Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial

Husain, Muhammad Ishrat; Chaudhry, Imran B; Khoso, Ameer B; Hodsoll, John; Ansari, Mohammed; Naqvi, Haider; Minhas, Fareed Aslam; Carvalho, André F.; Meyer, Jeffrey H.; Deakin, Bill; Mulsant, Benoit H.; Husain, Nusrat; Young, Allan H.

doi:10.1016/s2215-0366(20)30138-3

Cited by 129 publications

(91 citation statements)

References 37 publications

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“…Such evidence suggests that minocycline antidepressant effect might be diagnosis-specific, considering that results in bipolar depression are more conflicting. Indeed, a recent work pointed out that minocycline was not superior to placebo for the acute management of bipolar depression [53]. However, our study also indicates that conventional diagnosis should be complemented with the assessment of biological factors, like the immune markers, in order to identify effective treatments for depression, including antiinflammatories.…”

Section: Discussionmentioning

confidence: 65%

Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial

Nettis

Lombardo

Hastings

et al. 2021

Neuropsychopharmacol.

165

122

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This study aimed to investigate the role of baseline levels of peripheral inflammation when testing the efficacy of antidepressant augmentation with minocycline in patients with treatment-resistant depression. We conducted a 4-week, placebo-controlled, randomised clinical trial of minocycline (200 mg/day) added to antidepressant treatment in 39 patients selected for elevated levels of serum C-reactive protein (CRP ≥ 1 mg/L), n = 18 randomised to minocycline (M) and n = 21 to placebo (P). The main outcome was the change in Hamilton Depression Rating Scale (HAM-D-17) score from baseline to week 4, expressed both as mean and as full or partial response, in the overall sample and after further stratification for baseline CRP≥3 mg/L. Secondary outcomes included changes in other clinical and inflammatory measures. Changes in HAM-D-17 scores and the proportion of partial responders did not differ between study arms. After stratification for CRP levels <3 mg/L (CRP−) or ≥3 mg/L (CRP+), CRP+/M patients showed the largest changes in HAM-D-17 scores (mean ± SD = 12.00 ± 6.45) compared with CRP-/M (2.42 ± 3.20, p < 0.001), CRP+/P (3.50 ± 4.34, p = 0.003) and CRP−/P (2.11 ± 3.26, p = 0.006) patients, and the largest proportion (83.3%, p = 0.04) of partial treatment response at week 4. The threshold point for baseline CRP to distinguish responders from non-responders to minocycline was 2.8 mg/L. Responders to minocycline had higher baseline IL-6 concentrations than non-responders (p = 0.03); IFNγ was significantly reduced after treatment with minocycline compared with placebo (p = 0.03). Our data show some evidence of efficacy of add-on treatment with minocycline in MDD patients but only in those with low-grade inflammation defined as CRP ≥3 mg/L.

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Section: Discussionmentioning

confidence: 65%

Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial

Nettis

Lombardo

Hastings

et al. 2021

Neuropsychopharmacol.

165

122

View full text Add to dashboard Cite

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“…A trial involving 24 patients reported that the co-administration of NAC and aspirin could alleviate depressive symptoms after 16 weeks, which was remarkably better than NAC or aspirin treatment alone ( Bauer et al, 2018 ). In another trial, no evidence was found that minocycline plus celecoxib was more effective than placebo for treating depression ( Husain et al, 2020 ). However, these two studies were concerned on bipolar depression, and there was no direct evidence for the combined effect of different anti-inflammatory agents on MDD treatment.…”

Section: Discussionmentioning

confidence: 99%

Comparative Efficacy and Acceptability of Anti-inflammatory Agents on Major Depressive Disorder: A Network Meta-Analysis

Hang

Zhang

et al. 2021

Front. Pharmacol.

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Background: With the growing importance of research about the association between neuroinflammation and major depressive disorder (MDD), anti-inflammatory agents have been used as a new antidepressant therapy in clinical practice. We conducted a network meta-analysis (NMA) with up-to-date evidence to compare different anti-inflammatory agents for improving the treatment of MDD patients.Methods: To identify eligible randomized clinical trials, four databases (i.e, the Cochrane Library, Web of Science, PubMed and Embase) were searched from inception date to May 31, 2020. Anti-inflammatory agents were defined as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, cytokine inhibitors, statins, pioglitazone, minocycline, N-acetylcysteine (NAC) and omega-3 fatty acid (Omega-3 FA). The main outcomes of this NMA were efficacy, acceptability and remission rate. Risk ratio (RR) was adopted for dichotomous outcomes, and the confidence interval (CI) was set at 95%. STATA 14.0 and R 3.6.3 were used to conduct the NMA. The study protocol was registered with PROSPERO (CRD42020182531).Results: A total of 39 studies, involving 2871 participants, were included in quantitative data synthesis. For efficacy, NSAIDs (RR=0.50, 95%CI: 0.26-0.73) and pioglitazone (RR=0.45, 95%CI: 0.20-0.84) were more favorable than placebo. With respect to acceptability, NSAIDs were more acceptable than placebo (RR=0.89, 95%CI: 0.77-0.99) and minocycline (RR=1.22, 95%CI: 1.03-1.49). For remission, NSAIDs were more superior than placebo (RR=0.48, 95%CI: 0.27-0.79) and Omega-3 FA (RR=2.01, 95%CI: 1.09-3.90), while NACs were more favorable than placebo (RR=0.39, 95%CI: 0.13-0.99). Based on the surface under the cumulative ranking curve (SUCRA) value, corticosteroids (0.86) were the best anti-inflammatory agent for MDD patients in terms of efficacy, but the head-to-head comparisons for the efficacy of glucocorticoids and other agents were not statistically significant. As for acceptability, NSAIDs (0.81) were much better than other anti-inflammatory agents. Besides, NAC (0.80) was the best anti-inflammatory agent in the terms of remission.Conclusions: In summary, we found that corticosteroids were more superior than other agents in terms of efficacy according to the SUCRA value. However, this result must be interpreted with caution because the head-to-head comparisons for the efficacy of glucocorticoids and other agents did not reach statistical significance. NSAIDs were recommended for acceptability and NAC for remission rate.

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“…These results can inform the design of clinical trials of anti-inflammatory approaches and metabolic interventions by specifically selecting patients with an atypical, neurovegetative symptom presentation. As clinical trials for immune-modulating drugs are currently still characterised by relatively small sample sizes (Husain et al, 2020; Khandaker et al, 2018; McIntyre et al, 2019; Nettis et al, 2021; Raison et al, 2013), it may be worthwhile to pilot new interventions with neurovegetative symptoms/phenotypes as outcome variables. This might increase statistical power and sensitivity to detect effects for these proof-of-concept trials and could then be followed up by larger trials testing broader clinical efficacy measures.…”

Section: Discussionmentioning

confidence: 99%

Polygenic risk for immuno-metabolic markers and specific depressive symptoms: A multi-sample network analysis study

Kappelmann

Rost

Moser

et al. 2021

Preprint

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BackgroundAbout every fourth patient with major depressive disorder (MDD) shows evidence of systemic inflammation. Previous studies have shown inflammation-depression associations of multiple serum inflammatory markers and multiple specific depressive symptoms. It remains unclear, however, if these associations extend to genetic/lifetime predisposition to higher inflammatory marker levels and what role metabolic factors such as Body Mass Index (BMI) play. It is also unclear whether inflammation-symptom associations reflect direct or indirect associations, which can be disentangled using network analysis.MethodsThis study examined associations of polygenic risk scores (PRSs) for immuno-metabolic markers (C-reactive protein [CRP], interleukin [IL]-6, IL-10, tumour necrosis factor [TNF]-α, BMI) with seven depressive symptoms in one general population sample, the UK Biobank study (n=110,010), and two patient samples, the Munich Antidepressant Response Signature (MARS, n=1,058) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D, n=1,143) studies. Network analysis was applied jointly for these samples using fused graphical least absolute shrinkage and selection operator (FGL) estimation as primary analysis and, individually, using unregularized model search estimation. Stability of results was assessed using bootstrapping and three quality criteria were defined to appraise consistency of results across estimation methods, network bootstrapping, and samples.ResultsNetwork analysis results displayed to-be-expected PRS-PRS and symptom-symptom associations (termed edges), respectively, that were mostly positive. Using FGL estimation, results further suggested 28, 29, and six PRS-symptom edges in MARS, STAR*D, and UK Biobank samples, respectively. Unregularized model search estimation suggested three PRS-symptom edges in the UK Biobank sample. Applying our quality criteria to these associations indicated that only the association of higher CRP PRS with greater changes in appetite fulfilled all three criteria. Four additional associations fulfilled at least two quality criteria; specifically, higher CRP PRS was associated with greater fatigue and reduced anhedonia, higher TNF-α PRS was associated with greater fatigue, and higher BMI PRS with greater changes in appetite and anhedonia. Associations of the BMI PRS with anhedonia, however, showed an inconsistent valence across estimation methods.ConclusionsOur findings align with previous studies suggesting that systemic inflammatory markers are primarily associated with somatic/neurovegetative symptoms of depression such as changes in appetite and fatigue. We extend these findings by providing evidence that associations are direct (using network analysis) and extend to genetic predisposition to immuno-metabolic markers (using PRSs). Our findings can inform selection of patients with inflammation-related symptoms into clinical trials of immune-modulating drugs for MDD.

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Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial

Cited by 129 publications

References 37 publications

Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial

Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial

Comparative Efficacy and Acceptability of Anti-inflammatory Agents on Major Depressive Disorder: A Network Meta-Analysis

Polygenic risk for immuno-metabolic markers and specific depressive symptoms: A multi-sample network analysis study

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