Clinical trial NCT05415397: Treating Immuno-metabolic Depression With Anti-inflammatory Drugs
Official title: Precision Psychiatry: Anti-inflammatory Medication in Immuno-metabolic Depression
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Depressive Disorder, Major
Inflammation
Keywords: INFLAMED
Depression
Inflammation
Immuno-metabolic Depression
Celecoxib
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
Collaborators: name: Netherlands Brain Foundation
First posted: 2022-06-13
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Depressive symptoms severity
timeFrame: 12 weeks
Secondary outcomes:
measure: Number of participants achieving Response
timeFrame: 12 weeks
measure: Number of participants achieving Remission
timeFrame: 12 weeks
measure: Symptom profile: atypical, energy-related depressive symptoms (AES)
timeFrame: 12 weeks
Other outcomes:
measure: Fatigue
timeFrame: 12 weeks
measure: Food craving
timeFrame: 12 weeks
measure: Daytime sleepiness
timeFrame: 12 weeks
measure: Night-time sleep
timeFrame: 12 weeks
measure: Anxiety symptoms
timeFrame: 12 weeks
measure: Functionality
timeFrame: 12 weeks
measure: Pain severity
timeFrame: 12 weeks
measure: Therapy compliance
timeFrame: 12 weeks
measure: Inflammatory and metabolic blood markers
timeFrame: 12 weeks
measure: Side effects
timeFrame: 12 weeks
Locations:
city: Amsterdam
country: Netherlands
facility: Department of Psychiatry Amsterdam UMC
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Yuri Milaneschi, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Amsterdam UMC, location VUmc
name: Femke Lamers, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.
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.
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.