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Minocycline for people with depression AND inflammation:

Let’s talk about the MINDEP study, my PhD journey and life after it.


As a clinical scientist, it’s sometimes difficult to understand whether your ideas and research are good enough to have a future. You might present your project to your peers, or a much-feared funding panel, and, if unlucky, hear back three heart-sinking words: “And so what?”


I have learned that a good question to ask yourself — to better understand whether you are going in the right direction — is: how is my work helping others?


And if you are a medical doctor, like me, the ‘others’ I refer to are often people suffering from a debilitating disease.


Depression is a very debilitating disease, and this is why people affected by it were the focus of one of my PhD projects, the recently published MINDEP study.


MINDEP (MINocycline in DEPression) aims to improve the quality of care for people with Major Depressive Disorder. The results are the first step in the right direction, and I really hope they can be helpful for patients.


In this blog, as promised in my previous one where I wrote about how inflammation can affect our mood and behaviour, I will describe this study and its findings, and I will do it through the lens of my recently concluded PhD journey.


Let’s take a step back to understand exactly who I am trying to help with MINDEP, together with the members of my research group.


I want to tell the story of a particular person suffering from depression: Colin (not their real name), the person who is waving at you in the picture.


The story of Colin


Colin is part of a group of three close friends. Unfortunately, there was a time when they all suffered from depressive symptoms. Colin, in particular, had a very low mood, no energy, nor appetite … some days he didn’t even want to get out of bed to go to work. His family was getting increasingly worried, so, during one of his sleepless nights, he decided to ask for help from the Doctor, and his two friends did the same.


Colin and his friends were diagnosed with Major Depressive Disorder. The Doctor prescribed them an antidepressant that can have several effects, but the main one is to increase the levels of serotonin.


This is a chemical messenger in our body, which helps with sleep, eating and mood regulation, but its function might be low in people with Major Depressive Disorder.


After a while, both Colin’s friends felt much better and they went out to the park to celebrate together in the sunshine. However, Colin was quite disappointed, because the treatment did not work for him: he felt exactly the same as before.


And that’s where the MINDEP study comes in!

The MINDEP study


Approximately 1 out of 3 people with Major Depressive Disorder (MDD) do not benefit from standard antidepressant therapy.


You all might have a friend, a relative like Colin, who, despite therapy with antidepressants, don’t seem to get any better. Or you might be Colin.


MINDEP focused on those people who don’t respond to antidepressants and whose depression probably is not only related to a deficit of serotonin.


Some of these people have shown to have an alteration in their Immune System.


We have already encountered the Immune System in my previous blog, where I used the picture below to describe it as an army of soldiers defending the body from stress or infections, through a process called inflammation.


The most interesting part is that inflammation, reflecting the activity of the Immune System, can be assessed with a simple blood test, measuring the levels of a protein called C-reactive protein (CRP), which is directly associated with inflammation. If CRP is high, inflammation in the body is high, and vice versa.

The blood tests of some patients, like Colin, show that their CRP levels tend to be elevated compared to the general population and research has shown that this is correlated with the severity of their depression.

So, if increased inflammation in some people can contribute to depression, reducing inflammation might improve it! This is one of the novel approaches that researchers, including my research group, are adopting in recent times to help patients who do not benefit from antidepressants alone.

When the MINDEP study started, at the end of 2016, I was a Visiting Researcher at the Institute of Psychiatry (King’s College, London) and had only recently moved to the UK from Italy. Having joined the Stress Psychiatry and Immunology Lab (the team who bring you InSPIre the Mind), I started to wonder whether in the long term I would make a good researcher.

In the end, I decided to seize this opportunity to find out. A few months later, I started a PhD with MINDEP as one of my projects.

MINDEP is a Clinical Trial designed for a particular group of people with Major Depressive Disorder, not benefitting from antidepressants and with high levels of inflammation. Participants who took part in the study carried on taking their prescribed antidepressants and we then added a drug called minocycline, an antibiotic, regularly used to treat acne vulgaris and inflammatory diseases, with the ability to decrease levels of inflammation in the body.

To be sure that we were including patients who could actually benefit from this intervention, we specifically looked for participants like Colin: unresponsive to antidepressants and with elevated inflammation (CRP equal or above 1 mg/L) when entering the study.

It wasn’t easy to identify eligible participants and to engage them, and it took longer than we thought, but we did it. Eventually.

By the end of 2019, 39 patients suffering from MDD and who did not respond to at least one trial with antidepressant took part in MINDEP.

Following a process called Randomization, these 39 participants were randomly assigned minocycline or placebo for 4 weeks. In particular, 18 took minocycline for 4 weeks alongside their antidepressant, while 21 took placebo, a pill which looked like the minocycline one, but did not contain any active treatment (see the picture below).


Picture: 1) Screening visit: to check that the study was suitable and safe for participants. 2) Baseline visit: the beginning of treatment with minocycline or placebo. 3) Week 4 visit: end of treatment

My results


I have a vivid memory of the period when the analysis of MINDEP data started: It was the beginning of 2020, when Covid-19 suddenly appeared, overwhelming all aspects of everybody’s life. I remember spending my lock-down months at home, looking at the data, trying to work and not think about anything else.


What I found sounded interesting. At first, I found that minocycline was not more effective than placebo in improving depressive symptoms in our participants selected for CRP above or equal to 1 mg/L.


However, I explored whether using another — slightly higher — threshold for inflammation, CRP = 3 mg/L, gave different results. This threshold (CRP above 3 mg/L) identifies people with a higher risk of cardiovascular disorders, and, interestingly, it has also been associated with having “treatment-resistant” depression.


Among our 39 patients, 6 patients had CRP above or equal to 3 mg/L at the Baseline visit and were taking minocycline for the following 4 weeks. They showed a larger improvement in their depressive symptoms by the Week 4 visit when compared to all the other participants (those on minocycline with Baseline CRP below 3 mg/L and those on Placebo (as described in the picture below).


MINDEP: Improvement of depressive symptoms according to treatment and inflammation at Baseline visit Picture: The Hamilton Depression Rating Scale (HAM-D) measures depression severity. The figure shows results on the HAM-D change, that is how much the HAM-D score changed from the Baseline visit to the Week 4 visit. The larger the HAM-D change, the more effective the treatment. I found that patients in the group CRP+/M (CRP ≥ 3 mg/L and taking minocycline) had the larger HAM-D change when compared to the other groups: CRP-/M (CRP < 3 mg/L taking minocycline), CRP+/P (CRP ≥ 3 mg/L taking placebo) and CRP-/P (CRP < 3 mg/L taking placebo).

Another important aspect to add is that minocycline was not associated with significantly more side effects than placebo, so it resulted to be an overall safe intervention.


As mentioned above, these results were recently published in the scientific journal Neuropsychopharmacology, where you can find details about other clinical questionnaires that we used to assess depressive symptoms and other indicators of inflammation that we measured, in addition to CRP.


From a scientific point of view, the results from MINDEP indicate that we might have identified the threshold levels of inflammation (CRP~=3 mg/L) that patients like Colin should have in order to benefit from minocycline. If known at the stage of the diagnosis, this information could help identify early those patients with Major Depressive Disorder who could respond to anti-inflammatory treatments like minocycline.


Of course, we should interpret the data with caution. The number of patients who took part in our study, 39, is not a large number. Therefore, although positive, these results will need to be confirmed by future, larger studies. This is the intention of my research group!


 

By the time results from MINDEP were published, I had submitted my PhD thesis (and I also received my first dose of Covid-19 vaccine, as I have face-to-face clinical contacts). My PhD final exam was a constructive and stimulating discussion on my research work, its impact and its future implications.


I think the MINDEP study is important to me because it coincided with my personal trajectory into research. It was very exciting, painful at times, but I think this project and I grew up together.


I have now resumed working as a clinical psychiatrist, but I have not abandoned research, which is still a big part of my daily life. Indeed, being in contact with patients reminds me very clearly what the final aim of my work as a researcher should be.


With regards to MINDEP, if these findings are confirmed, they might contribute to help that 1 patient out of 3 who, like Colin, feels left behind in the battle against depression. I really hope this idea, and the research behind it, will have a future.



 


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