata, and statistical code {31c}

The full trial protocol was made publicly available prior to trial initiation through the EU Clinical Trials Information System (CTIS). Participant level, anonymized datasets will be accessible through the Zenodo repository (CERN) after the termination of the trial, as requested by the Novo Nordisk Foundation. Statistical code will be available through GitHub.

Oversight and monitoring

Composition of the coordinating center and trial steering committee {5d}

The day-to-day organization of the trial will be the responsibility the sub-investigators (TBR, CGF and PBH) under the supervision of the principal investigator (MEB) and will be carried out by a research group consisting of the sponsor/PI, sub-investigators, one senior statistician/data analysts (RHBC), one research nurse and a project secretary.

The sponsor/PI will oversee the conduct of the trial and be responsible for the adherence to the protocol, Danish law and Good Clinical Practice (GCP) of the trial. The sponsor/PI will be responsible for reporting SARs and SUSARs to the authorities. The sponsor/PI will be responsible for the education and supervision of the trial personnel in all trial-related procedures.

The sub-investigators will be responsible for pre-screening, screening, inclusion and enrollment of participants, database management, and outcome assessment up until day 10 and reporting of SARs and SUSARs to the sponsor/PI. The sub-investigators will be supervised by the PI and any day-to-day trial and/or treatment-related questions will be discussed between the sub-investigators and the PI on a daily, ad hoc basis and through regular supervisor-meetings.

Research nurses, sub-investigators, and/or medical students will conduct follow-up outcome assessments after completed wash-out (day 14, 28, and at 6 months follow-up) including extraction of data from electronic health records.

The statistician will be responsible for analyzing the trial data.

Composition of the data monitoring committee, its role and reporting structure {21a}

No data monitoring committee (DMC) will be created to oversee the trial. According to Danish law, the existence of a DMC is not required in an academic/investigator-initiated trial. The research group will monitor adverse events as stated in the protocol.

Adverse event reporting and harms {22}

Adverse events (AEs), adverse reactions (ARs), serious adverse reactions (SARs), serious adverse reactions (SARs), and SUSARs are defined according to GCP principles as stipulated in the full protocol.

AEs and ARs will be registered from day 1 to day 10, i.e., during the intervention itself (days 1–7), in the wash-out phase (day 8) and in the days following withdrawal (days 9–10), where there is a risk of developing adrenal gland insufficiency due to the reduction in exogenous glucocorticoid stimulation. For all participants, the presence or absence of AEs and ARs will be registered through physical contact on day 7 and telephonic contact on days 2 and 4. In addition, participants will be able and encouraged to report AEs and ARs through the trial hotline and app. For in-patients participating in the trial, we will additionally record AEs and ARs from electronic health records.

Furthermore, structured assessment of glucocorticoid toxicity, psychotic symptoms, antidepressant side-effects, and general side effects of psychotropic medications will be conducted on day 7 using the Glucocorticoid Toxicity Index (GTI) [28], the Structed Assessment of Psychotic Symptoms (SAPS), and the UKU-SSRI checklist [29], respectively, as well as structured questioning on somatic symptoms. For this purpose, the GTI will be modified to not include bone density, as the trial participants will not undergo a DEXA-/bone density scan. Any SAEs, SARs, or SUSARs will be reported by the sub-investigator to the sponsor/PI without unnecessary delay and latest after 24 h. If deemed a SUSAR by the sponsor/PI, he will report it to the Danish authorities without further delay and latest after 7 days if fatal and after 15 days if non-fatal. SUSARs will be reported through the EudraVigilance database.

Once a year, the sponsor/PI will submit a safety report, including details on SARs and SUSARs, in accordance with EU legislation through CTIS and thereby to the Danish Medicines Agency and National Ethics Committee.

The occurrence of any ARs, AEs, SARs, SAEs, and SUSARs in the groups will be report in the final trial report using the Medical Dictionary for Regulatory Activities (MedDRA) structured terminology.

Frequency and plans for auditing trial conduct {23}

The DEXA-PSYCH RCT will be continuously monitored by the Good Clinical Practice (GCP) unit of Copenhagen University Hospital, Frederiksberg Hospital, Nordre Fasanvej 57, Skadestuevej 1, 2000 Frederiksberg. This includes monitoring visits prior to the initiation of the trial, after inclusion of 1–2 participants, after trial termination, and on an ad hoc basis. A monitoring plan has been created between the monitors and the sponsor.

In addition, the sponsor/PI will allow direct access to the database and any source data/documents (including patient electronic health records) for monitoring, auditing, and/or inspection purpose from the GCP units, the Danish Medicines Agency (LMST), and the Danish Data Protection Agency (Datatilsynet), respectively.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

Any protocol amendments will be communicated to the relevant authorities and the trial monitor. All amendments will be made publicly available through CTIS. Any amendments with relevance for participants who have ended the treatment phase will be communicated in accordance with Danish laws and regulations.

Dissemination plans {31a}

The results of the trial will be published in international, peer-reviewed journals in accordance with the CONSORT Statement and irrespective of whether the results are positive, negative, or inconclusive. The results will furthermore be shared at relevant international conferences.

The funding sources will be acknowledged, but they will have no influence on the data handling or analyses, the writing of the manuscript or the decision to publish.

Discussion

The rationale and ethical justification of the trial relies on the following assumptions, all of which has been accounted for in the background section of this protocol:

1. Moderate-to-severe depression is a severe mental disorder with high costs to the individual and society; however,

2. Current treatment options show only small-to-moderate effects, which are often delayed by three to 6 weeks after treatment initiation, and they only relieve symptoms in a subset of patients.

3. Inflammatory pathophysiological processes have been associated with depression, and

4. Anti-inflammatory treatments have been shown to have effects against depression in meta-analyses, with the largest effect sizes detected for glucocorticoid drugs; however,

5. The current evidence on glucocorticoid treatment in depression is not strong enough to guide clinical practice.

If the trial demonstrates superiority of glucocorticoid treatment as add-on to TAU compared to placebo, this could pave the way for a new class of potentially fast-acting antidepressants that could alleviate symptoms in days rather than weeks. This could improve disease trajectories in depression, where the first weeks of treatment represent a crucial window [6]. The repurposing of existing medicine, in this case dexamethasone, can have a fast, positive impact on outcomes for patients [30]. However, this potential, clinical benefit can only be achieved if a large, high-quality randomized clinical trial (RCT) can provide sufficient evidence to warrant a change of guidelines. The potential benefit is, on a global scale, vast—especially since dexamethasone is a cheap, off-patent drug that can be readily employed for treatment in both low- and high-income countries.

If glucocorticoids, with their potent anti-inflammatory effects, indeed alleviate depressive symptoms, this could furthermore be an important, conceptual advance in our understanding of the etiology of depression. In addition, the trial will enable investigation of how specific biomarkers might enable prediction of treatment response. This will deepen our understanding of the underlying factors influencing the trajectories in depression treatment while potentially giving us the possibility of tailoring anti-inflammatory treatment to the patients exhibiting depressive symptoms with an inflammatory component and introduce a more personalized, biologically based treatment approach in psychiatry.

The trial will be the first clinical trial in 20 years to test glucocorticoids for treatment of depression and the, to date, largest trial of its kind globally. The trial will be conducted to the highest methodological standards with appropriate surveillance of adverse reactions. The placebo-controlled, double-blind design of the trial will provide causal evidence at the highest level of the evidence hierarchy, justifying the execution of the trial both medically and ethically. The trial is investigator-initiated and no parties with commercial interests in dexamethasone or treatment of depression are involved in the trial.

Consideration on choice of primary outcome

The primary aim of the trial is to investigate if dexamethasone can cause a rapid improvement in symptoms and thus “bridge” the effect until conventional anti-depressants have effect, which is why the primary outcome on treatment effect is evaluated already after 7 days of treatment. Additionally, previous studies of glucocorticoids in depression have not evaluated treatment effect later than 14 days after treatment initiation, which is why we have also included long-term follow-up assessments.

When evaluating the clinical efficacy of anti-depressant agents or psychotherapeutic interventions, it is standard practice to use a psychometric rating scale. The most widely used rating scales are MADRS and the Hamilton Depression Rating Scale (HAM-D). Current international guidelines are based on state-of-the-art meta-analyses that exclusively include studies measuring outcomes on MADRS or HAM-D [5]. Both scales can be used to graduate the severity of depression and follow treatment response; however, they cannot be used as diagnostic tools, where interviews according to diagnostic criteria should be used.

Both rating scales exist in 6-item versions (HAM-D₆ and MARDS₆), primarily rating the core symptoms of depression, and in extended versions consisting of 17 or 28 items for the HAM-D (HAM-D₁₇ and HAM-D₂₈) and 10 items for MADRS (MADRS₁₀). HAM-D₂₈ is rarely used, and HAM-D₆ has been found to “outperform” HAM-D₁₇ in anti-depressant trials, as the 6-item scale captures the core depressive symptoms, whereas the 17-item scale also encompasses anxiety symptoms and sleep disturbances not specific to depression and only partially responsive to anti-depressive treatment [31]. Both MADRS and HAM-D are interview-based, but reliable self-reporting versions of the scales have been developed [32]. The MADRS scale was developed specifically to measure the short-term effects of anti-depressant treatment, which is why is has been chosen for the DEXA-PSYCH trial [33]. MADRS₁₀ has a theoretical span of 0–60, with remission defined as a score of 11 or below (equivalent to a score of 7 on the HAM-D₁₇ and 4 on the HAM-D₆) [34]. Mild depression is defined as a MADRS₁₀ score of 18–21, moderate depression as a score of 22–29, and severe depression as a score of 30 or above. Each item on MADRS₁₀ is scored from 0–6, with only the scores 0, 2, 4, and 6 being used for each item. Psychometric testing using Rasch-analysis methodology has shown that MADRS₁₀ is multidimensional (i.e., measuring more than one latent construct), whereas MADRS-6 is considered unidimensional (i.e., only measures one latent construct) [35, 36].

A systemic review on minimum clinically important differences (MCIDs) for depression scales found one study investigating MCID for the MADRS. The study used a distribution-based method and data from clinical trials of patients between 18 and 65 years of age with MADRS scores above 22 (i.e., corresponding to the population in the DEXA-PSYCH trial) to determine a MCID of between 1.6 and 1.9. In the DEXA-PSYCH trial, we will therefore define the MCID for the primary outcome as a change from baseline in MADRS score of minimum 1.9., as detailed in the full protocol.

Trial status

Status: Recruiting.

Approved protocol: 1.1., 19^th of September 2022 (pre-registered and available through CTIS).

Current protocol version: 1.3., 20^th of November 2024 (available through CTIS).

Recruitment initiation: 28^th of December 2022.

First-patient, first-visit: 13^th of January 2023.

Projected last inclusion: 31^st of May 2026.

Projected last-patient, last-visit: 30^th of November 2026.

Abbreviations

AE

Adverse event

ALT

Alanine transaminase

ANCOVA

Analysis of covariance

AR

Adverse reaction

BACS

Brief Assessment of Cognition in Schizophrenia

BMI

Body mass index

CI

Confidence interval

C-SSRS

Columbia Suicide Severity Rating Scale

CPR

Central Person Register

CRP

C-reactive protein

CTIS

Clinical Trials Information System

eCRF

Electronic Case Record Form

DMC

Data monitoring committee

ECG

Electrocardiogram

ECT

Electroconvulsive treatment

EU

European union

FAS

Full analysis set

GCP

Good Clinical Practice

GDPR

General Data Protection Regulation

GTI

Glucocorticoid Toxicity Index

HAM-A

Hamilton Anxiety Rating Scale

HAM-D

Hamilton Depression Rating Scale

hCG

Human chorionic gonadotropin

HDL

High density lipoprotein

HPA

Hypothalamic-pituitary-adrenal

ICD

International Classification of Diseases

ITT

Intention-to-treat

LDL

Low-density lipoprotein

LMST

Danish Medicines Agency

MADRS

Montgomery–Asberg Depression Rating Scale

MAO

Monoamine oxidase

MAR

Missing at random

MedDRA

Medical Dictionary for Regulatory Activities

MCID

Minimum clinically important difference

MD

Medical Doctor

MHCC

Mental Health Center Copenhagen

MHSC

Mental Health Services in the Capital Region of Denmark

MMRM

Mixed Model for Repeated Measurements

PI

Principal Investigator

RCT

Randomized clinical trial

SAE

Serious adverse event

SAP

Statistical analysis plan

SAPS

Scale for the Assessment of Positive Symptoms

SAR

Serious adverse reaction

SAS

Safety analysis set

SCAN

Schedule for Clinical Assessment in Neuropsychiatry

SMD

Standardized Mean Difference

SNRI

Selective noradrenaline reuptake inhibitor

SOA

Schedule of activities

SSRI

Selective serotonin reuptake inhibitor

SUSAR

Suspicion of an unexpected serious adverse reaction

TAU

Treatment as usual

TCA

Tricyclic antidepressants

TMS

Transcranial magnetic stimulation

TSH

Thyroid stimulating hormone

ULN

Upper limit of normal range

YMRS

Youngs Mania Rating Scale

Biographies

Troels Boldt Rømer

is a medical doctor and PhD-student at MHSC and University of Copenhagen.

Camilla Gøtzsche Frederiksen

is a medical doctor and PhD-student at MHSC and University of Copenhagen.

Pernille Bølling Hansen

is a medical doctor at MHSC.

Rune Haubo Bojesen Christensen

is senior statistician at MHSC and has been employed as chief methodologist on previous clinical trials.

Michael Eriksen Benros

is clinical professor of immunopsychiatry at MHSC and University of Copenhagen.

Authors’ contributions {31b}

MEB is the sponsor and primary investigator of the study, supervises the study, provides administrative and material support for the study, obtained funding for the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. MEB (primary investigator) and TBR (sub-investigator) conceived the study, wrote the funding proposal and developed the protocol. CGF (sub-investigator) and RHBC (statistician) contributed to study design and the development of the protocol. TBR, CGF, and PBH are responsible for patient recruitment and data collection. RHBC is the trial methodologist and statistician and is responsible for the statistical analysis of the trial data. All authors have read and approved the final manuscript. Authorship for future trial publications will be granted in accordance with the Vancouver Declaration. For the primary study publication, TBR will be the first author and MEB the last author. For the main publication on biomarkers, CGF will be first author and MEB last author. No professional writers will be used for any trial publications.

Funding {4}

Open access funding provided by Copenhagen University The trial is funded by unrestricted grants to the PI (MEB) from the Novo Nordisk Foundation (grant number: NNF21OC0072020) and by the MHSC. The grant will be paid according to the grant agreement between the funding body and the sponsor/PI. The Novo Nordisk Foundation has not been or will not be involved in the design, conduct, analyses, or reporting of the trial nor will it have ownership of the data. The sponsor/principal investigator, sub-investigators, and other trial staff have no financial affiliations to the Novo Nordisk Foundation.

Data Availability {29}

The final trial data will be accessible to the PI, sub-investigators, and trial statistician. No contractual agreements limit access to the data for investigators

Declarations

Ethics approval and consent to participate {24}

Recruitment, screening, and enrollment commenced after approval from the Danish Medicines Agency, Ethics Committee, and the Capital Region Knowledge Center for Data Compliance. All documents and correspondences pertaining to the approval are publicly available through CTIS. Written, informed consent to participate will be obtained from all participants as described above.

Consent for publication {32}

Model consent forms and written patient information details the consent for publication of overall trial data. Both documents were approved by the Danish authorities in accordance with Danish law.

Competing interests {28}

The authors declare that they have no competing interests.