Chapter 9 270 burden of minority stress, which could also result in a different form and phenotype of the reported depressive symptoms, with possible weaker associations with insomnia and poor sleep. This hypothesis is supported somewhat by the findings of the exploratory factor analysis we conducted in Chapter 3: we find differences in symptomatology between our cohort and other Dutch cohorts, including a lack of associations between insomnia items and mood-related items, and a strong correlation between anxiety symptoms and fear of rejection and low self-image. This could imply that depression in transgender people starting GAHT is more strongly correlated with psychosocial adversity. Lastly, it is possible that exogenous sex hormones might affect mood via different mechanisms than those found in major depressive disorder, and that hormone-associated depressive symptoms may therefore have a less prominent link with poor sleep. As discussed in section 2.2.3 of this chapter, studies indicate that OCs and GAHT could affect the HPA axis but also the serotonergic system and the GABA-ergic system. It is possible that the biological mechanisms behind sex hormone-associated depressive symptoms are somewhat different than the biological changes seen in major depressive disorder. A possible mechanistic difference between hormone-associated depressive symptoms and major depressive disorder is seen in PMDD. In patients with PMDD, use of selective serotonin reuptake inhibitors (SSRIs) in the symptomatic luteal week has shown rapid therapeutic effects, showing significant reductions in symptom severity within 2 days (Reilly et al., 2023; Steinberg et al., 2012). This is a remarkably short time compared to the use of SSRIs in major depressive disorder, in which SSRIs can take between 4 to 8 weeks to start working (Ruhé et al., 2006). The rapid effects of SSRIs for PMDD symptoms is often be explained by the effects of SSRIs on allopregnanolone: SSRIs can increase the conversion of progesterone to allopregnanolone (Guidotti & Costa, 1998), and this can normalize lutealphase allopregnanolone levels in patients with PMDD (Gracia et al., 2009). The allopregnanolone-driven mechanism of SSRIs in PMDD is different from the classical mechanism of action of SSRIs, in which SSRIs change the availability of serotonin and serotonergic transmission. These mechanistic differences suggest the biological changes underlying depressive symptoms in PMDD might differ from biological changes underlying classical major
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