Reversible Effects of Oral Contraceptive Removal on Serotonergic Neurotransmission (REVERSE)

The goal of this study is to learn about potential reversible effects of combined oral contraceptive (COC) use on the serotonergic brain system. The main question it aims to answer is:

- If COC discontinuation results in an increase in serotonin 4 receptor binding in caudate, putamen, and hippocampus measured with Positron Emission Tomography from baseline to follow-up ≥ week 8 after discontinuation.

The secondary question it aims to answer is:

- Over what timeframe the serotonin 4 receptor binding is restored after COC discontinuation to the level previously seen in a group of premenopausal women who had not used hormonal contraception before.

Researchers will compare discontinuation with continuation of a 2nd generation COC containing 150 ug levonorgestrel and 30 microgram to see if COC discontinuation results in an increased serotonin 4 receptor level in the brain.

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Participants will:

• Be randomized to discontinue or continue their COC use for 1-52 weeks.
• Undergo an investigational program including brain scans, biological sampling, and neuropsychological testing at baseline and at follow-up.

The study uses a group sequential design with two sequential analyses planned, including an interim analysis after 60% of the brain scans have been acquired, which will be used to decide the timing of the last 40% of the scans - this is performed to best determine when the recovery of the serotonin 4 receptor level occurs.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy Adult Females; The Focus of the Study is to Investigate Reversible Effects of Combined Oral Contraceptive Use on Serotonergic Neurotransmission
• Intervention / Treatment: Drug: Continuation of 2nd generation combined oral contraceptive use; Drug: Discontinuation of 2nd generation combined oral contraceptive use

Detailed Description

• Background:

Large register-based studies have shown that initiation of combined oral contraceptives (COCs) is associated with an increased risk of developing depressive episodes. The biological mechanisms underlying this association remain unclear, but alterations in the serotonergic brain system may play a role. The investigators have demonstrated that COC use reduces global cerebral serotonin 4 receptor (5-HT4R) levels in healthy women. The magnitude of this difference is comparable to what has been observed in individuals with depression relative to healthy controls.

This study aims to determine if COC discontinuation (COCd) results in recovery of the 5-HT4R brain levels and over what time frame this may occur. Further it investigates other potential neurobiological effects of COCd and how these map onto relevant signatures of mental states, including mood, memory function and sexual desire. The researchers anticipate that this work will substantially advance the understanding of whether COC effects on serotonergic brain biology is reversible and whether such insights could provide novel preventive and therapeutic opportunities in depression.

- Study design: The investigators will conduct a randomized controlled trial assessing brain changes after COCd over a timeframe of up till one year. The investigators will include up to 60 healthy women (or until 25 women have completed follow-up in each arm) at 18-39 years of age who use a second-generation COC (containing 150 ug levonorgestrel and 30 ug ethinylestradiol), and have done this for a minimum of three months. The participants will undergo the same investigational program at baseline and at follow-up, which consists of PET (only COC discontinuers) and MRI/fMRI scans of the brain, oral glucose tolerance test, neuropsychological testing, collection of blood, saliva, and stool samples, completion of questionnaires regarding various trait- and state-related measures including a month at baseline and follow-up of daily questionnaires measuring psychometrics of mood/affect, sexual desire and sleep quality.

The timing of the follow-up assessment is determined by an adopted group sequential design; the first 15 COC discontinuers and 15 COC continuers will be distributed across week 8-24 after discontinuation/continuation. Hereafter, a planned assessment of the PET outcome will determine whether the last 10 COC discontinuers and 10 continuers will have their follow-up distributed within week 1-7 or week 8-52 after discontinuation (see more details under "Statistical analysis plan"). This procedure will allow an informed timing of the latter scans to better capture an estimate of the recovery time for 5-HT4R levels. Women allocated to COC continuation (COCc) will have their follow-up timepoint approximately matched to a COC discontinuer. Additionally, the timing of the follow-up will be during the active pill phase for COC continuers and during the follicular phase for COC discontinuers if menstrual cycle has returned. This will be planned based on pill cycle (COC continuers) and the reported first day of bleeding, menstrual cycle length, and LH tests during the follow-up (COC discontinuers). For the latter case, adjustment of the follow-up date may happen due to irregular cycles. Since the timing of each participant's follow-up assessment also needs to match personal calendar and availability of scan slots, the researchers allow follow-up to deviate from the planned cycle days.

- Randomization: Participants will be randomized in 1:1 in random block sizes (e.g., 2, 4, 6 and 8) to either COCd or COCc. The randomization will be carried out by an administrative staff member at Neurobiology Research Unit (Rigshospitalet, Denmark), who will not otherwise be involved in the study or enrollment.

- Evaluation of compliance: Pill count will be carried out at every pill cycle. The participants has to report to the investigators if they forget to take a pill during the study. Non-compliance is defined as >2 missed pill in a cycle. If more than two pills are missed during the baseline or follow-up pill cycle, the participant will be asked if they are willing to postpone their assessment until the next pill cycle.

- Statistical analysis plan: The researchers use a group sequential design where they plan to conduct two sequential analyses including one interim analysis after 60% of the PET scans have been acquired (i.e., after 15 participants have been PET scanned at baseline and follow-up week 8-24) to decide whether the last 10 should be rescanned within week 1-7 or week 8-52. If the null hypothesis is rejected (i.e., they observe a change from baseline) in the interim analysis then the last 10 will be scanned within week 1-7 after COCd, but if it is not rejected (i.e., they observe no change from baseline), they will be scanned within week 8-52 after COCd. Only in the latter case will all scans be included in the primary aim test, i.e., to determine if there is an increase in 5-HT4R binding in caudate, putamen, and hippocampus from baseline to week 8 weeks or longer after COCd (in the former case, the null hypothesis would already be rejected with 15 participants). To account for the inflated type I error due to two planned tests, they will correct the alpha level (significance level) for each test by use of the alpha spending function (α*(t) = α ln(1 + (e - 1)t), which is similar to the Pocock correction, but the timing of the analysis does not need to be specified in advance, i.e., it is more flexible in the case of unforeseen problems with data acquisition. From the decision to distribute the last 10 scans early or late, they are able to optimize the timing of scans to enable us to determine over what timeframe the 5-HT4R level is returning to the age-corrected level observed in approximately 18 premenopausal women who had never used hormonal contraception (secondary hypothesis).

To test the primary hypothesis, they will conduct a one-sided test by use of a latent variable model on log-transformed 5-HT4R binding potentials in caudate, putamen, and hippocampus to estimate the change from baseline after COCd adjusted for change in injected tracer mass per kg body weight. Adjusted p-values, confidence intervals, and median unbiased estimates will be computed according to stagewise ordering.

To test the secondary hypothesis, they will first model two latent variable models, one determining the back-transformed change in the log of the global 5-HT4R binding between follow-up and baseline and the other determining the back-transformed difference in log of the global 5-HT4R binding between premenopausal women who never used hormonal contraception (i.e., another cohort) and the baseline (i.e., from the current cohort). Both latent variables will be estimated across caudate, putamen and hippocampus, which in the first model will be adjusted for change in injected tracer mass per kg bodyweight, and in the second model for injected tracer mass per kg bodyweight and age mean-centered around the mean age at follow-up (i.e., for the current cohort). Hereafter, they will evaluate the change in global 5-HT4R binding over time by using the back-transformed estimates of the change (denoted Y) as a function of time since discontinuation (denoted x) using the following logarithmic model: Y(x)=(Ymax*Y0)/((Ymax-Y0 )*e^((-k*x) )+Y0 ) , where only the rate constant k is fitted using the 'change in global binding' and non-linear least squares. The other two parameters Y0 and Ymax are set, respectively, to 1 and to the back-transformed mean global 5-HT4R difference from the second latent variable model. Based on the fitted model, the researchers will estimate the time x such that the modeled mean change, Y(x), is equal to 90% of the mean global difference observed in the second latent variable model (Y0+0.9∙(Ymax-Y0)/Y0 ) to give an estimate of when the 5-HT4R binding has "recovered". If the model fit is poor, alternative models will be evaluated, including the logarithmic model without using a pre-defined Ymax (i.e., it will be estimated by the model) or a linear model with time on or not on the log-scale. If a linear model is used, time to recovery will be at the timepoint where the linear function is equal to Ymax.

For domain-specific hypotheses (see hypotheses below), the researchers will compare change scores adjusted for baseline values (except for the memory encoding fmri domain where only follow-up data will be collected). If it turns out relevant to deviate from the original statistical plan, the researchers will report this in detail in all publications of this study.

- Sample size calculation: Calculations based on intra-subject variability of the 5-HT4R binding from 40 premenopausal women with scan-rescan show that with two planned sequential analyses, including 60% and 100% of the planned scans, respectively, and with a power of 80%, an overall desired Type I error rate of 0.05 (one-sided), the alpha levels would be 0.035 and 0.028 for the interim and final analysis, respectively. With these, the researchers are able to detect a difference of 8.2-9.5% (interim analysis) and 6.5-7.5% (final analysis) in binding potential in caudatus, putamen, and hippocampus for the interim and the final analysis, respectively. the researchers will include up to 60 participants (or until at least 25 have completed baseline and follow-up in both arms) to allow a dropout rate of 20%. The primary analyses will be handled as complete case analysis. Missing data as well as dropouts will be reported in the relevant publications.

• Hypotheses:

• Primary hypothesis:

  5-HT4R binding in caudate, putamen, and hippocampus increases from baseline to follow-up ≥ week 8 after COCd.

• Secondary hypotheses:

  5-HT4R binding in caudate, putamen, and hippocampus has 'restored' within 12 months after COCd to the level seen in premenopausal women who never used hormonal contraception.

• Additional domain-specific hypotheses
• Memory encoding I. COCd compared to COCc improves verbal memory performance. II. COCd compared to COCc results in larger hippocampal brain activation during memory-encoding task.
• Insulin sensitivity III. COCd compared to COCc improves peripheral and brain insulin sensitivity. IV. COCd compared to COCC results in larger hypothalamic BOLD signal reduction after oral glucose load.
• Hedonic health V. COCd compared to COCc increases striatal reward response VI. COCd compared to COCc increases sexual desire
• Anxiety VII. COCd compared to COCc decreases anxiety levels.
• Hypothalamic-pituitary-adrenal axis dynamics VIII. COCd compared to COCc increases cortisol awakening response.
• Inflammatory system IX. COCd compared to COCc decreases extra-neurite mean diffusivity. XI: COCd compared to COCc increases, kynurenic acid, and kynurenic acid/quinolinic acid ratio and decreases pro-inflammatory markers.
• Brain structure XII. COCd compared to COCc results in increase in gray matter volumes of the (para)hippocampus and prefrontal cortex.
• Non-goal-oriented brain network organization XIII. COCd compared to COCc changes resting state functional connectivity brain networks.
• Gut microbiome XIV. COCd compared to COCc changes gut microbiome and gut microbiota-derived metabolites.
• Sleep:

XV: COCd compared to COCc improves sleep.

• Ethical considerations:

Exposure to radioactivity during the PET scans: The total exposure will not exceed 10 mSv equal to 3 years of natural background radiation in Denmark, which should be seen in the light of the new knowledge this study can generate.

Risk of unintended pregnancies in the COCd group. Those discontinuing COC are able to take other precautions and they will be thoroughly informed to use protection during intercourse. For this, the researchers will offer condoms for free during the study period.

The study will be conducted in agreement with the Declaration of Helsinki.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Søren Vinther Larsen, MD, PhD; Phone Number: +45 35456708; Email: soren.vinther@nru.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Neurobiology Research Unit (NRU)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Healthy women (assigned female at birth) at 18-39 years of age
2. Currently using a second-generation combined oral contraceptive containing 150 ug levonorgestrel and 30 ug ethinylestradiol for at least 3 months

Exclusion Criteria:

1. Current or previous neurological or psychiatric disease, severe somatic disease, or consumption of medical drugs (including psychoactive medication) likely to influence the test results
2. Non-fluent in Danish or pronounced visual or auditory impairments
3. Current or past learning disability
4. Pregnancy within the last year or previous pregnancy lasting into second or third trimester
5. A wish to become pregnant within the following 12 months
6. Participation in experiments with exposure to radioactivity (> 10 mSv) within the last year or significant occupational exposure to radioactivity
7. Contraindications for MRI (pacemaker, metal implants, claustrophobia)
8. A history of head injury or concussion resulting in loss of consciousness for more than 2 min
9. Alcohol or drug abuse
10. Drug use other than tobacco and alcohol within the last 30 days
11. Cannabis > 50 x lifetime
12. Recreational drugs other than cannabis > 10 x lifetime (for each substance)
13. Nicotine addiction
14. Non-compliance to COC within the last 3 months (i.e., > 2 missed pills in a cycle)
15. Contraindication for use of combined oral contraception

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Combined oral contraceptive continuation (COCc); COCc: between 1-52 weeks of second-generation combined oral contraceptive containing 150 microgram levonorgestrel and 30 microgram ethinylestradiol. Each cycle consists of 21 days of active pills and 7 days of placebo pills/pause days.	Drug: Continuation of 2nd generation combined oral contraceptive use; Continuation of 2nd generation combined oral contraceptive use
Experimental: Combined oral contraceptive discontinuation (COCd); COCd: between 1-52 weeks.	Drug: Discontinuation of 2nd generation combined oral contraceptive use; Discontinuation of 2nd generation combined oral contraceptive use

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in global serotonin 4 receptor (5-HT4R) brain binding across caudate, putamen, and hippocampus	Serotonin 4 receptor (5-HT4R) brain binding is measured with positron emission tomography. Change in global 5-HT4R brain binding is estimated using a latent variable model with a latent variable pooling the change in log-transformed binding potentials from baseline to follow-up across caudate, putamen, and hippocampus after adjustment for change in injected tracer mass per kg body weight.	1-52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in total Verbal Affective Memory Test-24 (VAMT-24) score	Verbal Affective Memory task 24 (VAMT-24) total recall score is calculated as the average score across the immediate (0-24), short- (0-24), and long-term (0-24) recall with higher scores representing better performance.	1-52 weeks
Difference in hippocampal activation during memory encoding	Hippocampal blood-oxygen-level-dependent (BOLD) activation during a memory encoding paradigm.	1-52 weeks
Change in brain insulin sensitivity	Hypothalamic blood flow response to oral glucose, used as a proxy for brain insulin sensitivity.	1-52 weeks
Change in hypothalamic blood-oxygen-level-dependent response to oral glucose	Hypothalamic blood-oxygen-level-dependent response to oral glucose.	1-52 weeks
Change in reward-stimulated blood-oxygen-level-dependent (BOLD) signal in ventral striatum	The blood-oxygen-level-dependent (BOLD) reward signal derived from the ventral striatum activity during monetary reward fMRI paradigm.	1-52 weeks
Change in sexual desire scores derived from daily ratings of the Element of Desire Questionnaire (EDQ)	The Element of Desire Questionnaire (EDQ) score ranges from 6-35 with higher scores representing higher sexual desire.	1-52 weeks
Change in General Anxiety Disorder 10 (GAD-10) score	GAD-10 score ranges from 0-50 with higher scores representing higher level anxiety	1-52 weeks
Change in Positive Affect (PA) and negative Affect (NA) score derived from daily ratings of the Positive and Negative Affect Schedule (PANAS) questionnaire	PA score ranges from 10-50 with higher scores representing higher levels of positive affect. NA score ranges from 10-50 with higher scores representing higher levels of negative affect.	1-52 weeks
Change in total symptom score from the Daily Report of Severity of Problems (DRSP)	The total symptom score is derived from the 21 symptoms item from the Daily Report of Severity of Problems (DRSP) which are rated on a Likert scale from 1-6 yielding a total score between 21 and 126 with higher scores representing higher symptom burden.	1-52 weeks
Change in Cortisol Awakening Response (CAR)	Cortisol Awakening Response derived from saliva samples collected during the first hour after awakening	1-52 weeks
Change in white matter microstructure	White matter microstructure, including extra-neurite mean diffusivity as a proxy for neuroinflammation, derived from neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI).	1-52 weeks
Change in hippocampal volume	Derived from structural T1/T2 MPRAGE brain MRI	1-52 weeks
Change in BOLD signal in resting state functional connectivity brain networks measured with fMRI	The blood-oxygen-level-dependent (BOLD) signal derived from the brain activity during resting state.	1-52 weeks
Change in gut microbiome	Gut microbiome composition from stool sample.	1-52 weeks
Change in gut microbiome-derived metabolites	Gut microbiota-derived metabolites assessed in blood	1-52 weeks
Change in mean daily sleep quality	Derived from serial daily sleep quality reporting on a scale from 0 (very good) to 3 (very bad) during baseline and follow-up cycles.	1-52 weeks
Change in Pittsburgh Sleep Quality Index (PSQI)	PSQI ranges from 0-21 with higher scores representing worse sleep quality.	1-52 weeks
Change in peripheral insulin sensitivity	Peripheral insulin sensitivity as measured with the Matsuda index where higher values indicate higher insulin sensitivity.	1-52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in area under the curve of glucose during an oral glucose tolerance test (OGTT)	Change in area under the curve during OGTT for glucose from baseline to follow-up.	1-52 weeks
Change in area under the curve of insulin during an oral glucose tolerance test (OGTT)	Change in area under the curve during OGTT for insulin from baseline to follow-up.	1-52 weeks
Change in area under the curve of c-peptide during an oral glucose tolerance test (OGTT)	Change in area under the curve during OGTT for c-peptide from baseline to follow-up.	1-52 weeks
Change in Hba1C	Change in Hba1C from baseline to follow-up	1-52 weeks
Change in depressive symptom score from the Daily Report of Severity of Problems (DRSP)	The depressive symptom score is derived from the Daily Report of Severity of Problems (DRSP) where items are rated on a Likert scale from 1-6 yielding a total score between 6 and 36 with higher scores representing higher symptom burden. It is assessed daily at baseline and follow-up.	1-52 weeks
Change in anger/irritability symptom score from the Daily Report of Severity of Problems (DRSP)	The anger/irritability symptom score is derived from the Daily Report of Severity of Problems (DRSP) where items are rated on a Likert scale from 1-6 yielding a total score between 2 and 12 with higher scores representing higher symptom burden. It is assessed daily at baseline and follow-up.	1-52 weeks
Change in physical symptom score from the Daily Report of Severity of Problems (DRSP)	The physical symptom score is derived from the Daily Report of Severity of Problems (DRSP) where items are rated on a Likert scale from 1-6 yielding a total score between 4 and 24 with higher scores representing higher symptom burden. It is assessed daily at baseline and follow-up.	1-52 weeks
Change in impaired work/daily routine score from the Daily Report of Severity of Problems (DRSP)	The impaired work/daily routine score is derived from the Daily Report of Severity of Problems (DRSP) where items are rated on a Likert scale from 1-6 yielding a total score between 1 and 6 with higher scores representing higher impairment. It is assessed daily at baseline and follow-up.	1-52 weeks
Change in impaired hobbies/social score from the Daily Report of Severity of Problems (DRSP)	The impaired hobbies/social score is derived from the Daily Report of Severity of Problems (DRSP) where items are rated on a Likert scale from 1-6 yielding a total score between 1 and 6 with higher scores representing higher impairment. It is assessed daily at baseline and follow-up.	1-52 weeks
Change in impaired relationships score from the Daily Report of Severity of Problems (DRSP)	The impaired relationships score is derived from the Daily Report of Severity of Problems (DRSP) where items are rated on a Likert scale from 1-6 yielding a total score between 1 and 6 with higher scores representing higher impairment. It is assessed daily at baseline and follow-up.	1-52 weeks
Change in kynurenic acid/quinolinic acid ratio	Plasma kynurenic acid/quinolinic acid ratio	1-52 weeks
Change in low-grade inflammation	Change in hsCRP from baseline to follow-up	1-52 weeks
Change in mean hours slept	Derived from serial daily reporting of hours slept during baseline and follow-up cycles	1-52 weeks
Change in number of nights with trouble sleeping due to 1) difficulty falling a sleep or 2) wakening in the night or early morning	Derived from serial daily reporting about trouble sleeping during baseline and follow-up cycles	1-52 weeks
Change in the Changes in Sexual Functioning Questionnaire (CSFQ) score	Changes in Sexual Functioning Questionnaire (CSFQ) score ranges from 14 to 70 points where higher score represents better sexual functioning.	1-52 weeks
Gene transcription and methylation profiles	Derived from mRNA and DNA methylation of genes involved in hormonal signaling pathways	1-52 weeks
Change in visuospatial memory test performance	Derived from immediate, short-term and delayed recall in a Complex Figure Test (CFT) (Taylor CTF will be used at baseline and Reys CTF at follow-up to avoid learning effects). Score ranges from 0-36 with higher scores representing better performance.	1-52 weeks
Change in Letter-Number Sequencing task score	Score ranges from 0-21 with higher scores representing better performance.	1-52 weeks
Change in Symbol Digit Modalities Test (SDMT) score	Derived from change in number of correct guesses with score ranges from 0-110 with higher scores representing better performance.	1-52 weeks
Change in affective bias for emotional detection	Affective bias measures is derived from the Intensity Morphing Task as detection time for sad minus detection time for happy averaged across increase and decrease conditions. Range score is -100% (indicating negative bias) to +100% (indicating positive bias).	1-52 weeks
Change in affective bias for emotion recognition	Affective bias calculated as hit rate for happy minus hit rate for sad in the Emotion Recognition Task. Range score is -100% (indicating negative bias) to +100% (indicating positive bias).	1-52 weeks
Change in Trail Making Test (TMT) Part A and B performance	Derived from time spent with short time representing better performance.	1-52 weeks
Change in Intra-Extra Dimensional (IED) performance	Derived from Extra Dimensional Set Errors and latency in Intra-Extra Dimensional Set Shifting	1-52 weeks
Change in Simple Reaction Time (SRT) task	Derived from time spent in trials with shorter time representing better performance.	1-52 weeks
Color Word Interference Test (CWIT) performance	Derived from test scores in condition 1-4 in D-KEFS Color Word Interference Test (CWIT). The test scores is calculated based on the time spent + corrected errors and uncorrected errors. Shorter time represents better performance.	1-52 weeks
Verbal Fluency (VF) performance	Derived from test scores from subcategories ("f", "a", "s", "animals", "boy names", "fruit/furniture") in the Verbal Fluency Task	1-52 weeks
Change in Snaith-Hamilton Pleasure Scale score	Snaith-Hamilton Pleasure Scale (score range: 0-14, higher score indicating higher level of anhedonia)	1-52 weeks
Ruminative Responses Scale score	Ruminative Responses Scale (score range: 22-88, higher score indicating higher level of ruminative symptoms),	1-52 weeks
Change in Beck Depression Inventory-II score	Beck Depression Inventory-II (score range: 0-63, higher score indicating more severe depressive symptoms)	1-52 weeks
Change in WHO-5 Well-being index	WHO-5 Well-being index (score range: 0-25, higher score representing higher quality of life)	1-52 weeks
Change in Perceived Stress Scale score	Perceived Stress Scale (score range: 0-40, higher score indicating more perceived stress)	1-52 weeks
Change in the Female Sexual Distress Scale score	The Female Sexual Distress Scale ranges from 0 to 48 point with higher score representing more sexual distress.	1-52 weeks
Change in Positive Affect (PA) score derived from the Positive and Negative Affect Schedule (PANAS) questionnaire (regarding "last few weeks")	PA score ranges from 10-50 with higher scores representing higher levels of positive affect	1-52 weeks
Change in Negative Affect (NA) score derived from the Positive and Negative Affect Schedule (PANAS) questionnaire (regarding "last few weeks")	NA score ranges from 10-50 with higher scores representing higher levels of negative affect	1-52 weeks
Change in State Trait Anxiety Inventory score	State Trait Anxiety Inventory (score range: 20-80, higher score indicating higher level of anxiety)	1-52 weeks
Change State-Trait Anger Expression Inventory 2 score	State-Trait Anger Expression Inventory 2 (score range: 15-60, higher score indicating higher level of anger)	1-52 weeks
Change in Barratt Impulsiveness Scale Version 11 score	Barratt Impulsiveness Scale Version 11 score ranges from 30-120 with higher score indicating more impulsiveness.	1-52 weeks
Change in satiety	Satiety visual analog scale ranges from 0-100 with higher score indicating higher satiety.	1-52 weeks
Change in Simplified Nutrition Assessment Questionnaire (SNAQ) score	Simplified Nutrition Assessment Questionnaire (SNAQ) ranges from 4-20 with higher score indicating more appetite	1-52 weeks
Change in cognitive complaints in bipolar disorder rating assessment (COBRA) score	Cognitive complaints in bipolar disorder rating assessment (COBRA) ranges from 0 to 48 with higher score indicating more cognitive complaints.	1-52 weeks
Change in Prospective and retrospective memory questionnaire (PRMQ) score	Prospective and retrospective memory questionnaire (PRMQ) ranges from 16-80 with higher score indicating more memory failures.	1-52 weeks
Change in Probabilistic Reversal Learning Task behaviour	Probabilistic Reversal Learning Task behaviour, including mean errors, switch probabilities, reinforcement behavior	1-52 weeks
Change in the Female Sexual Function Index (FSFI) score	Female Sexual Function Index (FSFI) score ranges from 2-36 with higher scores representing higher sexual functioning	1-52 weeks
Change in the 17-item Hamilton Depression Rating Scale (HDRS-17) score	17-item Hamilton Depression Rating Scale (HDRS-17) score ranges from 0-54 with higher scores representing higher level of depressive symptoms	1-52 weeks

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Søren Vinther Larsen, MD, PhD, Neurobiology Research Unit, Rigshospitalet

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: March 28, 2026
• First Submitted That Met QC Criteria: March 28, 2026
• First Posted (Actual): April 6, 2026

Study Record Updates

• Last Update Posted (Actual): April 9, 2026
• Last Update Submitted That Met QC Criteria: April 4, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: REVERSE; H-25059351 (Other Identifier: De Videnskabsetiske Komitéer for Region Hovedstaden)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: When the planned analyses from the trial are published, the data will become publicly available. According to the Danish legislation, data will be available only by approval by the Danish Data Protection Agency and with a signed agreement.
• IPD Sharing Time Frame: Data are expected to become available from December 2030.
• IPD Sharing Access Criteria: Data will be available on reasonable request via an application to the Cimbi database of molecular brain PET in healthy humans. Access can be requested through the procedures outlined here:
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No