Treating Immuno-metabolic Depression With Anti-inflammatory Drugs

NCT ID: NCT05415397

Last Updated: 2025-10-06

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 140 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-09-28
• Study Completion Date: 2026-07-31

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 (≥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.

Conditions

Depressive Disorder, Major; Inflammation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Celecoxib

Celecoxib 400 mg/day, 2 capsules (200 mg) daily, 12 weeks

Group Type: EXPERIMENTAL

Celecoxib 400mg

Intervention Type: DRUG

Celecoxib add-on (400mg daily) add-on to treatment as usual (standard antidepressant treatment)

Placebo

Placebo, 2 capsules daily, 12 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo add-on to treatment as usual (standard antidepressant treatment)

Interventions

Celecoxib 400mg

Celecoxib add-on (400mg daily) add-on to treatment as usual (standard antidepressant treatment)

Intervention Type: DRUG

Placebo

Placebo add-on to treatment as usual (standard antidepressant treatment)

Intervention Type: DRUG

Other Intervention Names

Celecoxib, ATC M01AH01

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 ≥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 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Netherlands Brain Foundation

OTHER

Sponsor Role: collaborator

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: lead

Responsible Party

Yuri Milaneschi

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yuri Milaneschi, PhD

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC, location VUmc

Femke Lamers, PhD

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC, location VUmc

Locations

Department of Psychiatry Amsterdam UMC

Amsterdam, , Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Joël Zwiep, MSc

Role: CONTACT

j.zwiep@amsterdamumc.nl

+31629680809

Yuri Milaneschi, PhD

Role: CONTACT

y.milaneschi@amsterdamumc.nl

Facility Contacts

Joël Zwiep, MSc

Role: primary

j.zwiep@amsterdamumc.nl

+31629680809

References

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.

Reference Type: BACKGROUND

PMID: 32247527 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 32272220 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23672628 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 34135474 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25322082 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30834514 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31258105 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 34375789 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26169573 (View on PubMed)

Zwiep JC, Bet PM, Rhebergen D, Nurmohamed MT, Vinkers CH, Penninx BWJH, Milaneschi Y, Lamers F. Efficacy of celecoxib add-on treatment for immuno-metabolic depression: Protocol of the INFLAMED double-blind placebo-controlled randomized controlled trial. Brain Behav Immun Health. 2022 Dec 30;27:100585. doi: 10.1016/j.bbih.2022.100585. eCollection 2023 Feb.

Reference Type: DERIVED

PMID: 36655056 (View on PubMed)

Related Links

https://immunometaboledepressie.nl/

Study website

Other Identifiers

NL79765.029.21

Identifier Type: -

Identifier Source: org_study_id