Treating Immuno-metabolic Depression With Anti-inflammatory Drugs

Inflammation Clinical Trial

— INFLAMED  

Official title:

Precision Psychiatry: Anti-inflammatory Medication in Immuno-metabolic Depression

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05415397
• Other study ID #: NL79765.029.21
• Status: Recruiting
• Phase: Phase 3
• Start date: September 28, 2022
• Est. completion date: December 2024

Study information

• Verified date: September 2023
• Source: Amsterdam UMC, location VUmc
• Contact: Joël Zwiep, MSc
• Phone: +31629680809
• Email: j.zwiep[@]amsterdamumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 140
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Inflammation

Intervention

Drug:
• Celecoxib 400mg
Celecoxib add-on (400mg daily) add-on to treatment as usual (standard antidepressant treatment)
• Placebo
Placebo add-on to treatment as usual (standard antidepressant treatment)

Locations

Country	Name	City	State
Netherlands	Department of Psychiatry Amsterdam UMC	Amsterdam

Sponsors (2)

Lead Sponsor	Collaborator
Amsterdam UMC, location VUmc	Netherlands Brain Foundation

Country where clinical trial is conducted

Netherlands, 

References & Publications (9)

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 — View 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 — View 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: — View 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 202 — View 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 — View 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. — View 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. — View 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. — View 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 201 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Fatigue	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	12 weeks
Other	Food craving	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)	12 weeks
Other	Daytime sleepiness	Daytime sleepiness measured with the Epsworth Sleepiness Scale (ESS; score ranging from 0 to 24, higher scores indicates higher propensity to daytime sleepiness)	12 weeks
Other	Night-time sleep	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)	12 weeks
Other	Anxiety symptoms	Anxiety symptoms measured with General Anxiety Disorder-7 (GAD-7, score ranging from 0 to 21, higher scores indicate higher anxiety)	12 weeks
Other	Functionality	General functioning and disability measured with the WHO Disability Schedule (WHODAS, score ranging from 12 to 60, higher scores indicate more disability)	12 weeks
Other	Pain severity	Pain measured by numeric rating scale (score ranging from 0 to 10, higher scores indicate higher pain)	12 weeks
Other	Therapy compliance	Pill count	12 weeks
Other	Inflammatory and metabolic blood markers	CRP, IL-6, TNF-a, cholesterol, triglycerides, glucose	12 weeks
Other	Side effects	Side effects measured with the list applied in the PREDDICT RCT and theThe Antidepressant Side-Effect Checklist (ASEC-21)	12 weeks
Primary	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	12 weeks
Secondary	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)	12 weeks
Secondary	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)	12 weeks
Secondary	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.	12 weeks

External Links

•   Study website