Changes in depression symptom profile with gender-affirming hormone use in transgender persons 89 Fourth, the use of the IDS-SR also has limitations in clinical applicability. It is a self-report questionnaire on depressive symptoms and it can therefore not be used to diagnose depression. Additionally, the IDS-SR measures depressive symptoms and negative mood, not taking into account increases in positive mood or well-being. The TF group might experience increases in both positive and negative emotion intensity (Matthys et al., 2021; Slabbekoorn et al., 2001; Wierckx et al., 2012). If increased emotionality would result in increases in both positive and negative moods, the IDS-SR would only detect increased negative mood. It is possible that neurobiological changes, such as changes in neuroactive steroids and neurotransmitters (Collet et al., 2021; Kiyar et al., 2022) or psychosocial changes (as reviewed by Doyle et al., 2023) contribute to changes in mood, and further research should focus on the intersection of biological and psychosocial changes in GAHT users. Lastly, the current study did not address possible within-group differences which could be driven by differences in gender identity, hormone formulations or hormone level dynamics. Previous work has shown that transgender persons with an non-binary gender identity report poorer mental health compared to persons with a binary gender identity (i.e. (transgender) man or woman; de Graaf et al., 2021), which indicates that both hormone use and gender identity could be of importance for mental well-being in transgender GAHT users. Furthermore, based on literature in cisgender women, especially work indicating a possible role of “sex hormone withdrawal” it is also possible that differences in hormone forms and resulting differences in hormone levels, dynamics and possible lack of suppression of the menstrual cycle could affect mood (Frokjaer, 2020; Schiller et al., 2022). Although sensitivity analyses (reported in Supplementary Table S3.2) showed no significant differences between different forms of estrogen and testosterone, future studies are necessary to better address the role of hormone dynamics in mood in transgender GAHT users. In the interpretation of our results for clinical practice, it is important to consider that the primary aim of GAHT use is to reduce gender dysphoria, and that starting GAHT is a long-awaited major life event for many transgender persons. Studies show that GAHT use results in decreases in gender dysphoria (Foster Skewis et al., 2021; van Leerdam et al., 2021) and
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