Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation: A Positron Emission Tomography Study

TY - JOUR

T1 - Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation

T2 - A Positron Emission Tomography Study

AU - Frokjaer, Vibe Gedsoe

AU - Pinborg, Anja

AU - Holst, Klaus Kähler

AU - Overgaard, Agnete

AU - Henningsson, Susanne

AU - Heede, Maria

AU - Larsen, Elisabeth Clare

AU - Jensen, Peter Steen

AU - Agn, Mikael

AU - Nielsen, Anna Pors

AU - Stenbæk, Dea Siggaard

AU - da Cunha-Bang, Sophie

AU - Lehel, Szabolcs

AU - Siebner, Hartwig Roman

AU - Mikkelsen, Jens Damsgaard

AU - Svarer, Claus

AU - Knudsen, Karen Birgitte Moos

N1 - Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PY - 2015/10/15

Y1 - 2015/10/15

N2 - 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 [11C]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.

AB - 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 [11C]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.

U2 - 10.1016/j.biopsych.2015.04.015

DO - 10.1016/j.biopsych.2015.04.015

M3 - Journal article

C2 - 26004162

SN - 0006-3223

VL - 78

SP - 534

EP - 543

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 8

ER -