Reversible Effects of Oral Contraceptive Removal on Serotonergic Neurotransmission

• 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.