2026 ECNP Congress

PS04-4074

Effects of combined oral contraceptive use on tryptophan metabolism and implications for serotonergic neurotransmission, memory and mood in healthy women

Laura Juul — A. Fuglsang-Damgaard, V.G. Frokjaer, S.V. Larsen · Rigshospitalet, Neurobiology Research Unit, Copenhagen, Denmark

2026 ECNP Congress

Introduction

Combined oral contraceptive (COC) use is associated with an increased risk of depression (1). One potential mechanism is that COC use may influence tryptophan metabolism, by shifting it away from serotonin synthesis towards the kynurenine pathway. Consequently, this could lead to an increased production of the neurotoxic metabolite quinolinic acid (QA), and a decreased production of the neuroprotective metabolite kynurenic acid (KA) (2). Such neurotoxic changes could potentially affect brain chemistry; we have shown that COC use results in 9-12% lower cerebral serotonin 4 receptor (5-HT4R) levels (3). The 5-HT4R can be interpreted as a marker of brain serotonergic tone (4) and is important in the context of depression and memory (5). If COCs affect tryptophan metabolism, this could alter serotonergic settings and consequently also mood and memory.

Aims

The primary aim was to access if COC use affects tryptophan metabolism by reducing the KA/QA-ratio, a neuroprotective index. The secondary aim was to access if change in KA/QA-ratio mediates the observed effect of COC use on global 5-HT4R brain binding, verbal memory and potentially mood.

Methods

This study presents post hoc analyses from a previous single-blind, randomized, placebo-controlled trial (ClinicalTrials.gov ID: NCT05212389), where healthy women were randomized 1:1 to either 3 months of COC (150 μg levonorgestrel and 30 μg ethinylestradiol) or placebo (n=43). Tryptophan metabolites were quantified using liquid chromatography tandem mass by Bevital A/S, Norway.

An analysis of covariance (ANCOVA) was applied to assess the effect of COC use vs. placebo on the KA/QA ratio at follow-up, with baseline values included as a covariate. Latent variable models (LVMs) were applied to evaluate whether changes in the KA/QA ratio were associated with global constructs of 5-HT4R brain binding, memory and mood, respectively. Positron Emmison Tomography (PET) with the radiotracer [11C]-SB207145 was used to quantify 5-HT4R binding potentials across neostriatum, hippocampus, and neocortex. The Hamilton Depression Rating Scale (HDRS-17), Beck Depression Inventory–II (BDI‑II) and Profile of Mood States (POMS) were used to assess mood, and the Verbal Affective Memory Task‑24 (VAMT24) to assess memory.

Results

The ANCOVA model showed that the intervention had no significant effect on KA/QA ratio change (β = -0.014, 95% CI [-0.37, -0.009], p = 0.236). LVMs showed no association between KA/QA ratio and the latent construct defined by 5-HT4R binding, memory or mood.

Conclusions

We found no significant effect of the intervention (i.e. COC versus placebo) on the KA/QA ratio. However, we note that the direction of the estimate fits the hypothesized direction of association. The LVMs revealed no associations between KA/QA ratio and a construct of 5-HT4R binding, memory and mood. This study finds no evidence to support that the lower 5-HT4R binding in COC users is due to alterations in tryptophan metabolism, thus we speculate that it involves other mechanisms such as changed 5-HT4R expression level due to changed hormonal environment.

References

  1. Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø. Association of Hormonal Contraception With Depression. JAMA Psychiatry. 1. november 2016;73(11):1154–62. doi:10.1001/jamapsychiatry.2016.2387 PubMed PMID: 27680324.
  2. Bjørke-Monsen AL, Varsi K, Sakkestad ST, Ulvik A, Ebbing C, Ueland PM. Lower levels of the neuroprotective tryptophan metabolite, kynurenic acid, in users of estrogen contraceptives. Sci Rep. 29. september 2023;13(1):16370. doi:10.1038/s41598-023-43196-6 PubMed PMID: 37773439; PubMed Central PMCID: PMC10541439.
  3. Larsen SV, Köhler-Forsberg K, Dam VH, Poulsen AS, Svarer C, Jensen PS, m.fl. Oral contraceptives and the serotonin 4 receptor: a molecular brain imaging study in healthy women. Acta Psychiatr Scand. oktober 2020;142(4):294–306. doi:10.1111/acps.13211 PubMed PMID: 33314049; PubMed Central PMCID: PMC7586815.
  4. Haahr ME, Fisher PM, Jensen CG, Frokjaer VG, McMahon B, Madsen K, m.fl. Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: A [11C]SB207145 PET study. Mol Psychiatry. 2014;19(4):427–32. doi:10.1038/mp.2013.147 PubMed PMID: 24189342.
  5. Köhler-Forsberg K, Dam VH, Ozenne B, Sankar A, Beliveau V, Landman EB, m.fl. Serotonin 4 Receptor Brain Binding in Major Depressive Disorder and Association With Memory Dysfunction. JAMA Psychiatry. 1. april 2023;80(4):296–304. doi:10.1001/jamapsychiatry.2022.4539 PubMed PMID: 36753296; PubMed Central PMCID: PMC9909578.