The Relationship Between Cardiovascular Disease Risk and Major Depression.

Introduction: Cardiovascular risk in depression has been investigated in small clinical samples and population-based studies revealing inconclusive results. However, cardiovascular risk in drug-naive depressed patients has not been tested extensively. Methods: Body mass index-based Framingham Cardiovascular Risk Scores and soluble intercellular adhesion molecule-1 (sICAM-1) levels were used to assess the risk of cardiovascular disease in drug-naive depressed patients and healthy volunteers. Conclusion: There were no significant differences in Framingham Cardiovascular Risk Scores and individually assessed risk variables between patients and healthy controls (HC). Both groups were comparable in terms of sICAM-1. Results: The widely recognized association between cardiovascular risk and major depression might be more prominent in older depressed patients and patients with recurring episodes.

Associations Between Blood Levels of NLRP3 Inflammasome Components and Obsessive Compulsive Disorder.

Introduction: Even though the effect of inflammation on pathogenesis of obsessive compulsive disorder (OCD) is known, information regarding the underlying mechanisms are yet to be revealed. The NLRP3 inflammasome complex is an important component of the innate immune system that initiates and mediates inflammatory response to a variety of stimuli. This study aims to inquire into a possible association between NLRP3 inflammasome complex and OCD. Methods: This case-control study included 103 participants (51 cases with OCD and 52 healthy controls). All participants were evaluated with the Yale Brown Obsessive Compulsive Scale, Hamilton Depression Scale, and Hewitt Multidimensional Perfectionism Scale. RNA and proteins were extracted from peripheral blood mononuclear cells. Expression of NLRP3 inflammasome components were determined using quantitative real-time polymerase chain reaction (PCR) and Western blotting. Levels of Serum IL-1beta and IL-18 cytokine were determined by ELISA. Results: NEK7 and CASP1 mRNA levels were significantly higher in OCD patients, compared to controls. Pro-caspase-1 protein levels were elevated, as well. Regression analysis showed that NEK7 mRNA and pro-caspase-1 protein levels can differentiate OCD and healthy control groups. Conclusion: Our results provide insight into the molecular alterations that could explain the inflammation-OCD association.

Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey

Objective: A significant rise in the number of trans adolescents seeking medical interventions has been reported in recent years. The aim of this study was to report the clinical features, treatment, and follow-up of adolescents with gender dysphoria (GD) with our increased experience. Methods: Twenty-six male-to-female (MTF) and twenty-seven female-to-male (FTM) adolescents who were referred to the GD-outpatient clinic between 2016 and 2022 were reviewed. The clinical and laboratory findings of thirty transgender adolescents (15 FTM /15 MTF) who received medical intervention were evaluated retrospectively. Results: Most individuals (60.4%) were admitted between 2020 and 2022, and the remaining (39.6%) were admitted between 2016 and 2019. At the time of referral, median age was 16.3 years [interquartile range (IQR) 1.53; range 13.2-19.4] in 26 MTF, and 16.4 years (IQR 1.74; range 11.7-21.6) in 27 FTM adolescents. The median age at pubertal blockage with gonadotropin-releasing hormone analog and androgen receptor blocker was 16.4 years (IQR 1.4; range 11.7-17.8) in 22 adolescents (9 MTF, 13 FTM), and 17.4 years (IQR 1.4; range 15.5-19.4) in 6 MTF individuals, respectively. Cross-sex hormone therapy was commenced in 21 adolescents (12 MTF, 9 FTM) at the median age of 17.7 years (IQR 0.61; range 16-19.5). Fifteen individuals (8 MTF, 7 FTM) have been transferred to the adult endocrinology department in transition clinics. Conclusion: All treatments were generally well tolerated and effective, including bicalutamide, and no significant side effects were observed. Transition clinics played an important role in the better management of gender reassignment processes.

Associations of neuroimaging markers with depressive symptoms over time in middle-aged and elderly persons.

BACKGROUND: Cerebrovascular disease is regarded as a potential cause of late-life depression. Yet, evidence for associations of neuroimaging markers of vascular brain disease with depressive symptoms is inconclusive. We examined the associations of neuroimaging markers and depressive symptoms in a large population-based study of middle-aged and elderly persons over time. METHODS: A total of 4943 participants (mean age = 64.6 ± 11.1 years, 55.7% women) from the Rotterdam Study were included. At baseline, total brain volume, gray matter volume, white matter volume, white matter hyperintensities volume, cortical infarcts, lacunar infarcts, microbleeds, white matter fractional anisotropy, and mean diffusivity (MD) were measured with a brain MRI (1.5T). Depressive symptoms were assessed twice with the Center for Epidemiologic Studies Depression scale (median follow-up time: 5.5 years, IQR = 0.9). To assess temporal associations of neuroimaging markers and depressive symptoms, linear mixed models were used. RESULTS: A smaller total brain volume (ß = -0.107, 95% CI -0.192 to -0.022), larger white matter hyperintensities volume (ß = 0.047, 95% CI 0.010-0.084), presence of cortical infarcts (ß = 0.194, 95% CI 0.047-0.341), and higher MD levels (ß = 0.060, 95% CI 0.022-0.098) were cross-sectionally associated with more depressive symptoms. Longitudinal analyses showed that small total brain volume (ß = -0.091, 95% CI -0.167 to -0.015) and presence of cortical infarcts (ß = 0.168, 95% CI 0.022-0.314) were associated with increasing depressive symptoms over time. After stratification on age, effect sizes were more pronounced at older ages. CONCLUSIONS: Neuroimaging markers of white matter microstructural damage were associated with depressive symptoms longitudinally in this study of middle-aged and elderly persons. These associations were more pronounced at older ages, providing evidence for the role of white matter structure in late-life depressive symptomatology.

Relationship of negative symptom severity with cognitive symptoms and functioning in subjects at ultra-high risk for psychosis.

AIM: Negative symptoms and cognition are related with functioning in schizophrenia. However, it is not clear whether they have a similar effect in individuals at ultra-high risk (UHR) for psychosis. In this study, we aimed to explore relationship of negative symptoms with cognition and functioning cross-sectionally in people with UHR for psychosis. METHODS: In total, 107 people participated in this study. We assessed negative symptoms with Scale for Negative Symptoms (SANS). We applied a cognitive battery including seven tests. We evaluated functioning by using Global Assessment of Functioning Scale and work/study status as an indicator of role functioning. RESULTS: SANS scores were correlated to global functioning cross-sectionally. SANS total score was correlated to cognitive test scores related to cognitive flexibility and attention. Only Trail Making Test B (TMT B) was negatively correlated to global functioning. SANS-affective blunting and SANS-avolition scores were independently related to global functioning. There was a significant indirect effect of the TMT B and composite attention scores on global functioning through negative symptoms indicating a complete mediation. CONCLUSION: Our findings suggest that negative symptoms, particularly avolition have an impact on functioning and the association of cognition with functioning was mediated by negative symptoms in UHR.

Bivariate genome-wide association analyses of the broad depression phenotype combined with major depressive disorder, bipolar disorder or schizophrenia reveal eight novel genetic loci for depression.

Although a genetic basis of depression has been well established in twin studies, identification of genome-wide significant loci has been difficult. We hypothesized that bivariate analyses of findings from a meta-analysis of genome-wide association studies (meta-GWASs) of the broad depression phenotype with those from meta-GWASs of self-reported and recurrent major depressive disorder (MDD), bipolar disorder and schizophrenia would enhance statistical power to identify novel genetic loci for depression. LD score regression analyses were first used to estimate the genetic correlations of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia. Then, we performed four bivariate GWAS analyses. The genetic correlations (rg ± SE) of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia were 0.79 ± 0.07, 0.24 ± 0.08, 0.53 ± 0.09 and 0.57 ± 0.05, respectively. From a total of 20 independent genome-wide significant loci, 13 loci replicated of which 8 were novel for depression. These were MUC21 for the broad depression phenotype with self-reported MDD and ZNF804A, MIR3143, PSORS1C2, STK19, SPATA31D1, RTN1 and TCF4 for the broad depression phenotype with schizophrenia. Post-GWAS functional analyses of these loci revealed their potential biological involvement in psychiatric disorders. Our results emphasize the genetic similarities among different psychiatric disorders and indicate that cross-disorder analyses may be the best way forward to accelerate gene finding for depression, or psychiatric disorders in general.

Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression.

BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

No Interaction Between Childhood Maltreatment and Serotonin Transporter Gene in Recurrent Major Depressive Disorder: A Clinical Sample.

INTRODUCTION: There is inconsistent evidence of interaction between childhood adversities and a serotonin transporter promoter polymorphism (5-HTTLPR) in depression. It is hypothesized that genetic sensitivity to stress could be more specific to recurrent major depressive disorder (MDD). The aim of the study is to replicate a recent study which provided preliminary evidence of interaction between severity of childhood maltreatment and the 5-HTTLPR polymorphism in recurrent MDD. METHODS: Participants included a well-characterized clinical sample of 70 recurrent MDD cases and 67 never psychiatrically ill controls, aged 18 years or over. Socio-demographic and clinical information form, Composite International Diagnostic Interview (CIDI), Childhood Trauma Questionnaire (CTQ), Beck Depression Inventory (BDI) were applied to both groups, along with genotyping. RESULTS: There was no interaction between childhood maltreatment and the 5-HTTLPR in relation to recurrent MDD. All forms of childhood maltreatment were reported as more severe by cases than controls, and there was an independent association between maltreatment and recurrent MDD. CONCLUSION: The path forward to detect genetic risk loci for depression remains challenging. Taking childhood maltreatment history into account could lead to a richer understanding of differences in biological correlates, genetic underpinnings, and outcomes.

Cortical thickness and surface area as an endophenotype in bipolar disorder type I patients and their first-degree relatives.

OBJECTIVES: So far, few studies have investigated cortical thickness (CT) and surface area (SA) measures in bipolar disorder type I (BDI) in comparison to a high genetic risk group such as first-degree relatives (FR). This study aimed to examine CT and SA differences between BDI, FR and healthy controls (HC). METHODS: 3D T1 magnetic resonance images were acquired from 27 euthymic BDI patients, 24 unaffected FR and 29 HC. CT and SA measures were obtained with FreeSurfer version 5.3.0. Generalized estimating equations were used to compare CT and SA between groups. Group comparisons were repeated with restricting the FR group to 17 siblings (FR-SB) only. RESULTS: \Mean age in years was 36.3 ±â€¯9.5 for BDI, 32.1 ±â€¯10.9 for FR, 34.7 ±â€¯9.8 for FR-SB and 33.1 ±â€¯9.0 for HC group respectively. BDI patients revealed larger SA of left pars triangularis (LPT) compared to HC (p = .001). In addition, increased SA in superior temporal cortex (STC) in FR-SB group compared to HC was identified (p = .0001). CONCLUSIONS: Our result of increased SA in LPT of BDI could be a disease marker and increased SA in STC of FR-SB could be a marker related with resilience to illness.

Schizophrenia in microcephalic osteodysplastic primordial dwarfism type II syndrome: supporting evidence for an association between the PCNT gene and schizophrenia.

Schizophrenia is a genetically complex disease that is related to neurodevelopmental abnormalities. Several genetic polymorphisms and genetic syndromes associated with neurodevelopmental processes have been linked to schizophrenia. In this case report, we present a case with an association between microcephalic osteodysplastic primordial dwarfism type II and schizophrenia. Microcephalic osteodysplastic primordial dwarfism type II syndrome is a rare, autosomal recessive disease that occurs as a result of the mutations in the pericentrin (PCNT) gene that are responsible for cell cycle and division. In this report, we discuss the possible association between the PCNT gene and schizophrenia.

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

Prolonged Grief and Cognitive Decline: A Prospective Population-Based Study in Middle-Aged and Older Persons.

OBJECTIVE: Bereavement can result in unresolved and prolonged grief, often termed prolonged grief disorder (PGD). The impact of PGD on cognitive functioning is poorly understood. The aim of the study was to compare the cognitive decline, assessed by repeated measures of different cognition domains, between persons with normal and PGD and a non-grieving reference population in a 7-year follow-up study. METHODS: The study sample comprised 3126 non-demented persons, mean age: 64 years, of the Rotterdam Study. Participants were classified into three groups: no grief (reference group, N = 2,582), normal grief (N = 418), and prolonged grief disorder (N = 126). Participants were assessed with the Complicated Grief Inventory and underwent cognitive testing (Mini-Mental State Examination [MMSE], Letter-Digit Substitution test, Stroop test, Word fluency task, Word learning test). Analyses were adjusted for baseline cognition and depressive symptoms; persons with major depressive disorders were excluded. RESULTS: Compared with the reference group, participants with PGD showed a decrease in global cognitive function, MMSE scores, and World learning test (immediate and delayed) over time. Participants with normal grief did not show a stronger cognitive decline in any of cognitive tests than the reference group. CONCLUSIONS: Participants with PGD showed a stronger cognitive decline than the reference group during 7 years of follow-up. This suggests that PGD is a risk factor for cognitive decline, but this study cannot detect the psychobiological mechanism underlying this longitudinal association.

The low single nucleotide polymorphism heritability of plasma and saliva cortisol levels.

Cortisol is an important stress hormone affected by a variety of biological and environmental factors, such as the circadian rhythm, exercise and psychological stress. Cortisol is mostly measured using blood or saliva samples. A number of genetic variants have been found to contribute to cortisol levels with these methods. While the effects of several specific single genetic variants is known, the joint genome-wide contribution to cortisol levels is unclear. Our aim was to estimate the amount of cortisol variance explained by common single nucleotide polymorphisms, i.e. the SNP heritability, using a variety of cortisol measures, cohorts and analysis approaches. We analyzed morning plasma (n=5705) and saliva levels (n=1717), as well as diurnal saliva levels (n=1541), in the Rotterdam Study using genomic restricted maximum likelihood estimation. Additionally, linkage disequilibrium score regression was fitted on the results of genome-wide association studies (GWAS) performed by the CORNET consortium on morning plasma cortisol (n=12,597) and saliva cortisol (n=7703). No significant SNP heritability was detected for any cortisol measure, sample or analysis approach. Point estimates ranged from 0% to 9%. Morning plasma cortisol in the CORNET cohorts, the sample with the most power, had a 6% [95%CI: 0-13%] SNP heritability. The results consistently suggest a low SNP heritability of these acute and short-term measures of cortisol. The low SNP heritability may reflect the substantial environmental and, in particular, situational component of these cortisol measures. Future GWAS will require very large sample sizes. Alternatively, more long-term cortisol measures such as hair cortisol samples are needed to discover further genetic pathways regulating cortisol concentrations.

Sexual Activity and Physical Tenderness in Older Adults: Cross-Sectional Prevalence and Associated Characteristics.

BACKGROUND: Despite a common misconception, older adults engage in sexual behavior. However, there is limited sexual behavior research in older adults, which is often restricted to small samples, to cohorts recruiting adults from 45 years old, and to questions regarding only sexual intercourse. AIM: To assess the cross-sectional prevalence of and characteristics associated with sexual activity and physical tenderness in community-dwelling older adults. METHODS: From the Rotterdam Study, sexual activity and physical tenderness were assessed in 2,374 dementia-free, community-dwelling men and women at least 65 years old from 2009 through 2012 in the Netherlands. Analyses were stratified by sex and partner status. OUTCOMES: Sexual activity and physical tenderness (eg, fondling or kissing) in the last 6 months. Potential associated characteristics included measurements of demographics, socioeconomic position, health behavior, and health status. RESULTS: The vast majority of partnered participants (men, n = 858; women, n = 724) had experienced physical tenderness in the previous 6 months (83.7% of men and 82.9% of women) and nearly half had engaged in sexual activity (49.5% and 40.4% respectively). Very few unpartnered women (n = 675) had engaged in sexual activity (1.3%) or physical tenderness (5.2%), whereas prevalence rates were slightly higher for unpartnered men (n = 117; 13.7% or 17.1%). Engaging in sexual behavior was generally associated with younger age, greater social support, healthier behaviors, and better physical and psychological health. CLINICAL IMPLICATIONS: Findings show that older adults engage in sexual activity. It is important not to assume that an older person is not interested in sexual pleasure or that an older person is unhappy with not having a sexual partner. Offering an opportunity for open discussion of sexuality and medical assistance without imposing is a difficult balance. We encourage health care professionals to proactively address sexuality and extend knowledge about safe sex and sexual function to older adults. STRENGTHS AND LIMITATIONS: Thus far, this is one of the largest samples of sexual behavior assessment in adults older than 60 years. Limitations of this study are common in sexual behavior research, including low sexual behavior engagement among unpartnered older adults and a small sample of unpartnered men, which restricted sex- and age-specific implications. CONCLUSION: Almost half of partnered older adults engaged in sexual activity and more than two thirds engaged in physical tenderness, but very few unpartnered older adults engaged in these behaviors. The greatest barrier to being sexually active at an older age is lack of a partner, which particularly affects women. Sexuality is an important aspect of active aging. Freak-Poli R, Kirkman M, De Castro Lima G, et al. Sexual Activity and Physical Tenderness in Older Adults: Cross-Sectional Prevalence and Associated Characteristics. J Sex Med 2017;14:918-927.

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits.

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

Happiness, rather than depression, is associated with sexual behaviour in partnered older adults.

Background: The relation between positive psychological well-being (PPWB) and sexual behaviour is understudied in older adult groups. Objective: To examine the relation between PPWB (positive affect and life satisfaction) and sexual behaviour (sexual activity and physical tenderness) in older adults, and whether it is independent from depressive symptoms and uniform across older age groups. Design: Cross-sectional. Setting: Community-dwelling adults aged 65 years or older, Rotterdam, The Netherlands. Methods: Sexual behaviour, the Cantril Self-Anchoring Striving Scale, the Center for Epidemiological Studies Depression (CES-D) scale and partner status were assessed in 2,373 dementia-free older adults from the Rotterdam Study. Results: For partnered participants, greater positive affect and life satisfaction was associated with more sexual activity and physical tenderness. Although CES-D was negatively associated with sexual behaviour within partnered older adults, there was no association between the negative affect sub-scale and sexual behaviour. The relations were independent of depressive symptoms, physical health and chronic disease status and were observed for both sexes at all older ages. For unpartnered participants, greater life satisfaction and was associated with more physical tenderness. There was low prevalence of sexual behaviour in unpartnered participants, limiting further stratification. Conclusion: Greater PPWB was associated with more sexual behaviour in partnered, community-dwelling older adults. We are the first to demonstrate that sexual behaviour is associated with PPWB, rather than lack of depressive symptoms; and that the association was present at all ages for partnered older adults. Limited conclusions can be drawn for unpartnered older adults as their sexual behaviour was infrequent.

An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.

BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10-9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10-9). CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.

The Impact of Complicated Grief on Diurnal Cortisol Levels Two Years After Loss: A Population-Based Study.

OBJECTIVE: Few studies have focused on the effect of complicated grief-unresolved and prolonged grief-on the neuroendocrine systems. The present study examined the association of complicated grief and normal grief with the diurnal cortisol patterns in a large population-based study. METHODS: This study was set in the Rotterdam Study and comprised 2084 persons aged older than 55 years (mean [SD] age, 64.9 [5.5] years). Participants were assessed with the Complicated Grief Inventory and classified into no grief (n = 1922), normal grief (n = 131), or complicated grief (n = 31) if they experienced the loss in the past 2 years. Saliva samples were collected to measure cortisol levels. Morning cortisol and summary measures (area under the curve and the slope) were studied to account for the diurnal pattern of cortisol. Persons with depressive disorders were excluded, and analyses were additionally adjusted for depressive symptoms. RESULTS: Compared to normal grievers, participants with complicated grief showed lower levels of morning cortisol (11.26 vs 15.51 nmol/L; difference, -4.24; 95% confidence interval [CI] = -7.87 to -0.62; p = .022), and lower levels of overall diurnal cortisol (6.89 vs 8.98 nmol/L; difference, -2.09; 95% CI = -3.81 to -0.37; p = .017). No difference was observed in slope between both groups. Participants with complicated grief also showed lower levels of morning cortisol than the nongrievers (11.26 vs 14.71; difference, -3.46; 95% CI = -6.78 to -0.13; p = .042). In contrast, cortisol secretion patterns did not differ between persons with normal grief and nongrieving controls. CONCLUSIONS: Participants with complicated grief showed low levels of morning cortisol and low overall diurnal cortisol levels characteristic for a chronic stress reaction.