Effect of Ethinylestradiol/Levonorgestrel Discontinuation vs Continuation on Antidepressant Efficacy and Verbal Memory in Major Depressive Disorder

The primary objective is to determine whether COC discontinuation compared with continuation influences (i) antidepressant treatment outcome and (ii) verbal memory performance at week 8 in participants receiving standard pharmacological antidepressant therapy for Major Depressive Disorder.

• Assess the impact of COC discontinuation versus continuation on antidepressant dose titration, add‑on therapy, or switches at week 8.
• Evaluate clinical recovery at weeks 1, 2, 4, and 12 under concurrent antidepressant treatment.
• Examine verbal memory performance at weeks 4 and 12.
• Measure striatal 5‑HT4R binding after 8 weeks of antidepressant therapy.
• Investigate peripheral and brain insulin sensitivity after 8 weeks.
• Determine cortisol dynamics at week 8.
• Assess peripheral and brain inflammation at week 8.
• Quantify hippocampal activation during memory encoding at week 8.
• Evaluate sexual desire at week 8.
• Measure reward‑related ventral striatum activation at week 8.
• Assess anxiety levels at week 8.
• Analyze resting‑state functional connectivity at week 8.
• Determine hippocampal volume changes at week 8.
• Characterize gut microbiome composition and metabolite profiles at week 8.
• Assess sleep quality at week 8.
• Examine depressive symptom severity and treatment titration rank 6 months after intervention.
• Determine probability of remission 6 months after intervention.
• Evaluate risk of hospitalization, suicide, suicide attempts, or further treatment modifications within 12 months.

The trial enrolled biologically female individuals aged 18–39 years who were current users of combined oral contraception for at least one month and who met ICD‑10 criteria for a primary moderate to severe unipolar depressive episode consistent with Major Depressive Disorder, for which SSRI monotherapy was clinically indicated; the sponsor did not provide the total number of participants, as Rowsubjectcount equals 0.

The study is a Major Depressive Disorder trial employing a randomized, double‑blind, placebo‑controlled design in which eligible women aged 18–39 who are current users of combined oral contraception are allocated to either continuation of the contraceptive or discontinuation while receiving standard SSRI monotherapy (sertraline 200 mg or duloxetine 120 mg daily). After a screening visit confirming eligibility, participants enter an 8‑week intervention period that includes baseline assessments, weekly follow‑up visits for safety monitoring, medication adherence checks, and outcome evaluations (Hamilton Depression Rating Scale‑6 and verbal memory tasks). The final visit occurs at week 8 to collect end‑of‑study data. Participant involvement therefore spans approximately 10 weeks including screening. Early termination may occur if a participant experiences a serious adverse event, becomes pregnant, withdraws consent, or fails to adhere to the study medication regimen.

The investigational product is a combined oral contraceptive (COC) tablet marketed as Femicept, overtrukne tabletter. Each coated tablet contains ethinylestradiol and levonorgestrel and is administered orally at a dose of 2 U once daily throughout the 8‑week treatment period. Participants assigned to the test arm receive the COC continuously, whereas those in the discontinuation arm discontinue the COC at study entry and receive a matching oral placebo.

The placebo comparator consists of an inert oral tablet, also dosed at 2 U once daily for 8 weeks, matching the appearance of the COC tablet to maintain blinding.

Standard‑of‑care antidepressant therapy is provided to all participants. Sertraline is supplied as an oral tablet at a fixed dose of 200 mg taken once daily. Duloxetine is supplied as an oral tablet at a fixed dose of 120 mg taken once daily. Both agents are administered throughout the study period in conjunction with the COC or placebo as appropriate.

Dosing adherence is monitored by pill count at each scheduled visit and by patient‑reported dosing diaries. Compliance is defined as intake of at least 80 % of the prescribed tablets for each study medication. Any missed doses are recorded, and participants with insufficient compliance may be excluded from per‑protocol analyses.

Efficacy will be evaluated primarily by the change in Hamilton Depressive Rating Scale 6-item (HRDS-6) score and the mean total Verbal Affective Memory Task 24 (VAMT-24) recall score, calculated as the average of immediate, short‑term, and long‑term recall. Both assessments are administered at baseline and at week 8 while participants continue concomitant antidepressant therapy. The HRDS‑6 is a clinician‑rated instrument, and the VAMT‑24 is a standardized neurocognitive task administered under controlled conditions.

Secondary efficacy measures include the antidepressant treatment titration rank, mean HRDS‑6 score, and the mean total Rey‑Auditory Verbal Learning Test (RAVLT) recall score (average of immediate, short‑term, and long‑term recall). Neuroimaging endpoints comprise mean striatal 5‑HT4R non‑displaceable binding potential (BPND) by PET, hypothalamic blood‑flow response to oral glucose, hypothalamic BOLD response to oral glucose, and mean hippocampal activation during a memory‑encoding fMRI paradigm. Metabolic and endocrine biomarkers include mean Homeostatic Model Assessment of Insulin Resistance (HOMA‑IR), mean cortisol awakening response, and mean extra‑neurite mean diffusivity as an index of brain inflammation, together with hsCRP and the kynurenic acid/quinolinic acid ratio (neuroprotective index). Additional functional imaging outcomes cover ventral striatal activation during a monetary reward task, resting‑state functional connectivity, and hippocampal gray‑matter volume by MRI. Peripheral and microbiome assessments consist of gut microbiome composition, gut‑derived metabolites, and the Pittsburgh Sleep Quality Index score. Patient‑reported outcomes comprise the Major Depression Inventory score, General Anxiety Disorder‑7 score, Element of Desire score, time to remission, and time to hospitalization, suicide, suicide attempt, or treatment switches/add‑on. All secondary endpoints are collected according to the protocol‑specified schedule, using validated scales, laboratory assays, and imaging modalities, and will be analyzed with appropriate statistical models to compare the discontinuation and continuation groups.