Trattamento della depressione immuno-metabolica con farmaci antinfiammatori (INFLAMED)
Psichiatria di precisione: farmaci antinfiammatori nella depressione immuno-metabolica
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.
Panoramica dello studio
Stato
Condizioni
Intervento / Trattamento
Descrizione dettagliata
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.
Tipo di studio
Iscrizione (Effettivo)
Fase
- Fase 3
Contatti e Sedi
Luoghi di studio
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Amsterdam, Olanda, 1081 HJ
- Department of Psychiatry Amsterdam UMC
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Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
Accetta volontari sani
Sessi ammissibili allo studio
Descrizione
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
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Trattamento
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione parallela
- Mascheramento: Quadruplicare
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
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Sperimentale: Celecoxib
Celecoxib 400 mg/day, 2 capsules (200 mg) daily, 12 weeks |
Celecoxib add-on (400mg daily) add-on to treatment as usual (standard antidepressant treatment)
Altri nomi:
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Comparatore placebo: Placebo
Placebo, 2 capsules daily, 12 weeks |
Placebo add-on to treatment as usual (standard antidepressant treatment) |
Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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Depressive symptoms severity
Lasso di tempo: 12 weeks
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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
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Misure di risultato secondarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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Number of participants achieving Response
Lasso di tempo: 12 weeks
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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
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Number of participants achieving Remission
Lasso di tempo: 12 weeks
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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
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Symptom profile: atypical, energy-related depressive symptoms (AES)
Lasso di tempo: 12 weeks
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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
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Altre misure di risultato
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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Fatigue
Lasso di tempo: 12 weeks
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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
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Food craving
Lasso di tempo: 12 weeks
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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
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Daytime sleepiness
Lasso di tempo: 12 weeks
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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
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Night-time sleep
Lasso di tempo: 12 weeks
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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
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Anxiety symptoms
Lasso di tempo: 12 weeks
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Anxiety symptoms measured with General Anxiety Disorder-7 (GAD-7, score ranging from 0 to 21, higher scores indicate higher anxiety) |
12 weeks
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Functionality
Lasso di tempo: 12 weeks
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General functioning and disability measured with the WHO Disability Schedule (WHODAS, score ranging from 12 to 60, higher scores indicate more disability) |
12 weeks
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Pain severity
Lasso di tempo: 12 weeks
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Pain measured by numeric rating scale (score ranging from 0 to 10, higher scores indicate higher pain) |
12 weeks
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Therapy compliance
Lasso di tempo: 12 weeks
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Pill count |
12 weeks
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Inflammatory and metabolic blood markers
Lasso di tempo: 12 weeks
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CRP, IL-6, TNF-α, cholesterol, triglycerides, glucose |
12 weeks
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Side effects
Lasso di tempo: 12 weeks
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Side effects measured with the list applied in the PREDDICT RCT and theThe Antidepressant Side-Effect Checklist (ASEC-21) |
12 weeks
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Collaboratori e investigatori
Sponsor
Collaboratori
Investigatori
- Investigatore principale: Yuri Milaneschi, PhD, Amsterdam UMC, location VUmc
- Investigatore principale: Femke Lamers, PhD, Amsterdam UMC, location VUmc
Pubblicazioni e link utili
Pubblicazioni generali
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Collegamenti utili
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Inizio studio (Effettivo)
Completamento primario (Effettivo)
Completamento dello studio (Effettivo)
Date di iscrizione allo studio
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Effettivo)
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Effettivo)
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
- Disordini mentali
- Processi patologici
- Sintomi comportamentali
- Disturbi dell'umore
- Disordine depressivo
- Condizioni patologiche, segni e sintomi
- Comportamento
- Depressione
- Infiammazione
- Disturbo depressivo, maggiore
- Composti di zolfo
- Prodotti chimici organici
- Composti eterociclici, 1-anello
- Composti eterociclici
- Azoli
- Idrocarburi
- Idrocarburi, ciclici
- Idrocarburi, aromatici
- Amides
- Derivati di benzene
- Benzenesulfonamides
- Sulfonamidi
- Solfoni
- Pirazoli
- Celecoxib
Altri numeri di identificazione dello studio
- NL79765.029.21
Piano per i dati dei singoli partecipanti (IPD)
Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?
Descrizione del piano IPD
Individual data collected during the study of participants explicitly agreeing on this possibility trough written informed consent; data will be de-identified
Periodo di condivisione IPD
Immediately following study closure and publication of the main results, no end date.
Criteri di accesso alla condivisione IPD
Investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose
Tipo di informazioni di supporto alla condivisione IPD
- STUDIO_PROTOCOLLO
Informazioni su farmaci e dispositivi, documenti di studio
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