The biology of Depression, and being on the path to discovery
I am a scientist and I work with a team of researchers who spend their careers trying to understand what depression is, and especially the role of the immune system.
That may sound odd, as almost everyone knows what depression is. But what is it on a biological level?
Although we have overcome the historic opinions that this is ‘all in the mind’, and we now have a lot of evidence to suggest the immune system may be involved, no one really understands what causes depression in a mechanistic sense and, crucially, where it originates.
It is also increasingly apparent that a ‘one size fits all’ approach is not appropriate, and that one person’s experience of depression can be markedly different from the next person’s. This suggests a layer of subtleties we have thus far been unable to pinpoint. Without advancing our knowledge and understanding at a molecular level, we cannot successfully stratify patients appropriately and we will not know what therapies we need to develop to truly help people.
Depression affects everyone. It may not be directly, and we may not even know it, but statistically speaking, we will all likely know someone who has or has had depression.
This is particularly topical since over the past 18 months, during the pandemic, the prevalence of depression has increased on an almost exponential level, with the Office for National Statistics reporting that around 1 in 5 people experienced depression in early 2021. Strikingly, this is more than double the pre-pandemic rate.
Despite its prevalence, very little therapeutic progress has been made over the past thirty years since the introduction of selective serotonin re-uptake inhibitors (SSRI's, the most common class of antidepressant) and current treatments do not work for everyone. This makes it even more important to understand the nuances of the disease and to aim for a more personalised medicine approach to treatment.
Regardless, the impact of depression on society is huge. Not just in terms of the effect it has on an individual’s quality of life, but also their associated medical costs, loss of earnings and the impact of suicide. This is a global problem and is one of the leading causes of disability worldwide.
We have been fortunate to be involved in the ‘Neuroimmunology of Mood and Alzheimer’s Disease’ (NIMA) Consortium, a programme of work that has been funded by the Wellcome Trust over a five-year period (now longer thanks to the disruption of COVID-19!). As indicated by the name, this consortium comprises of two research arms (and a long list of incredible scientists), covering both Alzheimer’s disease and mood, and we are involved with the latter.
As well as some pre-clinical ‘bench’ studies, this work package included a clinical study that recruited patients with a spectrum of depression; those who were diagnosed with depression but currently untreated, those who had been treated successfully and were therefore no longer depressed, those who were receiving treatment but were still depressed (we refer to this group as treatment-resistant) and healthy controls who did not have a history of depression. The aim of this particular study was to analyse the immune system of these patients and try to identify if and how they differ in terms of their inflammatory signals. If there was a signal, what cells could it be coming from and how does it relate to a patients’ disease outcome?
A robust immunophenotyping study (a fancy word that basically means mapping out immune system patterns) often uses a range of techniques to obtain measures of different cell types, different molecules, different biological processes etc., so that researchers get a big picture overview of what is a very complex system. This was done by the NIMA Consortium at great effort and expense, but I will focus on the study our group performed using RNA sequencing (RNAseq) that was recently published in Translational Psychiatry. There are more publication on blood immune measure collected in these patients, such as on c-reactive protein, immune genes, and immune cells.
We used RNAseq to measure gene expression in peripheral blood mononuclear cells (PBMCs, an important group of white blood cells found in the circulation) isolated from the study participants. We had four major findings.
First, there was no evidence of significantly different expression of individual genes or groups of genes across the different patient populations.
Second, when assessing gene expression in an enriched immune cell population (like we did), it is likely that false positive results will preferentially be immune genes by default (this is an important point to be aware of when analysing similar datasets to avoid unintended bias).
Third, we did find evidence of biological ageing in the depressed population, albeit subtle.
And fourth, this study highlighted that the contribution of weight and body mass index (BMI) to inflammation in depression is complex.
As with most scientific research, this study has raised as many questions as it has answered. Our interpretation of the data is such that PBMCs are unlikely to be the source of any inflammatory signal in this patient group. Of course, we have to start somewhere, but there are many other cell types that we are yet to explore, for example, neutrophils (another white blood cell type), endothelial cells (that line blood vessels), and adipocytes (cells in the adipose tissue).
Indeed, there are many studies linking inflammation with obesity, and adipocytes are thought to be an important source of pro-inflammatory molecules, however studies like ours often consider the effects of BMI as a confounding factor (something that could distort the variables you are actually interested in).
In doing so, however, we may be losing a really crucial part of the biological story since people with depression tend to have a higher BMI than the general population, but we are yet to confirm if this is a causal or consequential relationship.
This study also warrants further investigation into the importance of immune ageing as our findings echo other studies that have linked severe depression, and possibly chronic stress, with increased cell ageing. The precise consequence of increased immune age is opaque, but it is thought to be a bad thing since aged cells are less efficient and are more likely to be ‘abnormal’.
I think the most important take home message from this study is that it emphasises how complex this field of research really is and highlights the importance of continued efforts to address the many unanswered questions.
I feel optimistic that every study takes us that little bit closer to the truth and we are all eternally grateful to the patients who volunteer to be a part of our research.
