Treating Immuno-metabolic Depression With Anti-inflammatory Drugs

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.

Timeline

Start

2022-09-28

Primary completion

2026-07

Completion

2026-07

Publications

• Results 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 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 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 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.
• Results 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 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 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 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.
• Results 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.

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