Vibe Gedsoe Froekjaer

Background: Major depressive disorder (MDD) is clinically heterogeneous, hindering identification of reproducible biomarkers. Using a semi-supervised machine learning approach, HYDRA, we previously identified two neuroanatomical dimensions from structural MRI in medication-free MDD from COORDINATE-MDD consortium. These dimensions (D1, D2) showed differential responses to selective serotonin reuptake inhibitor (SSRI) antidepressants and placebo. External replication in UK Biobank linked D2, characterized by widespread subtle neuroanatomical reductions, to an immuno-metabolic profile. Here, we examined whether these dimensions are detectable early in the course of illness. Methods: We applied the pre-trained model to structural MRI data from the multisite PRONIA cohort, comprising individuals with recent-onset depression (ROD; n = 377; mean age 25.8 years, SD 6.0; 51.3% female) and healthy controls (n = 267; mean age 25.5 years, SD 6.4; 61.0% female). Participants were assigned to clusters (C1, C2) corresponding to the previously identified dimensions (D1, D2). Clusters were compared on clinical symptom profiles, peripheral inflammatory markers, and in a subset (n = 107), proteomic ageing indices. Results: Two neuroanatomical clusters were identified in PRONIA. C1 (n = 265) showed higher negative symptom severity and elevated interleukin-2 levels. C2 (n = 140) was associated with higher residual proteomic age. Overall depressive symptom severity did not differ significantly between clusters. Conclusions: Neuroanatomical dimensions of MDD are reproducible and detectable at illness onset. Associations with negative symptom severity, inflammatory signalling, and proteomic ageing suggest these dimensions capture biologically meaningful heterogeneity early in depression. These findings support a biologically informed framework for stratified treatment approaches in MDD.

Importance: Hormonal contraceptive (HC) use is associated with depression. It is, however, unknown whether this is also true in the postpartum period when women have a heightened depression risk and are routinely offered HC treatment.Objective: To examine whether HC initiation post partum is associated with the development of depression within 12 months post partum.Design, Setting, and Participants: A population-based cohort study based on nationwide Danish register data was conducted including all primiparous women who gave birth from January 1, 1997, through December 31, 2022. Women were excluded if they had depression within 24 months before delivery, multiple births or stillbirth, or a diagnosis of breast cancer or liver tumor. Data analysis was conducted between March 20, 2023, and January 17, 2025. Exposure: Hormonal contraceptive initiation within 12 months post partum was treated as a time-varying exposure. Hormonal contraceptive types were categorized as combined oral contraceptives (COCs), combined nonoral contraceptives (CNOCs), progestogen-only pills (POPs), and progestogen-only nonoral contraceptives (PNOCs).Main Outcomes and Measures: Depression within 12 months post partum, defined as filling an antidepressant prescription or receiving a hospital diagnosis of depression, was the main outcome. Adjusted hazard ratios (AHRs) and average absolute risks of depression within 12 months post partum were estimated using Cox proportional hazards regression and a G-formula estimator.Results: Of 610 038 first-time mothers, 248 274 (40.7%) initiated HCs within 12 months post partum (mean [SD] age, 27.6 [4.3] years for HC users vs 29.6 [4.8] years for nonusers). Hormonal contraceptive initiation was associated with subsequent depression, with an AHR of 1.49 (95% CI, 1.42-1.56) compared with no use, resulting in an increase in the 12-month absolute risk from 1.36% (95% CI, 1.32%-1.39%) to 1.54% (95% CI, 1.50%-1.57%). The AHR for COC was 1.72 (95% CI, 1.63-1.82); CNOC, 1.97 (95% CI, 1.64-2.36); and PNOC, 1.40 (95% CI, 1.25-1.56). Progestogen-only pill exposure was associated with an instantaneously reduced risk in the early study period, but it was increased late post partum. The earlier COCs were initiated post partum the higher the associated rate ratio of depression.Conclusions and Relevance: In this cohort study, HC initiation post partum was associated with an instantaneous increased risk of developing depression. The associated risk was higher the earlier it was initiated post partum, at least for COC. This finding raises the issue of whether the incidence of depression post partum is increased by routine HC initiation after childbirth.

Importance: Hormonal contraceptive (HC) use is associated with depression. It is, however, unknown whether this is also true in the postpartum period where women have a heightened depression risk and are routinely offered to start HC. Objective: To determine if HC initiation postpartum is associated with depression development within 12 months postpartum. Design: A cohort study based on Danish register data. Setting: Nationwide population-based. Participants: All primiparous women in Denmark who gave birth from 1997 through 2022. Women were excluded if they had a depression within 24 months prior to delivery, had multiple birth or stillbirth, or a diagnosis of breast cancer or liver tumor. Exposure: HC initiation within 12 months postpartum treated as a time-varying exposure. HC types were categorized as combined oral contraceptives (COCs), combined non-oral contraceptives (CNOCs), progestogen-only pills (POPs), and progestogen-only non-oral contraceptives (PNOCs). Main Outcome and Measure: Depression defined as filling an antidepressant prescription or receiving a hospital depression diagnosis. Adjusted hazards ratios (HRs) and average absolute risks of depression within 12 months postpartum were estimated using Cox regression and a G-formula estimator. Results: Of 610,038 first-time mothers, 41% initiated HC within 12 months postpartum (mean [SD] age; 27.6 [4.3] years for HC users vs. 29.6 [4.8] years for non-users). HC initiation was associated with subsequent depression with a HR of 1.49 (95% CI, 1.42;1.56) compared to no use resulting in an increase in the 12-month absolute risk from 1.36% (1.32;1.39) to 1.54% (1.50;1.57).The HR for COC was 1.72 (1.63;1.82); CNOC 1.97 (1.64;2.36); PNOC 1.40 (1.25;1.56). POP exposure was associated with an initially reduced instantaneous risk but it was increased late postpartum. Investigating the impact of timing of initiation showed that the earlier COC was initiated postpartum the higher the associated rate ratio of depression. Conclusions and Relevance: HC initiation postpartum was associated with 49% higher instantaneous depression risk resulting in an increase in 12-month risk from 1.36% to 1.54% in the observed population. Such associated risk was higher the earlier it was initiated postpartum, at least for COC. This raises the question if depression incidence postpartum is inflated by routine HC initiation after childbirth.

Background: Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT₄) in a cohort of healthy individuals (N = 254) and, for 5-HT_4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT₄ and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. Results: We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. Conclusions: We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.