Vibe Gedsoe Frokjaer1, Anja Pinborg2, Klaus Kähler Holst3, Agnete Overgaard4, Susanne Henningsson5, Maria Heede6, Elisabeth Clare Larsen7, Peter Steen Jensen6, Mikael Agn6, Anna Pors Nielsen6, Dea Siggaard Stenbæk6, Sophie da Cunha-Bang6, Szabolcs Lehel8, Hartwig Roman Siebner9, Jens Damsgaard Mikkelsen10, Claus Svarer6, Gitte Moos Knudsen11. 1. Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen. Electronic address: vibe@nru.dk. 2. The Fertility Clinic, PET, Copenhagen; University of Copenhagen, Copenhagen. 3. Department of Biostatistics, Copenhagen. 4. Neurobiology Research Unit, Copenhagen. 5. University of Copenhagen, Copenhagen. 6. Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen. 7. The Fertility Clinic, PET, Copenhagen. 8. Cyclotron Unit (SL), Rigshospitalet, Copenhagen. 9. Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre; University of Copenhagen, Copenhagen; Department of Neurology, Bispebjerg, Copenhagen, Denmark. 10. Center for Integrated Molecular Brain Imaging, Copenhagen; University of Copenhagen, Copenhagen. 11. Center for Integrated Molecular Brain Imaging, Copenhagen; Neurobiology Research Unit, Copenhagen; University of Copenhagen, Copenhagen.
Abstract
BACKGROUND: An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention. METHODS: A double-blind, randomized, placebo-controlled study included 63 healthy female volunteers (mean age 24.3 ± 4.9 years) with regular menstrual cycles between 23 and 35 days. Participants were randomized to active (goserelin [GnRHa] 3.6 mg implant) or placebo intervention. Sixty women completed follow-up and entered the analyses. Primary outcome measures were changes from baseline in depressive symptoms assessed on the 17-item Hamilton Depression Rating Scale and SERT binding as imaged by [(11)C]DASB positron emission tomography. Outcome measures were acquired at baseline in the follicular phase (cycle day 6.6 ± 2.2) and at follow-up (16.2 ± 2.6 days after intervention start). RESULTS: Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p = .003) and relative to placebo (p = .02), which were positively associated with net decreases in estradiol levels (p = .02) from baseline within the GnRHa group. Depressive symptoms were associated with increases in neocortical SERT binding in the GnRHa group relative to placebo (p = .003). CONCLUSIONS: Our data imply both serotonergic signaling and estradiol in the mechanisms by which sex-steroid hormone fluctuations provoke depressive symptoms and thus provide a rationale for future preventive strategies in high-risk groups.
RCT Entities:
BACKGROUND: An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention. METHODS: A double-blind, randomized, placebo-controlled study included 63 healthy female volunteers (mean age 24.3 ± 4.9 years) with regular menstrual cycles between 23 and 35 days. Participants were randomized to active (goserelin [GnRHa] 3.6 mg implant) or placebo intervention. Sixty women completed follow-up and entered the analyses. Primary outcome measures were changes from baseline in depressive symptoms assessed on the 17-item Hamilton Depression Rating Scale and SERT binding as imaged by [(11)C]DASB positron emission tomography. Outcome measures were acquired at baseline in the follicular phase (cycle day 6.6 ± 2.2) and at follow-up (16.2 ± 2.6 days after intervention start). RESULTS: Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p = .003) and relative to placebo (p = .02), which were positively associated with net decreases in estradiol levels (p = .02) from baseline within the GnRHa group. Depressive symptoms were associated with increases in neocortical SERT binding in the GnRHa group relative to placebo (p = .003). CONCLUSIONS: Our data imply both serotonergic signaling and estradiol in the mechanisms by which sex-steroid hormone fluctuations provoke depressive symptoms and thus provide a rationale for future preventive strategies in high-risk groups.
Authors: Martin Nørgaard; Melanie Ganz; Claus Svarer; Vibe G Frokjaer; Douglas N Greve; Stephen C Strother; Gitte M Knudsen Journal: Neuroimage Date: 2019-06-01 Impact factor: 6.556
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