Depression is a significant contributor to both disability and premature mortality worldwide. As a heterogeneous condition, it is crucial to understand the biological pathways involved in advancing precision psychiatry (a new approach in mental health care that moves away from the one-size-fits-all method). Biological sex plays a substantial role in the heterogeneity of depression, as it affects males and females differently. While females are more frequently diagnosed with depression, males are at a significantly higher risk of suicide. Interestingly, despite experiencing similar symptoms, males are often underdiagnosed, which can delay timely intervention leading to tragic consequences. Understanding the unique symptoms in males and females, as well as their biological differences, is key to developing more effective and tailored treatments.

Two systems in our body are particularly important in the context of depression: the immune system and the system that produces sex hormones.

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The immune system defends our body against infections and other threats. However, in some individuals with depression, this system can show some dysfunctions, leading to a state of chronic inflammation (inflammation is a sign of immune system activity), even when there is no infection present. This increased inflammation is a marker of immune system activity and has been linked to the onset and persistence of depressive symptoms. Researchers believe that this inflammatory state may disrupt mood regulation and contribute to specific symptoms, such as fatigue, often seen in depression.

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Sex hormones, such as testosterone and estrogen, have far-reaching effects beyond their primary roles in regulating the reproductive system. These hormones influence brain development, memory, and mood regulation, and their levels fluctuate across the lifespan and differ between males and females. Importantly, sex hormones also interact with the immune system and can modulate inflammation. The balance of these hormones is critical, as shifts in hormone levels—whether due to ageing, menstrual cycles, or other factors—can influence both the immune response and mood. 

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This project builds upon the findings of my PhD research, which was funded by the Psychiatry Research Trust, and explores further sex differences in depression, specifically examining the roles of the immune system, sex hormones, and their interactions within this context.

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The first part of my project involves working with the Department of Psychiatry at Amsterdam UMC, with Dr Yuri Milaneschi and Professor Brenda Penninx, I will spend some time analysing data from the Netherlands Study of Depression and Anxiety. This large study has been following thousands of people with depression (and anxiety) over more than a decade and offers measures on both the immune system and sex hormones, as well as scales investigating relevant depressive symptoms such as suicide risk. 

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In the second part, I will hold focus group discussions with individuals who have experienced depression. Including people with lived experience (PWLE) in research is crucial, not only for enhancing our understanding of specific medical or psychiatric conditions but also for improving the way these conditions are studied. Their firsthand insights provide valuable perspectives that can refine research approaches, making them more relevant, patient-centred, and impactful, to ultimately help implement clinical care and research study design.

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Understanding how these two biological systems interact in depression and learning from the PWLE of depression can offer insights into how the disorder manifests differently in males and females. The overarching goal of this research is to enhance our understanding of depression, especially its differences between sexes, and to contribute to the development of more personalised and targeted treatments tailored to both males and females in view of sex-specific precision psychiatry. 

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