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.

Neuroinflammatory Basis of Depression: Learning From Experimental Models

“…Recent literature highlights the crucial role of brain immune cells in depression pathology and any modality that can modulate the activity of these cells or reduce neuroinflammation, thereby bearing the potential to treat depressive symptoms. Supporting this notion, beneficial effects of anti-inflammatory drugs have been observed in MDD patients (Muller et al, 2006;Abbasi et al, 2012;Kobayashi et al, 2013;Majd et al, 2015;Cao et al, 2020;Nettis et al, 2021). Clinical trials using non-steroidal anti-inflammatory drugs in depressed patients have reported promising results, with increased remission rates in patients when used in combination with conventional antidepressant drugs (Abbasi et al, 2012;Cao et al, 2020).…”

“…Yet, these models have provided useful insights into the neuroinflammatory mechanism of depression. Given that the role of neuroinflammation in human depression is yet not clear, the results of in vivo depression studies appear to be missing pieces of the puzzle of depression pathology (Nettis et al, 2021).…”

“…Clinical trials using non-steroidal anti-inflammatory drugs in depressed patients have reported promising results, with increased remission rates in patients when used in combination with conventional antidepressant drugs (Abbasi et al, 2012;Cao et al, 2020). A tetracycline antibiotic, minocycline, an inhibitor of microglial inflammatory activation, has also shown promising antidepressant activity in treatmentresistant depression patients (Kobayashi et al, 2013;Nettis et al, 2021). The antidepressant effects of minocycline were independent of changes in peripheral inflammatory biomarkers, reflecting the possible decrease in central inflammation (Nettis et al, 2021).…”

“…A tetracycline antibiotic, minocycline, an inhibitor of microglial inflammatory activation, has also shown promising antidepressant activity in treatmentresistant depression patients (Kobayashi et al, 2013;Nettis et al, 2021). The antidepressant effects of minocycline were independent of changes in peripheral inflammatory biomarkers, reflecting the possible decrease in central inflammation (Nettis et al, 2021).…”

Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

“…Yet, in the same diseases or disease models, more targeted treatments focused on discrete or downstream inflammatory processes and effector cells have shown more promise. For example, in a double-blind randomized clinical trial with treatment resistant depression patients, found augmentation of minocycline (a tetracycline antibacterial) to anti-depressants improved behavioral symptoms in patients with low grade inflammation [ 31 ]. A meta-analysis also found minocycline to have significant anti-depressant activity and several clinical trials aimed to improve depression outcomes and improve treatment response scores in mood disorders with minocycline are currently underway [ 32 , 33 ].…”