LNG-IUS use ups risk of depression

Use of a levonorgestrel-releasing intrauterine system (LNG-IUS) appears to increase the risk of incident depression, defined as initiation of an antidepressant or receipt of a depression diagnosis, in a dose-dependent manner, suggests a study.

Specifically, high-dose LNG-IUS was associated with a 26-percent higher relative risk than medium-dose LNG-IUS, which correlated with a 21-percent higher relative risk than low-dose LNG-IUS. 

“These differences remained after controlling for medical diagnoses and indications for prescribing high-dose LNG-IUSs,” the investigators said.

This national cohort study utilized Danish register data on first-time users of LNG-IUS, aged 15–44 years, between 2000 and 2022. 

The investigators used Cox regression and a G-formula to assess the 1-year average absolute risks, risk differences, and risk ratios of incident depression, standardized for calendar year, age, education level, parental history of mental disorders, endometriosis, menorrhagia, polycystic ovary syndrome, dysmenorrhea, leiomyoma, and postpartum initiation.

Nearly 150,000 women initiated the use of LNG-IUS. Of these, 22,029 started with a low dose (mean age 22.9 years), 47,712 a medium dose (mean age 25.2 years), and 79,459 a high dose (mean age 30.2 years). [Am J Psychiatry 2024;doi:10.1176/appi.ajp.2023090]

At 1 year, the adjusted absolute risks of incident depression were 1.21 percent (95 percent confidence interval [CI], 1.06–1.36) for low-dose LNG-IUS, 1.46 percent (95 percent CI, 1.33–1.59) for medium-dose LNG-IUS, and 1.84 percent (95 percent CI, 1.72–1.96) for high-dose LNG-IUS.

The risk ratios of incident depression for high-dose users were 1.52 (95 percent CI, 1.30–1.74) compared with low-dose users and 1.26 (95 percent CI, 1.10–1.41) versus medium-dose users. For users of medium-dose LNG-IUS, the risk ratio was 1.21 (95 percent CI, 1.03–1.39) as opposed to low-dose users.

“As hypothesized, this study provides evidence of a dose-dependent association between intrauterine levonorgestrel exposure and incident depression,” the investigators said.

"Although the observational design of the study does not permit causal inference, the dose-response relationship contributes to the body of evidence suggesting a relationship between levonorgestrel exposure and risk of depression,” they noted.

Depressive symptoms

The current findings support those from an international multicentre randomized study, which found a link between LNG exposure and risk of developing depressive symptoms. [Contraception 1994;49:56-72]

The said study reported a higher frequency of self-reported depressive symptoms during the initial treatment period, as well as increased rates of discontinuation reported due to depression among women treated with LNG-IUS relative to counterparts who received copper IUS.

"Furthermore, our results are consistent with those from a recent observational study that showed a 13-percent higher risk of antidepressant use among high-dose compared with medium-dose LNG-IUS users,” said the investigators of the current study. [JAMA 2023;329:257-259]

The present findings also provide new evidence on the possible role of the progestogen component of hormonal contraception in developing mood disorders. However, the mechanism behind the impact of progestogens on the brain and mood and whether the administration route plays a role remain unclear. [Front Neuroendocrinol 2021;63:100943; Pharmaceuticals (Basel) 2023;16:520]

“Some evidence points to a potential mechanism through modulating effects on the regulation of stress reactivity via the hypothalamic-pituitary-adrenal axis, and preclinical evidence points to a link between LNG-induced alterations in brain γ-aminobutyric acid receptor plasticity and anxiety-like behaviour in rats,” according to the investigators. [Psychoneuroendocrinology 2017;80:39-45; Pharmacol Biochem Behav 2012;102:366-372]