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Sex-specific immune profiles in adolescent depression

A few years ago, a group of scientists from different parts of the world met and discovered that they shared the same aspiration- they wanted to understand what made some adolescents more likely to develop depression than others, and whether it was possible to identify those at risk and help them before they became depressed. They also agreed that it was important to understand this in the context of low-and-middle-income countries (LMICs) because 90% of the adolescent population worldwide lives in LMICs, which is a lot! In fact, the term 'vast majority' would be an understatement. And yet, most research comes from high-income countries (HICs).

With that in mind, the IDEA project was born. It stands for Identifying Depression Early in Adolescence and I was lucky to be part of it from the beginning.

I am a postdoctoral researcher at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London and I have spent the past decade trying to understand the biological and environmental risk factors of depression across different populations.

With the support from the MQ Mental Health Research, the IDEA project started in 2018 and it involved five countries: Brazil, the USA, the UK, Nepal, and Nigeria. It had (and still has) several sub-projects investigating the topic from different angles, but for the purpose of this blog, I will talk about the aspects of the project I was directly involved in. These included systematic reviews and meta-analysis – reviewing and analysing the existing scientific literature on the topic - as well as my research investigating how biological markers, specifically increased inflammation, were associated with the risk and presence of depression in a newly recruited group of adolescent participants in Brazil.

What we know so far

From the studies in adults, we know that chronically higher levels of the stress hormone, cortisol, and chronic low-grade inflammation, are linked with depression. We also know that prolonged and severe experience of childhood trauma increases the likelihood of developing depression later in life. However, studies in adolescents are less common. Considering that 1 in 4 adolescents worldwide experience depression, we thought it was a good idea to get a better understanding of the risk factors for depression in that period of life.

So, we looked at all the studies published worldwide so far on the topic (systematic review), and we focused on how early life experience interacts with biological changes leading to depression. First of all, we found that there were very few studies from LMICs, which confirmed that there was a need for more research in these settings. We also found that increased inflammation in the body and some changes in brain function, like lower activity in response to reward and changes in the limbic system (the region responsible for emotional activation) were associated with depression in adolescents, but mainly in the context of early life stress. We published our results in the Journal of Psychiatric Research, and in a blog as part of Inspire the Mind (ITM).

As the majority of the studies looking at biological changes in depression included cortisol, we had enough studies to look at these results in more detail and do a meta-analysis. Our results showed that adolescents who developed depression had higher levels of morning cortisol prior to becoming ill, compared to those who did not go on to develop depression. Interestingly, we did not see differences in cortisol levels between adolescents who were already depressed and those who were not, suggesting that higher cortisol might be more of a marker of future rather than current depression. We published our results in Psychoneuroendocrinology, and as a blog on ITM.

The results from the systematic review and the meta-analysis gave us an idea and an overview of what was out there and informed us where to go next.

Sex-specific inflammatory makers of depression – results from our study

As Aristotle once said: “The whole is greater than the sum of its parts”, perfectly describing one of the main concepts behind the IDEA project, which was not only to look at risk factors for depression but to look at them together. We know from other fields in medicine that it is only when we combine multiple factors together that we can increase the accuracy for identifying individuals at risk, and in our case adolescents at higher risk of depression.

And so, as part of the IDEA project, we developed a composite risk score based on 11 different sociodemographic factors, including early life stress, child abuse and neglect, difficult relationship with parents, and drug use, to name a few.

Using this composite risk score, we recruited adolescents in Brazil to take part in our study. The idea was to look at whether inflammation in the body, measured by proteins present in the blood called cytokines, was associated with the risk and presence of depression. We ended up with 150 adolescents in total, 50 were at low risk for depression, 50 were at high risk for depression, and 50 were currently depressed.

We found that cytokines associated with depression in adolescence were sex-specific. Boys at low risk for depression had lower levels of a cytokine called interleukin (IL)-2 compared with those who were currently depressed. Instead, girls who had more severe depressive symptoms had higher levels of IL-6, but not IL-2. We published our results in the Journal of Affective Disorders.

So, what do these recent results tell us?

IL-2 and IL-6 are both produced when there is inflammation, although, they also differ in what they do. IL-2 is mainly responsible for activating cells that fight pathogens, like viruses or cancer cells, in other words boosting immune activity, and it has been used commonly in immunotherapy to treat conditions like cancer. IL-6 on the other hand has a wider range of functions and is produced by a variety of cells. It regulates immune response including acute infections, and when excessive, it is associated with inflammatory conditions including autoimmune disorders.

So, how does it tie in with our results? The short answer is we don’t know yet. However, we now do know that it is important to take into consideration sex differences when looking at the biological mechanisms underlying depression development, in order to find the best tailored prevention and treatment plans and achieve equity in treating individuals with this condition. And of course, we must also remember that so far these findings are only for adolescents in Brazil.

But what about the main question – can we predict and prevent depression development based on inflammatory markers? We just finished analysing the data to answer this question and will be publishing it soon, so stay tuned because there is more to come!

Editor’s Note

The research discussed in the blog can be found in a journal article published by the Journal of Affective Disorders. This blog can also be found co-published in the MQ Mental Health Research.


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