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

Abstract

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.

Fig. 1. Difference in HAM-D-17 mean change, calculated as baseline scores minus week 4 scores, between patients divided by Study Arm X baseline hsCRP.

Patients with hsCRP levels ≥ 3 mg/L and taking minocycline (CRP⁺/M) showed a significantly larger improvement compared with all other patients. HAM-D-17 = Hamilton Depression Rating Scale. CRP⁺ = baseline hsCRP levels ≥ 3 mg/L. CRP⁻ = baseline hsCRP levels <3 mg/L. M = Minocycline, P = Placebo.