Studies over the past 20 years have demonstrated that increased inflammation and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis are 2 of the most consistent biological findings in major depression disorder (MDD) and are often associated, but the molecular and clinical mechanisms underlying these abnormalities are still unclear.¹ At the recent EPA 2023: 31^st European Congress of Psychiatry, Professor Carmine Maria Pariante from the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, the United Kingdom (UK), introduced the recent progress of his team on the clinical and molecular evidence underlying the increased inflammation in depression carried out at the King's College.¹ 

In the study evaluating C-reactive protein (CRP) in the UK Biobank sample of MDD patients, the CRP levels >3mg/L, an indication of low-grade inflammation, were found to be more prevalent in MDD patients than in the control subjects (21.2% vs. 16.8%).¹ Although the CRP levels were associated with age, gender, body mass index (BMI), smoking status, and poor health, depression remained strongly positively associated with log CRP level in model 1 that regressed out age and gender (beta=0.144; 95% CI: 0.129-0.158; p=5.84 × 10^-80), and this association remained significant in model 2 that additionally regressed out BMI and smoking (beta=0.036; 95% CI: 0.023-0.05; p=1.02 × 10^-7).¹ In another study, although BMI-corrected CRP was found to significantly elevate in all patients with MDD compared with the controls, the post-hoc t-tests indicated that only the treatment-resistant patients had significantly higher mean BMI-corrected peripheral CRP than the controls, implying that MDD patients stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that may respond to second-line treatment with anti-inflammatory drugs.¹ 

In the BIODEP study, by using whole-blood messenger ribonucleic acid (mRNA) quantitative polymerase chain reaction (qPCR), it was found that mRNAs of inflammation biomarkers, including interleukin (IL)-1-beta, IL-6, tumor necrosis factor (TNF)-alpha, alpha-2-macroglobulin (A2M), macrophage migration inhibitory factor (MIF) and tacrolimus (FK506)-binding proteins (FKBPs) were upregulated in MDD cases compared with the controls.¹ More interestingly, there was no difference in these gene expressions between CRP groups within the depressed patients.¹ Prof. Pariante then concluded that HPA axis hyperactivity and inflammation might be part of the same pathophysiological process, which hyperactivity of the HPA axis indicated glucocorticoid resistance caused by insufficient effectiveness of glucocorticoid hormones on their target tissues.¹ This resistance could lead to immune activation.¹ Similarly, inflammation could also stimulate the HPA axis via direct cytokine effects on the brain and the induction of glucocorticoid resistance.¹ 

This molecular evidence has led to growing interest in exploring the antidepressant properties of anti-inflammatory agents.¹ Minocycline is a tetracycline antibiotic with broad anti-inflammatory properties and, critically, good penetration into the central nervous system (CNS) via the blood-brain barrier (BBB), which accounts for its neuroprotective capacity.¹ Prof. Pariante then presented their findings from MINDEP, a 4-week, placebo-controlled, double-blind, randomized clinical trial that aimed to examine the role of baseline levels of peripheral inflammation in the efficacy of minocycline in MDD patients who were resistant to antidepressant treatment.¹ Stratification analysis revealed a significant difference among 4 groups of patients [i.e., CRP ≥3mg/L + minocycline (CRP⁺/M), CRP <3mg/L + minocycline (CRP⁻/M), CRP ≥3mg/L + placebo (CRP⁺/P), CRP <3mg/L + placebo (CRP^-/P)].¹ Regarding the primary endpoint of the Hamilton Depression Rating Scale (HAM-D-17) score change, CRP⁺/M patients had the greatest changes from baseline to week 4 when compared with CRP^-/M (p<0.001; Cohen d=1.9), CRP⁺/P (p=0.002; Cohen d=1.5) and CRP^-/P (p<0.001; Cohen d=1.9).¹ These findings suggested that minocycline might be only effective in MDD patients with low-grade inflammation (i.e., CRP ≥3mg/L).¹ 

In an additional secondary analysis of MINDEP, investigators found the differential effects of minocycline on HAM-D-17 scale changes in females and males, taking the CRP and IL-6 levels into account.¹ Model 1 analysis showed an effect at the statistical trend for the study arms (placebo vs. minocycline) on Δ-HAMD-17 in the overall samples (F=3.10; p=0.087).¹ Model 2 analysis showed a significant effect of the study arms (F=12.17; p=0.001), and of their interaction with the CRP groups (F=9.18; p=0.005).¹ Additionally, they found an interaction, at the statistical-trend level, between the sex and CRP groups (F=3.80; p=0.060) on Δ-HAMD-17, suggesting that the effects of the response to minocycline on the CRP groups were different in males and females.¹ Interestingly, CRP was found to be strongly correlated with IL-6 in females (p=0.658) but not in males (p=0.007).¹ 

In conclusion, although replications in larger samples are needed, Prof. Pariante believed that the MINDEP study result is biologically and clinically consistent, with a potentially important clinical impact by moving a step towards the identification of personalized treatments for MDD patients.¹