Understanding the role of peripheral and central inflammation in the development and treatment of Major Depressive Disorder

Student thesis: Doctoral ThesisDoctor of Philosophy


There is a well-established link between increased peripheral inflammation and the pathogenesis of Major Depressive Disorder (MDD). However, how inflammation contributes to the development of MDD is still partly unclear. Several pathways of communication between the peripheral and the central immune system have been described so far, suggesting this as the mechanism leading to the development of brain inflammation and of symptoms of depression. However, further evidence is required to understand the biological mechanisms underpinning the immune pathways to the brain. Moreover, since evidence has emerged on the role of the immune system in MDD, there has been a growing interest in testing the anti-depressant properties of anti-inflammatories, particularly in patients not responding to standard antidepressants. However, the precision of such interventions could be further tuned by identifying patient populations with increased peripheral inflammation.

To this regard, my thesis illustrates data from 2 studies; the first study aimed to investigate the mechanism of the communication between peripheral and central inflammation (FLAME); the second one investigate the role played by peripheral inflammation in the response to anti- inflammatory treatment in MDD (MINDEP).

In the FLAME study, after injecting 7 healthy males with the immune challenge Interferon-alpha (IFN-α), I used the TSPO binding, Positron Emission Tomography (PET) tracer [11C]PR28 to examine microglial cells activation, the core process of brain inflammation, 24 hours after the challenge. I then investigated the association between microglial activation, levels of peripheral inflammatory biomarkers and temporary mood changes. Finally, I explored brain inflammation with Magnetic Resonance Imaging (MRI), which provides indirect measures of central inflammatory processes but is less invasive and less expensive than PET.

In the MINDEP randomized clinical trial, I tested augmentation therapy with the antibiotic minocycline in patients with Treatment Resistant Depression (TRD) selected for elevated peripheral inflammation (C-reactive protein (CRP) levels ≥1 mg/L).

Results from the FLAME project showed that IFN-α increased serum levels of peripheral biomarkers and induced temporary mood changes and sickness symptoms. On the other side, brain TSPO-PET signal was highly dependent of inflammation-induced changes in ligand binding to plasma proteins and this limited data interpretation. However, I found changes in MRI Relaxometry measures at 24 hours after IFN-α, in terms of increased T1 and Proton Density (PD). Such measures correlated with changes in peripheral inflammatory markers.

Results from the MINDEP study showed no difference between minocycline and placebo in reducing the Hamilton Depression Rating Scale after 4 weeks. Secondary analyses showed some evidence of efficacy of add-on treatment with minocycline in TRD patients, but only in those with CRP ³3 mg/L (low-grade inflammation). The only peripheral inflammatory marker which decreased alongside the improvement in depressive symptoms was interferon-gamma (IFN-γ).

My PhD results show that IFN-α is a good model of immune related depression, but, due to PET imaging methodological limitations, I could not show whether it is able to induce brain inflammation. MRI results suggest brain changes possibly reflecting increased central inflammation, but studies in larger samples are needed to confirm these data. My PhD also provided preliminary evidence of a subpopulation of TRD patients (those with CRP≥3 mg/L) who could benefit from minocycline, which has unique neuroprotective abilities and could target not only peripheral, but also central inflammation.
Date of Award1 Aug 2022
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorValeria Mondelli (Supervisor), Mattia Veronese (Supervisor) & Carmine Pariante (Supervisor)

Cite this