Treating Immuno-metabolic Depression With Anti-inflammatory Drugs (INFLAMED)
Primary Purpose
Depressive Disorder, Major, Inflammation
Status
Recruiting
Phase
Phase 3
Locations
Netherlands
Study Type
Interventional
Intervention
Celecoxib 400mg
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Depressive Disorder, Major focused on measuring INFLAMED, Depression, Inflammation, Immuno-metabolic Depression, Celecoxib
Eligibility 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 โฅ26 (moderate to severe depressive symptoms) and a score โฅ6 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
Sites / Locations
- Department of Psychiatry Amsterdam UMCRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Celecoxib
Placebo
Arm Description
Celecoxib 400 mg/day, 2 capsules (200 mg) daily, 12 weeks
Placebo, 2 capsules daily, 12 weeks
Outcomes
Primary Outcome Measures
Depressive symptoms severity
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
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
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)
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.
Full Information
NCT ID
NCT05415397
First Posted
June 3, 2022
Last Updated
September 22, 2023
Sponsor
Amsterdam UMC, location VUmc
Collaborators
Netherlands Brain Foundation
1. Study Identification
Unique Protocol Identification Number
NCT05415397
Brief Title
Treating Immuno-metabolic Depression With Anti-inflammatory Drugs
Acronym
INFLAMED
Official Title
Precision Psychiatry: Anti-inflammatory Medication in Immuno-metabolic Depression
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 28, 2022 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Amsterdam UMC, location VUmc
Collaborators
Netherlands Brain Foundation
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. 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.
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 (โฅ6 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Depressive Disorder, Major, Inflammation
Keywords
INFLAMED, Depression, Inflammation, Immuno-metabolic Depression, Celecoxib
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
12-week double-blind, randomized (1:1), placebo-controlled trial comparing celecoxib add-on (400 mg/d) versus placebo add-on to TAU in the treatment of 140 subjects with MDD and Immuno-metabolic Depression features
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
140 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Celecoxib
Arm Type
Experimental
Arm Description
Celecoxib 400 mg/day, 2 capsules (200 mg) daily, 12 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo, 2 capsules daily, 12 weeks
Intervention Type
Drug
Intervention Name(s)
Celecoxib 400mg
Other Intervention Name(s)
Celecoxib, ATC M01AH01
Intervention Description
Celecoxib add-on (400mg daily) add-on to treatment as usual (standard antidepressant treatment)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo add-on to treatment as usual (standard antidepressant treatment)
Primary Outcome Measure Information:
Title
Depressive symptoms severity
Description
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
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Number of participants achieving Response
Description
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)
Time Frame
12 weeks
Title
Number of participants achieving Remission
Description
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)
Time Frame
12 weeks
Title
Symptom profile: atypical, energy-related depressive symptoms (AES)
Description
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.
Time Frame
12 weeks
Other Pre-specified Outcome Measures:
Title
Fatigue
Description
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
Time Frame
12 weeks
Title
Food craving
Description
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)
Time Frame
12 weeks
Title
Daytime sleepiness
Description
Daytime sleepiness measured with the Epsworth Sleepiness Scale (ESS; score ranging from 0 to 24, higher scores indicates higher propensity to daytime sleepiness)
Time Frame
12 weeks
Title
Night-time sleep
Description
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)
Time Frame
12 weeks
Title
Anxiety symptoms
Description
Anxiety symptoms measured with General Anxiety Disorder-7 (GAD-7, score ranging from 0 to 21, higher scores indicate higher anxiety)
Time Frame
12 weeks
Title
Functionality
Description
General functioning and disability measured with the WHO Disability Schedule (WHODAS, score ranging from 12 to 60, higher scores indicate more disability)
Time Frame
12 weeks
Title
Pain severity
Description
Pain measured by numeric rating scale (score ranging from 0 to 10, higher scores indicate higher pain)
Time Frame
12 weeks
Title
Therapy compliance
Description
Pill count
Time Frame
12 weeks
Title
Inflammatory and metabolic blood markers
Description
CRP, IL-6, TNF-ฮฑ, cholesterol, triglycerides, glucose
Time Frame
12 weeks
Title
Side effects
Description
Side effects measured with the list applied in the PREDDICT RCT and theThe Antidepressant Side-Effect Checklist (ASEC-21)
Time Frame
12 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
DSM-5 diagnosis of MDD confirmed with clinical interview (MINI-S voor DSM-5 Nederlandse versie 2019)
Currently using pharmacotherapy (e.g., SSRI, SNRI, TCA, TetraCA, MAOI, other antidepressant [bupropion, vortioxetine, agomelatine])) and/or psychotherapy. Subjects should be on the current treatment for at least 4 weeks
IDS-SR score โฅ26 (moderate to severe depressive symptoms) and a score โฅ6 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 other psychotropic drugs
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joรซl Zwiep, MSc
Phone
+31629680809
Email
j.zwiep@amsterdamumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Yuri Milaneschi, PhD
Email
y.milaneschi@amsterdamumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yuri Milaneschi, PhD
Organizational Affiliation
Amsterdam UMC, location VUmc
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Femke Lamers, PhD
Organizational Affiliation
Amsterdam UMC, location VUmc
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Psychiatry Amsterdam UMC
City
Amsterdam
ZIP/Postal Code
1081 HJ
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joรซl Zwiep, MSc
Phone
+31629680809
Email
j.zwiep@amsterdamumc.nl
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual data collected during the study of participants explicitly agreeing on this possibility trough written informed consent; data will be de-identified
IPD Sharing Time Frame
Immediately following study closure and publication of the main results, no end date.
IPD Sharing Access Criteria
Investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose
Citations:
PubMed Identifier
32247527
Citation
Milaneschi Y, Lamers F, Berk M, Penninx BWJH. Depression Heterogeneity and Its Biological Underpinnings: Toward Immunometabolic Depression. Biol Psychiatry. 2020 Sep 1;88(5):369-380. doi: 10.1016/j.biopsych.2020.01.014. Epub 2020 Jan 28.
Results Reference
result
PubMed Identifier
32272220
Citation
Lamers F, Milaneschi Y, Vinkers CH, Schoevers RA, Giltay EJ, Penninx BWJH. Depression profilers and immuno-metabolic dysregulation: Longitudinal results from the NESDA study. Brain Behav Immun. 2020 Aug;88:174-183. doi: 10.1016/j.bbi.2020.04.002. Epub 2020 Apr 6.
Results Reference
result
PubMed Identifier
23672628
Citation
Penninx BW, Milaneschi Y, Lamers F, Vogelzangs N. Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Med. 2013 May 15;11:129. doi: 10.1186/1741-7015-11-129.
Results Reference
result
PubMed Identifier
34135474
Citation
Milaneschi Y, Kappelmann N, Ye Z, Lamers F, Moser S, Jones PB, Burgess S, Penninx BWJH, Khandaker GM. Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts. Mol Psychiatry. 2021 Dec;26(12):7393-7402. doi: 10.1038/s41380-021-01188-w. Epub 2021 Jun 16. Erratum In: Mol Psychiatry. 2021 Nov 16;:
Results Reference
result
PubMed Identifier
25322082
Citation
Kohler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, Krogh J. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014 Dec 1;71(12):1381-91. doi: 10.1001/jamapsychiatry.2014.1611.
Results Reference
result
PubMed Identifier
30834514
Citation
Kohler-Forsberg O, N Lydholm C, Hjorthoj C, Nordentoft M, Mors O, Benros ME. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019 May;139(5):404-419. doi: 10.1111/acps.13016. Epub 2019 Mar 28.
Results Reference
result
PubMed Identifier
31258105
Citation
Osimo EF, Baxter LJ, Lewis G, Jones PB, Khandaker GM. Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychol Med. 2019 Sep;49(12):1958-1970. doi: 10.1017/S0033291719001454. Epub 2019 Jul 1.
Results Reference
result
PubMed Identifier
34375789
Citation
Baune BT, Sampson E, Louise J, Hori H, Schubert KO, Clark SR, Mills NT, Fourrier C. No evidence for clinical efficacy of adjunctive celecoxib with vortioxetine in the treatment of depression: A 6-week double-blind placebo controlled randomized trial. Eur Neuropsychopharmacol. 2021 Dec;53:34-46. doi: 10.1016/j.euroneuro.2021.07.092. Epub 2021 Aug 8. Erratum In: Eur Neuropsychopharmacol. 2022 Oct 1;64:61-62.
Results Reference
result
PubMed Identifier
26169573
Citation
Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: A meta-analysis. Eur Neuropsychopharmacol. 2015 Oct;25(10):1532-43. doi: 10.1016/j.euroneuro.2015.06.007. Epub 2015 Jun 20.
Results Reference
result
Links:
URL
https://immunometaboledepressie.nl/
Description
Study website
Learn more about this trial
Treating Immuno-metabolic Depression With Anti-inflammatory Drugs
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