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• W3086892435 abstract "We thank Andrew Miller and Carmine Pariante for continuing the discussion of our study, published in The Lancet Psychiatry.1Husain MI Chaudhry IB Khoso AB et al.Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial.Lancet Psychiatry. 2020; 7: 515-527Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar They propose that our negative study might have detected an antidepressant benefit of the two anti-inflammatory drugs (minocycline and celecoxib) if we had selected a group with evidence of inflammation, used more nuanced outcome measures, and tested other drugs. We accept that anti-inflammatory trials in depression should aim to show efficacy in people with inflammation and not in people without. The problem is that evidence of inflammation is ill-defined and so far confined to minor increases in C-reactive protein (CRP), with cut-offs varying between 1 mg/L in 60% and 5 mg/L in 30% of patients with depression.2Miller AH Raison CL The role of inflammation in depression: from evolutionary imperative to modern treatment target.Nat Rev Immunol. 2016; 16: 22-34Crossref PubMed Scopus (1399) Google Scholar No validated stratification algorithm incorporates the many other peripheral markers of inflammation, and none are convincingly predictive of neuroinflammation. Recent trials of anti-inflammatory drugs that stratified participants at baseline according to biochemical (CRP) and phenotypic (obesity) evidence of inflammation failed to show superiority of two drugs over placebo in patients with both unipolar and bipolar depression.3McIntyre RS Subramaniapillai M Lee Y et al.Efficacy of adjunctive infliximab vs placebo in the treatment of adults with bipolar I/II depression: a randomized clinical trial.JAMA Psychiatry. 2019; 76: 783-790Crossref PubMed Scopus (71) Google Scholar, 4Salvadore G, Nash A, Bleys C, et al. A double-blind, placebo-controlled, multicenter study of sirukumab as adjunctive treatment to a monoaminergic antidepressant in adults with major depressive disorder. American College of Neuropsychopharmacology Annual Meeting; Hollywood, FL, USA; December 2018.Google Scholar If our sample had an appreciable number of patients with a responsive immune pathogenesis, this was not reflected in greater variance in outcome measures in the actively treated groups. Regarding outcome, improvement in overall depressive symptoms must surely remain the gold standard in randomised controlled trials of pharmacological and psychosocial interventions in mood disorders. However, it is entirely appropriate to use exploratory and experimental measures to probe mechanisms such as anhedonia, but Miller and Pariante leave these measures undefined. There are several questionnaire and performance measures of anhedonia, which itself has several dissociable components. Using multiple nuanced outcome measures dilutes statistical power. Miller and Pariante cite two studies showing anti-inflammatory effects on anhedonia, but both are negative for depression, and one assessed anhedonia by a single item (work and interests) of the Hamilton Depression scale, which seems like a flimsy proof of concept for anhedonia as the primary outcome in an anti-inflammatory trial in depression. The suggestion that minocycline and celecoxib have too many off-target effects to interpret a negative effect has no basis. The unspecified off-target actions do not prevent the undoubted efficacy these drugs in treating inflammatory disorders such as rheumatoid arthritis. The same actions in bipolar depression did not affect depressive symptoms. Furthermore, we reported that minocycline was clearly an effective adjunct in non-bipolar treatment-resistant depression,5Husain MI Chaudhry IB Husain N et al.Minocycline as an adjunct for treatment-resistant depressive symptoms: a pilot randomised placebo-controlled trial.J Psychopharmacol. 2017; 31: 1166-1175Crossref PubMed Scopus (75) Google Scholar a subtype convincingly associated with raised CRP.6Chamberlain SR Cavanagh J De Boer P et al.Treatment-resistant depression and peripheral C-reactive protein.Br J Psychiatry. 2019; 214: 11-19Crossref PubMed Scopus (114) Google Scholar In keeping with the current study, the effective anti-inflammatory cytokine inhibitor, infliximab, did not affect depression in bipolar patients selected for having CRP of at least 5 mg/L.3McIntyre RS Subramaniapillai M Lee Y et al.Efficacy of adjunctive infliximab vs placebo in the treatment of adults with bipolar I/II depression: a randomized clinical trial.JAMA Psychiatry. 2019; 76: 783-790Crossref PubMed Scopus (71) Google Scholar It seems a reasonable inference that in bipolar disorder, inflammation is not a pervasive mechanism of depression. We fully agree that stratification, use of target-specific drugs, and innovative trial designs are important for progress in developing the immune strategy for treating depression. For this to happen, an urgent need exists for the definition and validation of immune subtypes of depression and for feasible biomarkers for neuroinflammation. MIH is a principal investigator for a trial sponsored by COMPASS Pathways Limited, for which he receives salary support. BD has worked as scientific consultant to Autifony in the past 3 years and has share options in P1vtal.com. IBC has given lectures and advice to Eli Lilly, Bristol-Myers Squibb, Lundbeck, AstraZeneca, and Janssen Pharmaceuticals, for which he or his employing institution have been reimbursed. BHM currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the UK Centre for Addiction and Mental Health Foundation (CAMH), the Patient-Centered Outcomes Research Institute, the US National Institutes of Health (NIH), Capital Solution Design (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). Within the past 5 years, BHM has also received research support (medications for NIH-funded clinical trials) from Bristol-Myers Squibb, Eli Lilly, and Pfizer, and he directly own stocks of General Electric (less than US$ 5000). AHY has been commissioned to provide lectures and advice to all major pharmaceutical companies with drugs used in affective and related disorders and has undertaken investigator-initiated studies funded by AstraZeneca, Eli Lilly, Lundbeck, and Wyeth. Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trialWe found no evidence that minocycline or celecoxib was superior to placebo for the treatment of bipolar depression. This large trial casts doubt on the potential therapeutic benefits of adjunctive anti-inflammatory drugs for the acute management of bipolar depression. Full-Text PDF Trial failures of anti-inflammatory drugs in depressionIn the largest randomised controlled trial of its kind, published by Muhammad Husain and colleagues in The Lancet Psychiatry,1 two drugs with anti-inflammatory properties failed to separate from placebo in reducing depressive symptom scores in a sample of patients with bipolar depression. The pressing question is: why did this trial fail? If left unanswered, an entire strategy for treating depression could be jeopardised. Among the many considerations are the design of the trial and the drugs used. 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• W3086892435 title "Trial failures of anti-inflammatory drugs in depression – Authors' reply" @default.
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