Association Between Intrauterine System Hormone Dosage and Depression Risk.

OBJECTIVE: The authors compared the associated risk of incident depression between first-time users of low-, medium-, and high-dose levonorgestrel-releasing intrauterine systems (LNG-IUSs). METHODS: This national cohort study was based on Danish register data on first-time users of LNG-IUSs, 15-44 years of age, between 2000 and 2022. Cox regression and a G-formula estimator were used to report 1-year average absolute risks, risk differences, and risk ratios of incident depression, defined as initiation of an antidepressant or receipt of a depression diagnosis, standardized for calendar year, age, education level, parental history of mental disorders, endometriosis, menorrhagia, polycystic ovary syndrome, dysmenorrhea, leiomyoma, and postpartum initiation. RESULTS: In total, 149,200 women started using an LNG-IUS, among whom 22,029 started a low-dose one (mean age, 22.9 years [SD=4.5]), 47,712 a medium-dose one (mean age, 25.2 years [SD=6.2]), and 79,459 a high-dose one (mean age, 30.2 years [SD=5.6]). The associated subsequent 1-year adjusted absolute risks of incident depression were 1.21% (95% CI=1.06-1.36), 1.46% (95% CI=1.33-1.59), and 1.84% (95% CI=1.72-1.96), respectively. For the users of high-dose LNG-IUSs, the risk ratios were 1.52 (95% CI=1.30-1.74) and 1.26 (95% CI=1.10-1.41) compared with users of the low- and medium-dose LNG-IUSs, respectively. For users of medium-dose LNG-IUSs, the risk ratio was 1.21 (95% CI=1.03-1.39) compared with users of low-dose LNG-IUSs. CONCLUSIONS: First-time use of an LNG-IUS was positively associated with incident depression in an LNG-dose-dependent manner across low-, medium-, and high-dose LNG-IUSs. 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.

Depression Associated With Hormonal Contraceptive Use as a Risk Indicator for Postpartum Depression.

Importance: Hormonal sensitivity may contribute to the risk of depression in some women, as observed during the premenstrual, postpartum, and perimenopausal phases, and when initiating hormonal contraception (HC). However, little evidence exists to support that such depressive episodes are linked across the reproductive life span. Objective: To determine whether prior depression associated with HC initiation is coupled with a higher risk of postpartum depression (PPD) than prior depression not associated with HC initiation. Design, Setting, and Participants: This cohort study used Danish health registry data collected from January 1, 1995, through December 31, 2017, and analyzed from March 1, 2021, through January 1, 2023. All women living in Denmark born after 1978 with their first delivery between January 1, 1996, and June 30, 2017, were eligible for inclusion; 269 354 met these criteria. Women were then excluded if they had never used HC or if they had a depressive episode before 1996 or within 12 months prior to delivery. Exposures: Prior depression associated with vs not associated with HC initiation, ie, if developed within 6 months after start of an HC exposure or not. Depression was defined as a hospital diagnosis of depression or filling a prescription for antidepressant medication. Main Outcomes and Measures: Crude and adjusted odds ratios (ORs) were calculated for the incidence of PPD defined as the development of depression within 6 months after first delivery. Results: Of 188 648 first-time mothers, 5722 (3.0%) (mean [SD] age, 26.7 [3.9] years) had a history of depression associated with initiation of HC use, and 18 431 (9.8%) (mean [SD] age, 27.1 [3.8] years) had a history of depression not associated with the initiation of HC. Women with HC-associated depression had a higher risk of PPD than women with prior non-HC-associated depression (crude OR, 1.42 [95% CI, 1.24-1.64]; adjusted OR, 1.35 [95% CI, 1.17-1.56]). Conclusions and Relevance: These findings suggest that a history of HC-associated depression may be associated with a higher risk of PPD, supporting that HC-associated depression may indicate PPD susceptibility. This finding offers a novel strategy in clinical PPD risk stratification and points to the existence of a hormone-sensitive subgroup of women.

Deep phenotyping towards precision psychiatry of first-episode depression - the Brain Drugs-Depression cohort.

BACKGROUND: Major Depressive Disorder (MDD) is a heterogenous brain disorder, with potentially multiple psychosocial and biological disease mechanisms. This is also a plausible explanation for why patients do not respond equally well to treatment with first- or second-line antidepressants, i.e., one-third to one-half of patients do not remit in response to first- or second-line treatment. To map MDD heterogeneity and markers of treatment response to enable a precision medicine approach, we will acquire several possible predictive markers across several domains, e.g., psychosocial, biochemical, and neuroimaging. METHODS: All patients are examined before receiving a standardised treatment package for adults aged 18-65 with first-episode depression in six public outpatient clinics in the Capital Region of Denmark. From this population, we will recruit a cohort of 800 patients for whom we will acquire clinical, cognitive, psychometric, and biological data. A subgroup (subcohort I, n = 600) will additionally provide neuroimaging data, i.e., Magnetic Resonance Imaging, and Electroencephalogram, and a subgroup of patients from subcohort I unmedicated at inclusion (subcohort II, n = 60) will also undergo a brain Positron Emission Tomography with the [11C]-UCB-J tracer binding to the presynaptic glycoprotein-SV2A. Subcohort allocation is based on eligibility and willingness to participate. The treatment package typically lasts six months. Depression severity is assessed with the Quick Inventory of Depressive Symptomatology (QIDS) at baseline, and 6, 12 and 18 months after treatment initiation. The primary outcome is remission (QIDS ≤ 5) and clinical improvement (≥ 50% reduction in QIDS) after 6 months. Secondary endpoints include remission at 12 and 18 months and %-change in QIDS, 10-item Symptom Checklist, 5-item WHO Well-Being Index, and modified Disability Scale from baseline through follow-up. We also assess psychotherapy and medication side-effects. We will use machine learning to determine a combination of characteristics that best predict treatment outcomes and statistical models to investigate the association between individual measures and clinical outcomes. We will assess associations between patient characteristics, treatment choices, and clinical outcomes using path analysis, enabling us to estimate the effect of treatment choices and timing on the clinical outcome. DISCUSSION: The BrainDrugs-Depression study is a real-world deep-phenotyping clinical cohort study of first-episode MDD patients. TRIAL REGISTRATION: Registered at clinicaltrials.gov November 15th, 2022 (NCT05616559).

The Impact of Hormonal Contraceptive Use on Serotonergic Neurotransmission and Antidepressant Treatment Response: Results From the NeuroPharm 1 Study.

Background: Hormonal contraceptive (HC) use has been associated with an increased risk of developing a depressive episode. This might be related to HC's effect on the serotonergic brain system as suggested by recent cross-sectional data from our group, which show that healthy oral contraceptive (OC) users relative to non-users have lower cerebral serotonin 4 receptor (5-HT4R) levels. Here, we determine if cerebral 5-HT4R binding differs between HC non-users, OC users, and hormonal intrauterine device (HIUD) users among women with an untreated depressive episode. Also, we test if antidepressant drug treatment response and its association with pre-treatment 5-HT4R binding depends on HC status. Methods: [11C]-SB207145 Positron Emission Tomography imaging data from the NeuroPharm-NP1 Study (NCT02869035) were available from 59 depressed premenopausal women, of which 26 used OCs and 10 used HIUDs. The participants were treated with escitalopram. Treatment response was measured as the relative change in the Hamilton Depression Rating Scale 6 items (rΔHAMD6) from baseline to week eight. Latent variable models were used to evaluate the association between global 5-HT4R binding and OC and HIUD use as well as rΔHAMD6. Results: We found no evidence of a difference in global 5-HT4R binding between depressed HC users and non-users (p≥0.51). A significant crossover interaction (p=0.02) was observed between non-users and OC users in the association between baseline global 5-HT4R binding and week eight rΔHAMD6; OC users had 3-4% lower binding compared to non-users for every 10% percent less improvement in HAMD6. Within the groups, we observed a trend towards a positive association in non-users (padj=0.10) and a negative association in OC users (padj=0.07). We found no strong evidence of a difference in treatment response between the groups (p=0.13). Conclusions: We found no difference in 5-HT4R binding between HC users vs. non-users in depressed women, however, it seemed that 5-HT4R settings differed qualitatively in their relation to antidepressant drug treatment response between OC users and non-users. From this we speculate that depressed OC users constitutes a special serotonin subtype of depression, which might have implications for antidepressant drug treatment response.

Associations between the cortisol awakening response and patient-evaluated stress and mood instability in patients with bipolar disorder: an exploratory study.

OBJECTIVE: The Cortisol Awakening Response (CAR) measured as the transient increase in cortisol levels following morning awakening appears to be a distinct feature of the HPA axis. Patients with bipolar disorder (BD) experience daily stress, mood instability (MI) and studies have shown disrupted HPA-axis dynamics. AIMS: to evaluate (1) patient-evaluated stress against the CAR, (2) associations between the CAR and mood symptoms, and (3) the effect of smartphone-based treatment on the CAR. METHODS: Patients with BD (n = 67) were randomized to the use of daily smartphone-based monitoring (the intervention group) or to the control group for six months. Clinically rated symptoms according to the Hamilton Depression Rating Scale 17-items (HDRS), the Young Mania Rating Scale (YMRS), patient-evaluated perceived stress using Cohen's Perceived Stress Scale (PSS) and salivary awakening cortisol samples used for measuring the CAR were collected at baseline, after three and six months. In the intervention group, smartphone-based data on stress and MI were rated daily during the entire study period. RESULTS: Smartphone-based patient-evaluated stress (B: 134.14, 95% CI: 1.35; 266.92, p = 0.048) and MI (B: 430.23, 95% CI: 52.41; 808.04, p = 0.026) mapped onto increased CAR. No statistically significant associations between the CAR and patient-evaluated PSS or the HDRS and the YMRS, respectively were found. There was no statistically significant effect of smartphone-based treatment on the CAR. CONCLUSION: Our data, of preliminary character, found smartphone-based patient-evaluations of stress and mood instability as read outs that reflect CAR dynamics. Smartphone-supported clinical care did not in itself appear to disturb CAR dynamics.

Trait aggression and trait impulsivity are not related to frontal cortex 5-HT2A receptor binding in healthy individuals.

Numerous studies indicate that the serotonergic (5-HT) transmitter system is involved in the regulation of impulsive aggression and there is from post-mortem, in vivo imaging and genetic studies evidence that the 5-HT2A receptor may be involved. We investigated 94 healthy individuals (60 men, mean age 47.0±18.7, range 23-86) to determine if trait aggression and trait impulsivity were related to frontal cortex 5-HT2A receptor binding (5-HT2AR) as measured with [18F]-altanserin PET imaging. Trait aggression and trait impulsivity were assessed with the Buss-Perry Aggression Questionnaire (AQ) and the Barratt Impulsiveness Scale 11 (BIS-11). Statistical analyses were conducted using a multiple linear regression model and internal consistency reliability of the AQ and BIS-11 was evaluated by Cronbach's alpha. Contrary to our hypothesis, results revealed no significant associations between 5-HT2AR and the AQ or BIS-11 total scores. Also, there was no significant interaction between gender and frontal cortex 5-HT2AR in predicting trait aggression and trait impulsivity. This is the first study to examine how 5-HT2AR relates to trait aggression and trait impulsivity in a large sample of healthy individuals. Our findings are not supportive of a selective role for 5-HT2AR in mediating the 5-HT related effects on aggression and impulsivity in psychiatrically healthy individuals.

Cardiovascular events before and after surgery for primary hyperparathyroidism.

Cardiovascular disease [atherosclerosis and subsequent myocardial infarction (MI)] has been associated with primary hyperparathyroidism. We aimed at studying cardiovascular events before and after surgery and mortality after surgery for primary hyperparathyroidism using a historical follow-up design. A total of 674 patients who underwent surgery at three Danish centers between January 1, 1979 and December 31, 1997 were compared with 2021 age- and gender-matched controls. There was an increased incidence of acute MI up to 10 years prior to surgery [relative risk (RR) 2.5, 95% confidence interval (95% CI) 1.5-4.2] and within the first year following surgery (RR 3.6, 95% CI 1.7-7.6). The risk of MI subsequently declined to a normal level more than 1 year after surgery. Patients with MI prior to diagnosis also had a higher postoperative risk of new infarction than did patients without [odds ratio (OR) 6.0, 95% CI 1.2-30.0]. The risk of hypertension, stroke, congestive heart failure, and diabetes was increased before surgery. More than 1 year after surgery only hypertension and congestive heart failure were more frequent in patients than controls. Preoperative cardiovascular disease was associated with an increased risk of death (RR 1.8, 95% CI 1.1-2.8). Mortality following surgery was higher than in the general population between 1979 and 1990 but not between 1991 and 1997. We concluded that there was an increase in acute MI up to 10 years prior to surgery. The risk of MI decreased to a normal level after surgery, which may be important for preventing cardiovascular disease in patients with primary hyperparathyroidism.

Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study.

AIM: To study the risk of renal stone episodes and risk factors for renal stones in primary hyperparathyroidism before and after surgery. DESIGN: Register based, controlled retrospective follow up study. SETTING: Tertiary hospitals in Denmark. PARTICIPANTS: 674 consecutive patients with surgically verified primary hyperparathyroidism. Each patient was compared with three age- and sex-matched controls randomly drawn from the background population. Hospital admissions for renal stone disease were compared between patients and controls. Risk factors for renal stones among patients were assessed. MAIN OUTCOME MEASURES: Number of renal stone episodes; comparison of hospital admissions for renal stones in patients and controls; assessment of risk factors for renal stones. RESULTS: Relative risk of a stone episode was 40 (95% confidence interval 31 to 53) before surgery and 16 (12 to 23) after surgery. Risk was increased 10 years before surgery, and became normal more than 10 years after surgery. Stone-free survival 20 years after surgery was 90.4% in patients and 98.7% in controls (risk difference 8.3%, 4.8% to 11.7%). Patients with preoperative stones had 27 times the risk of postoperative stone incidents than controls. Before surgery, males had more stone episodes than females and younger patients had more stone episodes than older patients. Neither parathyroid pathology, weight of removed tissue, plasma calcium levels, nor skeletal pathology (fractures) influenced the risk of renal stones. After surgery, younger age, preoperative stones and ureteral strictures were significant risk factors for stones. CONCLUSIONS: The risk of renal stones is increased in primary hyperparathyroidism and decreases after surgery. The risk profile is normal 10 years after surgery. Preoperative stone events increase the risk of postoperative stones. Stone formers and non-stone formers had the same risk of skeletal complications.