Depression is a mental health condition that goes beyond feeling temporarily sad or down. It's when someone feels persistently low, hopeless, or uninterested in life for a long time, affecting how a person thinks, feels, and functions in daily life. People with depression may struggle to enjoy things they used to like, feel tired all the time, have trouble sleeping, experience changes in appetite, and often require treatment like psychotherapy or antidepressants to improve. 

Research shows some patients with depression as well as those with suicidal thoughts exhibit increased activity of the immune system (that is the body’s self-defence mechanism) without the presence of an ongoing infection. Furthermore, those patients who don’t show improvement with the common medication, known as treatment-resistant depression (TRD), have even higher levels of inflammation (a sign telling us that the immune system is activated) than the others. Several studies have looked at whether anti-inflammatory treatments can help people with depression, but the results have been mixed and not always clear.

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Differences between men and women affect multiple areas, for instance in how depression and inflammation interact may help explain some of the mixed results. For instance, women are more likely to develop depression while men are more likely to commit suicide. Moreover, women have higher inflammation and are more prone to autoimmune disorders – that is when the body's immune system, instead of protecting us, mistakenly attacks its healthy cells. 

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Given the relevant role of the immune system in depression, sex hormones like testosterone and estrogen have been studied in this context. Sex hormones are known as the main actors of reproduction and the development of secondary sex characteristics, but they can also affect mood and behaviour. Interestingly, they can affect the immune system too, however, limited literature has been dedicated to the study of the interaction between sex hormones and the immune system in patients with depression.  

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Therefore, my PhD aimed to address two main questions. 

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Is there any difference between TRD men and women with increased inflammation in the efficacy of anti-inflammatory treatments? 

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To answer this, I studied a group of people with depression who didn’t improve with regular antidepressant treatment and had increased inflammation. As part of the Minocycline in Depression clinical trial, the patients were taking minocycline (an antibiotic with anti-inflammatory properties). I found that the way inflammation and its markers affect the response to minocycline is different between men and women, suggesting that different indicators of inflammation can predict the response to minocycline based on sex. In this case, increased C-reactive protein (an alarm signal of ongoing inflammation) predicts a better improvement in depressive symptoms in women only, while increased interleukin-6 (a "messenger" of the immune system) in both sexes. 

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Do patients with depression and increased inflammation have altered levels of sex hormones?  

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To answer this, I investigated a group of people with and without depression, and I found that testosterone (a male sex hormone) was lower in men with depression and higher inflammation, and similar patterns were observed in women with a protein that regulates the availability of sex hormones (called sex hormone binding globulin). These findings suggest that sex hormones and inflammation might interact in complex ways in depression, especially in men.

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Identifying markers that differ between men and women could help customise treatments for people with TRD, making it easier to find the right approach for each person. These findings could also suggest that hormonal treatments might be beneficial, especially if patients show high levels of inflammation, ultimately leading to better prevention and care in the future.

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