Neuropsychobiological Correlates of Sex-steroid Hormone Manipulation in Healthy Women: a Risk Model for Depression

NCT02661789 | Completed DMC

• 2 other identifiers: GnRHaH-2-2010-108
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

Brief Summary

The project aimed at identifying neuropsychobiological signatures of pharmacological sex-steroid hormone manipulations in healthy women as a risk model for depression. The study is a double-blind, randomized, placebo-controlled study. Investigators included 63 healthy female volunteers with regular menstrual cycles between 23 and 35 days. Participants were randomized to active Gonadotrophin-Releasing-Hormone agonist (GnRHa) (goserelin 3.6 mg implant) or placebo (saline injection) intervention, which was initiated in the mid follicular phase (i.e. cycle day 22.6 ±2.5). Sixty women completed follow-up and entered the analyses, except for a few drop outs on some domains. The following domains were addressed at baseline and at follow-up (16±3 days post intervention), (which corresponded to the early ovarian suppression phase of the biphasic hormone response to GnRHa): 1) serotonin transporter binding as imaged by 11CDASB Positron Emission Tomography (PET), 2) functional Magnetic Resonance Imaging (fMRI) emotional processing, 3) fMRI reward processing, 3) rating state fMRI (rsfMRI), 4) structural MRI, 5) Neuropsychology, 6) Psychophysiology, 7) Hypothalamus-Pituitary-Adrenal cortex (HPA)-axis dynamics, 8) Peripheral markers of immunoactive cell responses, 9) Epigenetic factors. Psychometrics in terms of self reported mental distress and interview based ratings were monitored across the intervention period to monitor potential symptoms of mental distress and psychopathology. Also ovarian hormone responses, peripheral blood markers, and side effects scores were collected across the intervention period.

Conditions

Postpartum Depression; Major Depressive Disorder; Postpartum Psychosis; Menopause; Neurodegeneration; Schizophrenia

Keywords

Mental health; Brain Imaging; Steroid hormones; Serotonin; PET; MRI; fMRI; human; gender; risk model

Outcome Measures

Primary Outcomes (15)

• Changes from baseline in symptoms of depression

  Hamilton 17 item score

  Baseline to follow-up 16±3 days after intervention

• Changes from baseline in serotonin transporter binding in volumes of interest (VOIs)

  PET scan assessed serotonin transporter binding changes

  Baseline to follow-up 16±3 days after intervention

• Changes from baseline in fMRI response to emotional faces

  fMRI response changes to emotional faces in emotion processing network including amygdala reactivity

  Baseline to follow-up 16±3 days after intervention

• Changes from baseline in fMRI response to gambling paradigm

  fMRI response changes to reward (monetary win) paradigm in reward processing network

  Baseline to follow-up 16±3 days after intervention

• Changes from baseline in rsfMRI changes in functional connectivity

  rsfMRI changes in functional connectivity in response to intervention

  Baseline to follow-up 16±3 days after intervention

• Changes from baseline in affective cognition (VAMT-24 test)

  Neuropsychological (VAMT-24 test) outcomes on affective cognition

  Baseline to follow-up 16±3 days after intervention

• Changes from baseline in reaction time

  Changes in reaction time

  Baseline to follow-up 16±3 days after intervention

• Serial mood fluctuations (SD of total mood disturbance (TMD) score of daily POMS across intervention period)

  Mood fluctuations measured by serial collection of daily POMS

  Intervention start to follow-up 16±3 days after intervention

• Changes from baseline in hippocampal volume

  Hippocampal volumes from structural MRI

  Baseline to follow-up 16±3 days after intervention

• Changes in pre-pulse-inhibition (PPI) from baseline

  Change in amplitude of the startle response to pulse after pre-pulse warning as measured by EMG in the orbicularis oculi muscle (subtraction of averages across a series of 10 repititions at baseline and at follow-up 16±3 days).

  Baseline to follow-up 16±3 days after intervention

• Changes in a set of markers of immunoactivity across study period

  Cytokines, hsCRP and gene transcript profile markers of

  Baseline, intervention time, flare-up phase and follow-up

• Changes in epigenetic markers of estrogen sensitivity

  Epigenetic (methylation) markers

  Baseline to follow-up 16±3 days after intervention

• Changes in HPA-axis dynamics (the cortisol awakening response)

  The cortical awakening response

  Baseline to follow-up 16±3 days after intervention

• Changes in sensorimotor gating (P50 suppression) from baseline

  Changes in sensorimotor gating (P50 suppression) from baseline

  Baseline to follow-up 16±3 days after intervention

• Changes from baseline in hippocampal microstructure

  Hippocampal microstructure from MRI

  Baseline to follow-up 16±3 days after intervention

Secondary Outcomes (7)

• Changes from baseline in fMRI responses to emotional memory paradigm

  Baseline to follow-up 16±3 days after intervention

• Changes from baseline in Cohens perceived stress score

  Baseline to follow-up 16±3 days after intervention

• Changes in Pittsburg Sleep Quality Inventory (PSQI)

  Baseline and 1 time per week until follow-up at 16 ±3 days

• Side effects scores (project specific 15 items questionnaire)

  7, 12 and 30 days post intervention

• Changes in SCL-R (Symptom check-list revised)

  Baseline and 1 time per week from intervention to follow up at 16±3 days post intervention

Other Outcomes (1)

• Ovarian hormone responses to intervention

  Baseline (i.e, cycle day 5-8), intervention time (i.e cycle day 21-23), flare-up phase (i.e, 3-4 days post intervention) and follow-up (i.e.,16±3 days post intervention)

Study Arms (2)

GnRHa

ACTIVE COMPARATOR

Goserelin 3.6 mg implant

Drug: Goserelin 3.6 mg implant

Placebo

PLACEBO COMPARATOR

Injection of saline

Drug: Placebo

Interventions

Goserelin 3.6 mg implant DRUG

Pharmacologically induced biphasic sex-steroid hormone fluctuation

Also known as: Zoladex

GnRHa

Placebo DRUG

Injection of saline

Also known as: Saline

Placebo

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy women
• Regular menstrual cycles (23 -35 days cycle length)
• No systemic or intrauterine steroid hormone use

You may not qualify if:

• Psychiatric disorder (DSM IV Axis I or WHO ICD-10 diagnostic classification).
• Prior or present neurological or other severe medical condition including substance abuse.
• No drug intake suspected to influence results
• Conditions that may increase risk by participating in the study program including ovarian cysts
• Pregnancy during the last year
• Delivery during the last 2 years
• Presently wishing to obtain pregnancy
• Breast feeding
• Not fluent in Danish or severe visual or hearing impairments
• Earlier or present learning disabilities
• Claustrophobia (due to MRI scans)
• Metal implants (excludes MRI)

Sponsors & Collaborators

• Gitte Moos Knudsen: lead
• Center for Integrated Molecular Brain Imaging, Copenhagen, Denmak: collaborator
• Rigshospitalet, Denmark: collaborator
• Glostrup University Hospital, Copenhagen: collaborator
• Danish Multiple Sclerosis Center Rigshospitalet: collaborator
• Dept. of Clinical Immunology, Rigshospitalet: collaborator

Study Sites (1)

Neurobiology Research Unit, Rigshospitalet

Copenhagen, 2100, Denmark

Location

Related Publications (2)

• Mehta D, Rex-Haffner M, Sondergaard HB, Pinborg A, Binder EB, Frokjaer VG. Genome-wide gene expression in a pharmacological hormonal transition model and its relation to depressive symptoms. Acta Psychiatr Scand. 2019 Jul;140(1):77-84. doi: 10.1111/acps.13038. Epub 2019 May 24.

  PMID: 31099405 DERIVED

• Fisher PM, Larsen CB, Beliveau V, Henningsson S, Pinborg A, Holst KK, Jensen PS, Svarer C, Siebner HR, Knudsen GM, Frokjaer VG. Pharmacologically Induced Sex Hormone Fluctuation Effects on Resting-State Functional Connectivity in a Risk Model for Depression: A Randomized Trial. Neuropsychopharmacology. 2017 Jan;42(2):446-453. doi: 10.1038/npp.2016.208. Epub 2016 Sep 21.

  PMID: 27649641 DERIVED

MeSH Terms

Conditions

Depression, Postpartum; Depressive Disorder, Major; Nerve Degeneration; Schizophrenia; Psychological Well-Being; Coitus

Interventions

Goserelin; Drug Implants; Sodium Chloride

Condition Hierarchy (Ancestors)

Puerperal Disorders; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Depressive Disorder; Mood Disorders; Mental Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Schizophrenia Spectrum and Other Psychotic Disorders; Personal Satisfaction; Behavior; Sexual Behavior

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Delayed-Action Preparations; Dosage Forms; Pharmaceutical Preparations; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Vibe G Frokjaer, MD, Phd

  Neurobiology Research Unit

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Center director of Center for Integrated Molecular Brain Imaging

Study Record Dates

• First Submitted: January 13, 2016
• First Posted: January 22, 2016
• Study Start: January 1, 2011
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: January 22, 2016

Record last verified: 2016-01

Data Sharing

• IPD Sharing: Will share

Locations

DK (1)