INFLAMED: Treating Immuno-metabolic Depression With Anti-inflammatory Drugs
Study Details
Study Description
Brief Summary
As the role of (neuro)inflammation in depression is emerging, augmentation of antidepressant treatments with anti-inflammatory drugs such as celecoxib has shown encouraging preliminary results. However, inflammation is not present in all depressed patients. Depression is heterogeneous: patients express diverse and sometimes opposing symptoms and biological profiles. The investigators of the present trial recently introduced the concept of ImmunoMetabolic Depression (IMD), characterized by the clustering of inflammatory/metabolic dysregulations and atypical, energy-related symptoms (hyperphagia, weight gain, hypersomnia, fatigue and leaden paralysis), and present in approximately 30% of cases. Converging evidence suggests that in this subgroup of depression cases, inflammation may exert a crucial pathobiological mechanism, representing therefore an actionable therapeutic target. In this trial IMD will be applied as a tool to personalize treatment, by matching depressed subjects with IMD with a targeted anti-inflammatory add-on treatment.
In this study, 140 persons with IMD will be selected. In this specific group of patients, the investigators will test whether celecoxib add-on (400 mg/d) is more effective than placebo in the treatment of depression through a 12-week double-blind, randomized (1:1), placebo-controlled trial. By selecting specifically depressed patients with IMD, the proposed treatment selectively targets key inflammatory pathophysiological pathways to enhance clinical outcome for depression. This personalized approach is expected to lead to large health gains for a sizable proportion of patients. The main hypothesis is that the group of patients with IMD receiving TAU + celecoxib, as compared to the TAU + placebo, will show a better symptom course over the 12-week follow-up.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
Rationale: Depression is a major driver of disability and related health-care costs. Available treatment options are far from optimal, with only ~60% response. Developing effective treatments requires new treatment targets to depression pathophysiology. As the role of (neuro)inflammation in depression is emerging, augmentation of antidepressant treatments with anti-inflammatory drugs such as celecoxib has shown encouraging preliminary results. However, inflammation is not present in all depressed patients. Depression is heterogeneous: patients express diverse and sometimes opposing symptoms and biological profiles. The investigators of the present study recently introduced the concept of ImmunoMetabolic Depression (IMD), characterized by the clustering of inflammatory/metabolic dysregulations and atypical, energy-related symptoms (hyperphagia, weight gain, hypersomnia, fatigue and leaden paralysis), and present in 30% of cases. Converging evidence suggests that in this subgroup of depression cases, inflammation may exert a crucial pathobiological mechanism, representing therefore an actionable therapeutic target. In this study IMD will be applied as a tool to personalize treatment, by matching depressed subjects with IMD with a targeted anti-inflammatory add-on treatment. The underlying hypothesis is that this personalized intervention in subjects with IMD, through a reduction of inflammation, lowers depressive symptoms and associated physical fatigue, while increasing functioning compared to placebo.
Objective: Among patients under treatment for depression, 140 persons with IMD will be selected. In this specific group of patients, the investigators will test whether celecoxib add-on (400 mg/d) is more effective than placebo in the treatment of depression through a 12-week double-blind, randomized (1:1), placebo-controlled trial.
Study design:12-week double-blind placebo-controlled randomized clinical trial Study population: 140 persons with major depressive disorder (DMS-5) with atypical, energy-related symptoms (≥6 on IDS atypical, energy-related symptoms) AND low-grade inflammation (CRP>1mg/L) (e.g. ImmunoMetabolic Depression), and under treatment with SSRI or SNRIs.
Intervention: celecoxib add-on (400 mg/d) vs placebo Main study parameters/endpoints: Primary outcome parameter is the difference in trajectories of depression symptoms, as measured with the 30-item Inventory of Depressive Symptomatology - self-report during follow-up. Secondary outcome parameters include amongst others, response on the IDS, remission, anxiety, fatigue, food craving, sleep and adverse side events.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Celecoxib Celecoxib 400 mg/day, 2 capsules (200 mg) daily, 12 weeks |
Drug: Celecoxib 400mg
Celecoxib add-on (400mg daily) add-on to treatment as usual (standard antidepressant treatment)
Other Names:
|
| Placebo Comparator: Placebo Placebo, 2 capsules daily, 12 weeks |
Drug: Placebo
Placebo add-on to treatment as usual (standard antidepressant treatment)
|
Outcome Measures
Primary Outcome Measures
- Depressive symptoms severity [12 weeks]
Depressive symptoms severity measured with the Inventory of Depressive Symptomatology - Self Report (IDS-SR; score ranging from 0 to 84, higher scores indicate higher severity of depressive symptoms). Trajectories of depressive symptoms will be modeled via mixed models including bi-weekly assessments
Secondary Outcome Measures
- Number of participants achieving Response [12 weeks]
Response is defined as 50% reduction in depressive symptoms severity measured with Inventory of Depressive Symptomatology - Self Report (IDS-SR; score ranging from 0 to 84, higher scores indicate higher severity of depressive symptoms)
- Number of participants achieving Remission [12 weeks]
Remission is defined as absence of DSM-5 Major Depressive Disorder (MDD), identified using the Mini International Neuropsychiatric Interview - Simplified (MINI-S voor DSM-5 Nederlandse versie 2019)
- Symptom profile: atypical, energy-related depressive symptoms (AES) [12 weeks]
AES measured with 5 items (N 4, 12, 14, 20, 30) of the Inventory of Depressive Symptomatology - Self Report (IDS-SR). AES score ranging from 0 to 15, higher scores indicate higher severity of depressive symptoms.
Other Outcome Measures
- Fatigue [12 weeks]
Fatigue measured by the Checklist Individuele Spankracht (CIS), which assess fatigue in 4 subscales: subjective experience of fatigue, reduction in motivation, reduction in activity and reduction in concentration. In each domain, higher scores indicate higher fatigue
- Food craving [12 weeks]
Food craving measured with General Food Craving Questionnaire Trait (G-FCQ-T; score ranging from 21 to 126, higher scores indicate more intense food craving)
- Daytime sleepiness [12 weeks]
Daytime sleepiness measured with the Epsworth Sleepiness Scale (ESS; score ranging from 0 to 24, higher scores indicates higher propensity to daytime sleepiness)
- Night-time sleep [12 weeks]
Sleep Duration measured with items 1,2,3 and 4 (self reports of bed time, asleep time, wake-time, sleep duration) of the Pittsburgh Sleep Quality Index (PSQI)
- Anxiety symptoms [12 weeks]
Anxiety symptoms measured with General Anxiety Disorder-7 (GAD-7, score ranging from 0 to 21, higher scores indicate higher anxiety)
- Functionality [12 weeks]
General functioning and disability measured with the WHO Disability Schedule (WHODAS, score ranging from 12 to 60, higher scores indicate more disability)
- Pain severity [12 weeks]
Pain measured by numeric rating scale (score ranging from 0 to 10, higher scores indicate higher pain)
- Therapy compliance [12 weeks]
Pill count
- Inflammatory and metabolic blood markers [12 weeks]
CRP, IL-6, TNF-α, cholesterol, triglycerides, glucose
- Side effects [12 weeks]
Side effects measured with the list applied in the PREDDICT RCT and theThe Antidepressant Side-Effect Checklist (ASEC-21)
Eligibility Criteria
Criteria
Inclusion Criteria:
-
DSM-5 diagnosis of MDD confirmed with clinical interview (MINI-S voor DSM-5 Nederlandse versie 2019)
-
Currently using an SSRI or SNRI, subjects should be on the current medication for at least 4 weeks
-
IDS-SR score ≥26 (moderate to severe depressive symptoms) and a score ≥6 on atypical, energy-related symptoms scale from IDS
-
CRP > 1mg/L
-
A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: 1) is not a woman of child bearing potential (WOCBP); 2) Is a WOCBP and agrees to use, or is already using, a contraceptive method during the intervention period and up to 1 month after the intervention
-
Signed informed consent
Exclusion Criteria:
-
Contraindications for celecoxib (history of: peptic ulcers, gastrointestinal bleeding, ischemic heart disease, stroke, heart failure, allergic reactions to aspirin/NSAIDs/coxibs; impaired kidney function (creatinine clearance < 30 ml/min), impaired liver function (ALT > 2x ULT)
-
ECT in the past 3 months
-
Being on antidepressants other than SSRIs or SNRIs or being on other psychotropic drugs
-
Starting other evidence-based non-pharmacological intervention for depression (e.g. psychotherapy) in the 4 weeks before randomization.
-
Clinically overt alcohol/drug dependence or other primary psychiatric diagnoses (schizophrenia, schizoaffective, OCD, or bipolar disorder)
-
Chronic use of anti-inflammatory drugs and corticosteroids
-
Current use of anticoagulants
-
Not speaking Dutch
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Department of Psychiatry Amsterdam UMC | Amsterdam | Netherlands | 1081 HJ |
Sponsors and Collaborators
- Amsterdam UMC, location VUmc
- Netherlands Brain Foundation
Investigators
- Principal Investigator: Yuri Milaneschi, PhD, Amsterdam UMC, location VUmc
- Principal Investigator: Femke Lamers, PhD, Amsterdam UMC, location VUmc
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- NL79765.029.21