TABLE 1.

Main findings from the GnRHa clinical trial

Article	N	Main outcomes	Main findings
Frokjaer et al. (2015)	30 GnRHa	Changes from baseline in: HDRS 17‐item Serotonin transporter BPnd Estradiol	GnRHa induced depressive symptoms (HDRS 17‐item) in about 13% relative to placebo
	30 placebo
			No main effects of GnRHa versus placebo on serotonin transporter BPnd
			The emergence of depressive symptoms was associated with both increased serotonin transporter binding in neocortex from baseline and with the magnitude of estradiol decrease
Henningsson et al. (2015)	26 GnRHa	Emotional faces fMRI Amygdala (primary) medial prefrontal cortex anterior cingulate cortex ventrolateral prefrontal cortex insula	No main effects of GnRHa versus placebo
	29 placebo		Women who displayed larger GnRHa‐induced increase in depressive symptoms had a larger increase in both negative and positive emotion‐elicited activity in insula (anterior)
Macoveanu et al. (2016)	26 GnRHa	Gambling fMRI, brain activation related to reward	GnRHa reduced activation reward‐related activation of amygdala, relative to placebo
	29 placebo
Stenbæk et al. (2016)	31 GnRHa	Affective verbal memory Reaction time Self‐reported mental distress Profile of mood states	GnRHa was associated with slower reaction time and more labile mood relative to placebo
	30 placebo
			No effects of GnRHa were seen on affective verbal memory
Fisher et al. (2017)	29 GnRHa	rs‐fMRI: functional connectivity (rs‐FC) for amygdala hippocampus anterior cingulate dorsal raphe, median raphe posterior cingulate cortex	No main effects of GnRHa versus placebo
	29 placebo		Women who displayed larger GnRHa‐induced increase in depressive symptoms had an increased amygdala–right temporal cortex rs‐FC and decreased hippocampus–cingulate rs‐FC
Mehta (2019)		A priori PND biomarker set of 116 gene transcripts (from Mehta et al. 2014)	Of the a priori defined PND predictive set of 116 genes, 19% were differentially expressed post‐GnRHa and 49% were differentially methylated relative to placebo
			Within the GnRHa group, a large proportion of PND genes were significantly associated (gene expression; DNA methylation) with changes in depressive symptoms (28%; 66%), estradiol levels (49%; 66%), and neocortex serotonin transporter binding (8%; 45%) between baseline and later follow‐up
Stenbaek, Budtz‐Jorgensen, Pinborg, Jensen, and Frokjaer (2019)	28 GnRHa	Profile of mood states day 0 to 14 post‐intervention. Neuroticism scores at baseline (NEO‐PI‐R)	GnRHa with and without concomitant infertility‐related stress heightened total mood disturbances most pronounced at the early stimulatory phase day 0–5 post‐GnRHa in a manner dependent on neuroticism scores
	27 placebo
	37 IVF‐GnRHa