Valeria Mondelli, MD, PhD, on Minocycline May Improve Depressive Symptoms in Patients With Low Level Inflammation

In this video, Valeria Mondelli, MD, PhD, King’s College London, United Kingdom, discusses her research which found that in patients with treatment-resistant depression and low-grade peripheral inflammation, minocycline, a widely used antibiotic, improved depressive symptoms.

TRANSCRIPT:

Hi, I'm Valeria Mondelli. I'm a Clinical Reader in Psychoneuroimmunology, and Liaison Consultant Psychiatry at King's College London in the United Kingdom. I'm here to talk to you a little bit today about our new study, which has been recently published in Neuropsychopharmacology.

This is about some findings that we had before from a clinical trial, where we tried the augmentation therapy of the antidepressant with an antibiotic which is minocycline, in patients with treatment‑resistant depression.

We decided to look in particular at an anti‑inflammatory treatment as an augmentation for antidepressants. Over the past few decades, we understood that increased inflammation may have a role in the development of depression.

What we also show is that patients who are not responding to antidepressant treatment, seem to have these higher increased levels of peripheral inflammatory markers. Really, all this evidence was in a way supporting the fact that maybe we will need to try some anti‑inflammatory treatment in patients with depression.

What we did is actually to do this double‑blind placebo‑controlled randomized clinical trial in patients with treatment‑resistant depression. What is different in our trial is that the patients have been selected on the basis of inflammation.

This is really the novelty, compared to previous clinical trials. We are using basically a biomarker which is a very simple blood sample. An example, the C‑reactive protein levels, which you all know is very widely used inflammatory markers, and we selected the patients to target on the basis of the level of CRP.

We chose minocycline for a number of reasons. Minocycline is a tetracycline antibiotic and is used to treat bacterial infections. What has also minocycline that is quite important in particular, for depression, it has a quite large wide action as an anti‑inflammatory and anti‑oxidative effect.

What we know is also that it decreases the activation of microglia, which are the main brain immune cells. This activation of the microglia is also the one that has been connected with more severe depressive symptoms, and suicidal ideation. Having a medication like minocycline which can target the microglia, might have been particularly relevant.

Also, what we know is that it doesn't have much side effects compared to other anti‑inflammatory medication. Also, you can cross the blood brain barrier, which is important when we are trying really to target the inflammation in the brain.

As I mentioned, what we did is a double‑blind placebo‑controlled randomized trial, and we excluded patients who had particular acuity infection or inflammatory condition at the time in which we recruited them. We selected patients on the basis of the levels of CRP, as I was saying at the beginning, to try really to target those patients who may be more likely to respond to an anti‑inflammatory treatment.

We chose the levels of CRP as 1 mg/L because that was what we saw from the literature, as 60% of patients with depression having increased inflammation being reported with a CRP around that level. What we did was to randomize to a 4 week treatment with either minocycline or placebo in our study.

They were taking minocycline or placebo in addition, so as an augmentation on top of their current antidepressant treatment. The dose of minocycline that we used was 200 milligrams a day, and the treatment as I was saying, it was for 4 weeks. After 4 weeks we assessed again the symptoms.

We try to look if in a way there was an improvement or deterioration in symptoms with the minocycline or placebo. What we did also is to do a secondary analysis, to look also at particularly another threshold of CRP, so looking at patients with a CRP higher or lower than 3 mg/L.

This was because a higher threshold of CRP in particular, the threshold of 3, is the one that has been also seen to be associated with more treatment resistance. We wanted to understand if a different threshold might have more importance in terms of our results.

What we found with our clinical trial is that the difference in changes of symptoms between the placebo arm and the minocycline arm was not particularly significant. In the overall sample, we didn't really identify beneficial effects of the minocycline.

What was very interesting is that when we consider the threshold of CRP of 3, we then saw that patients with C‑reactive protein higher than 3 had a significantly better response to the minocycline than placebo.

The patients who had high inflammations with the CRP higher than 3 were the ones that were improving more when taking the minocycline, not only compared with the placebo but also compared with those who are taking minocycline but had CRP lower than 3.

This was very interesting. We did also some analysis to try to understand what would be the best threshold for treating patients with the minocycline. Indeed, from our analysis, it seems like 2.8, which is basically like 3 mg/L was the right threshold for identifying the patients who were having the best response from the other minocycline treatment.

Although the sample of course on the secondary analysis is smaller, this is very interesting. In a way, it gives us a little bit of a hope that we could actually use some very easy biomarkers such as like the inflammatory markers, so CRP, to try to understand how we can better treat some of our patients who are currently not responding to the antidepressant treatment.

Of course, we will need probably as a next step, do a larger trial, this time focusing only maybe on patients with a CRP higher than 3 to confirm the results in a larger study before we can probably move into clinical practice. I think this is a really good example of how we could do more tailored and individualized treatment also in psychiatry by using biomarkers.

I hope you enjoyed. The paper is published open access, so everybody can read it. Thank you very much for your attention.

Reference

Nettis MA, Lombardo G, Hastings C. et al. Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomized clinical trial. Neuropsychopharmacology. 2021 January 28.


Dr. Valeria Mondelli is a Clinical Reader in Psychoneuroimmunology at the Institute of Psychiatry Psychology and Neuroscience, King’s College London and Honorary Consultant Psychiatrist at King’s College Hospital. Dr Mondelli's research interest focuses on the interplay between physical and mental health and on the role of biological systems involved in the stress response in the pathogenesis of psychiatric disorders. Among her most important research achievements are describing the abnormal biological response to stress at the onset of psychosis, identifying the biological response to stress as one of the factors contributing to brain abnormalities and worse clinical outcome at psychosis onset, and showing the potential of inflammatory biomarkers for developing individualized treatments using anti-inflammatory medications in patients with depression. More recently, she has been leading a new project looking at the link between obesity and depression in patients undergoing bariatric surgery. She has recently been awarded funding to lead a new global mental health consortium aiming to identify predictors of depression early in adolescence (the IDEA project).

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