Subtyping late-life depression according to inflammatory and metabolic dysregulation: a prospective study.

BACKGROUND: Inflammation and metabolic dysregulation are age-related physiological changes and are associated with depressive disorder. We tried to identify subgroups of depressed older patients based on their metabolic-inflammatory profile and examined the course of depression for these subgroups. METHODS: This clinical cohort study was conducted in a sample of 364 depressed older (⩾60 years) patients according to DSM-IV criteria. Severity of depressive symptoms was monitored every 6 months and a formal diagnostic interview repeated at 2-year follow-up. Latent class analyses based on baseline metabolic and inflammatory biomarkers were performed. Adjusted for confounders, we compared remission of depression at 2-year follow-up between the metabolic-inflammatory subgroups with logistic regression and the course of depression severity over 2-years by linear mixed models. RESULTS: We identified a 'healthy' subgroup (n = 181, 49.7%) and five subgroups characterized by different profiles of metabolic-inflammatory dysregulation. Compared to the healthy subgroup, patients in the subgroup with mild 'metabolic and inflammatory dysregulation' (n = 137, 37.6%) had higher depressive symptom scores, a lower rate of improvement in the first year, and were less likely to be remitted after 2-years [OR 0.49 (95% CI 0.26-0.91)]. The four smaller subgroups characterized by a more specific immune-inflammatory dysregulation profile did not differ from the two main subgroups regarding the course of depression. CONCLUSIONS: Nearly half of the patients with late-life depressions suffer from metabolic-inflammatory dysregulation, which is also associated with more severe depression and a worse prognosis. Future studies should examine whether these depressed older patients benefit from a metabolic-inflammatory targeted treatment.

Is Sarcopenic Obesity an Indicator of Poor Prognosis in Gastric Cancer Surgery? A Cohort Study in a Western Population.

BACKGROUND: The prognostic value of sarcopenic obesity in gastric cancer surgery remains debated. We aimed to evaluate the impact on outcomes of body composition and sarcopenic obesity after gastrectomy for gastric cancer. METHODS: A retrospective review of prospectively maintained database of patients undergoing gastrectomy for gastric cancer from 2010 to 2017 was performed. Skeletal muscle mass and visceral adipose tissue were evaluated by preoperative computed tomography to define sarcopenia and obesity. Patients were classified in body composition groups according to the presence or absence of sarcopenia and obesity. Prognostic factors for survival were assessed by multivariate Cox analysis. RESULTS: Of the 198 patients undergoing gastrectomy for gastric cancer, 90 (45.4%) patients were sarcopenic, 130 (67.7%) obese, and in the subclassification for body composition categories: 33 (17%) nonsarcopenic nonobesity, 75 (38%) non sarcopenic obesity, 35 (17%) sarcopenic nonobesity, and 55 (28%) sarcopenic obesity. No category of body composition was a predictor of postoperative complications and worse overall and disease-free survival outcomes. Multivariable analysis identified ASA III classification, preoperative weight loss > 10%, postoperative surgical re-intervention, and advanced tumor stage as independent prognostic factors for overall survival, and patients aged 75 years or older, preoperative weight loss > 10%, elevated netrophil-lymphocyte ratio, and advanced tumor stage as independent prognostic factors for disease-free survival. CONCLUSIONS: Sarcopenia, obesity, and sarcopenic obesity were not associated with worse outcomes after gastric cancer surgery.

Cerebellar Grey Matter Volume in Older Persons Is Associated with Worse Cognitive Functioning.

The cerebellum is increasingly recognised for its role in modulation of cognition, behaviour, and affect. The present study examined the relation between structural cerebellar damage (grey matter volume (GMV), white matter hyperintensities (WMHs), lacunar infarcts (LIs) and microbleeds (MBs)) and measures of cognitive, psychological (i.e. symptoms of depression and apathy) and general daily functioning in a population of community-dwelling older persons with mild cognitive deficits, but without dementia. In 194 participants of the Discontinuation of Antihypertensive Treatment in Elderly People (DANTE) Study Leiden, the association between cerebellar GMV, WMHs, LIs and MBs and measures of cognitive, psychological and general daily functioning was analysed with linear regression analysis, adjusted for age, sex, education and cerebral volume. Cerebellar GMV was associated with the overall cognition score (standardised beta 0.20 [95% CI, 0.06-0.33]). Specifically, posterior cerebellar GMV was associated with executive function (standardised beta 0.18 [95% CI, 0.03-0.16]). No relation was found between vascular pathology and cognition. Also, no consistent associations were found on the cerebellar GMV and vascular pathology measures and psychological and general daily functioning. In this population of community-dwelling elderly, less posterior cerebellar GMV but not vascular pathology was associated with worse cognitive function, specifically with poorer executive function. No relation was found between cerebellar pathology and psychological and general daily functioning.

Hair cortisol in patients with a depressive episode treated with electroconvulsive therapy.

BACKGROUND: There is substantial evidence showing changes in hypothalamic pituitary adrenal (HPA)-axis activity in patients with major depressive disorder (MDD). Also, there seem to be differences in HPA-axis functioning between MDD subgroups. It is however unclear whether hair cortisol concentrations (HCC), which are a stable marker of long-term cortisol levels, are suitable as a biomarker for identifying subgroups in MDD. METHODS: We were able to attain valid HCC from a scalp hair sample of sixty-two patients with a major depressive episode right before electroconvulsive therapy (ECT). HCC were our main biological outcome measure. We created subgroups using depression severity as defined by the Hamilton Depression Rating Scale, the presence/absence of psychotic symptoms, the presence of melancholia as defined by the CORE and catatonia as defined by the Bush-Francis Catatonia Rating Scale. RESULTS: Our analyses of the total group showed a median HCC of 4.4 pg/mg. We found patients with catatonia (N = 10) to have substantially higher median HCC (8.3 pg/mg) than patients without catatonia (3.8 pg/mg). Although presence of melancholia and depression severity were not significantly associated with HCC, more severe psychomotor agitation was associated with higher HCC. Pre-treatment HCC was not associated with ECT outcome. STRENGTHS AND LIMITATIONS: A complicating factor in interpretation of our results was the large variability in HCC. This could be related to potential confounders such as cardiometabolic and other comorbidities, that were however addressed to the extent possible. CONCLUSIONS: HCC is a potential biomarker for MDD patients with severe agitation and/or catatonia. CLINICALTRIALS.GOV: Identifier: NCT02562846.

Inflammatory markers and cortisol parameters across depressive subtypes in an older cohort.

BACKGROUND: There is growing evidence that inflammatory and cortisol dysregulation are underlying pathophysiological mechanisms in the aetiology of major depressive disorder, particularly in younger adults. However, findings of biological disturbances in late-life depression have been divergent, probably due to the even greater heterogeneity of depression in older adults with aging processes influencing biological factors. Using empirically derived subtypes may enable the identification of biological disturbances underlying depression in older adults. METHODS: Data were used from the Netherlands Study of Depression in Older Persons (NESDO) of 359 persons aged 60 years or older, with a current diagnosis of major depressive disorder (MDD). Depressive subtypes (severe atypical, severe melancholic, and moderate severe subtype) that were previously identified through latent class analysis (LCA), were examined on differences in inflammatory markers including C-reactive protein (CRP), interleukin-6 (IL-6), and neutrophil gelatinase-associated lipocalin (NGAL), as well as cortisol parameters. RESULTS: No differences in measures for inflammation and cortisol across subtypes were observed in uncorrected or for putative confounders corrected models. LIMITATIONS: Several subjects had missing cortisol and inflammatory data, decreasing the power. However, results did not change after imputation analysis. DISCUSSION: In this cohort of depressed older adults, no differences in inflammation and cortisol measures between depression subtypes were observed. This is probably due to the many (patho)physiological processes that are involved in aging, thereby clouding the results.

Suicidal ideation and subsequent completed suicide in both psychiatric and non-psychiatric populations: a meta-analysis.

AIMS: Several authors claimed that expression of suicidal ideation is one of the most important predictors of completed suicide. However, the strength of the association between suicidal ideation and subsequent completed suicide has not been firmly established in different populations. Furthermore, the absolute suicide risk after expression of suicidal ideation is unknown. In this meta-analysis, we examined whether the expression of suicidal ideation predicted subsequent completed suicide in various populations, including both psychiatric and non-psychiatric populations. METHODS: A meta-analysis of cohort and case-control studies that assessed suicidal ideation as determinant for completed suicide in adults. Two independent reviewers screened 5726 articles for eligibility and extracted data of the 81 included studies. Pooled risk ratios were estimated in a random effects model stratified for different populations. Meta-regression analysis was used to determine suicide risk during the first year of follow-up. RESULTS: The risk for completed suicide was clearly higher in people who had expressed suicidal ideation compared with people who had not, with substantial variation between the different populations: risk ratio ranging from 2.35 (95% confidence interval (CI) 1.43-3.87) in affective disorder populations to 8.00 (95% CI 5.46-11.7) in non-psychiatric populations. In contrast, the suicide risk after expression of suicidal ideation in the first year of follow-up was higher in psychiatric patients (risk 1.40%, 95% CI 0.74-2.64) than in non-psychiatric participants (risk 0.23%, 95% CI 0.10-0.54). Past suicide attempt-adjusted risk ratios were not pooled due to large underreporting. CONCLUSIONS: Assessment of suicidal ideation is of priority in psychiatric patients. Expression of suicidal ideation in psychiatric patients should prompt secondary prevention strategies to reduce their substantial increased risk of suicide.

Impaired cognition is associated with adverse outcome in older patients in the Emergency Department; the Acutely Presenting Older Patients (APOP) study.

Objective: to investigate whether cognitive impairment, measured early after Emergency Department (ED) arrival and irrespective of its cause, is independently associated with functional decline or mortality after 3 and 12 months in older ED patients. Design and setting: a prospective multi-centre cohort study in all Acutely Presenting Older Patients visiting the Emergency Department (APOP study) of three hospitals in the Netherlands. Participants: 2,130 patients, ≥70 years. Measurements: data on demographics, disease severity and geriatric characteristics were collected during the first hour of the ED visit. Cognition was measured using the 6-Item-Cognitive-Impairment-Test ('6CIT'). Cognitive impairment was defined as 6CIT ≥11, self-reported dementia or the inability to perform the cognition test. The composite adverse outcome after 3 and 12 months was defined as a 1-point decrease in Katz Activities of Daily Living (ADL), new institutionalisation or mortality. Multivariable regression analysis was used to assess whether cognitive impairment independently associates with adverse outcome. Results: of 2,130 included patients, 588 (27.6%) had cognitive impairment at baseline and 654 patients (30.7%) suffered from adverse outcome after 3 months. Cognitive impairment associated with increased risk for adverse outcome (adjusted odds ratio (OR) 1.72, 95%CI 1.37-2.17). After 12 months, 787 patients (36.9%) suffered from adverse outcome. Again, cognitive impairment independently associated with increased risk for adverse outcome (adjusted OR 1.89, 95%CI 1.46-2.46). ORs were similar for patients who were discharged home versus hospitalised patients. Conclusion: cognitive impairment measured during the early stages of ED visit, irrespective of the cause, is independently associated with adverse outcome after 3 and 12 months in older patients.

Large normal-range TBP and ATXN7 CAG repeat lengths are associated with increased lifetime risk of depression.

Depression is one of the most prevalent and debilitating psychiatric disorders worldwide. Recently, we showed that both relatively short and relatively long cytosine-adenine-guanine (CAG) repeats in the huntingtin gene (HTT) are associated with an increased risk of lifetime depression. However, to what extent the variations in CAG repeat length in the other eight polyglutamine disease-associated genes (PDAGs) are associated with depression is still unknown. We determined the CAG repeat sizes of ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, ATN1 and AR in two well-characterized Dutch cohorts-the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons-including 2165 depressed and 1058 non-depressed individuals-aged 18-93 years. The association between PDAG CAG repeat size and the risk for depression was assessed via binary logistic regression. We found that the odds ratio (OR) for lifetime depression was significantly higher for individuals with >10, compared with subjects with ≤10, CAG repeats in both ATXN7 alleles (OR=1.90, confidence interval (CI) 1.26-2.85). For TBP we found a similar association: A CAG repeat length exceeding the median in both alleles was associated with an increased risk for lifetime depression (OR=1.33, CI 1.00-1.76). In conclusion, we observed that carriers of either ATXN7 or TBP alleles with relatively large CAG repeat sizes in both alleles had a substantially increased risk of lifetime depression. Our findings provide critical evidence for the notion that repeat polymorphisms can act as complex genetic modifiers of depression.

Depressive subtypes in an elderly cohort identified using latent class analysis.

BACKGROUND: Clinical findings indicate heterogeneity of depressive disorders, stressing the importance of subtyping depression for research and clinical care. Subtypes of the common late life depression are however seldom studied. Data-driven methods may help provide a more empirically-based classification of late-life depression. METHODS: Data were used from the Netherlands Study of Depression in Older People (NESDO) derived from 359 persons, aged 60 years or older, with a current diagnosis of major depressive disorder. Latent class analysis (LCA) was used to identify subtypes of depression, using ten CIDI-based depression items. Classes were then characterized using various sociodemographic and clinical characteristics. RESULTS: The most prevalent class, as identified by LCA, was a moderate-severe class (prevalence 46.5%), followed by a severe melancholic class (prevalence 38.4%), and a severe atypical class (prevalence 15.0%). The strongest distinguishing features between the three classes were appetite and weight and, to a lesser extent, psychomotor symptoms and loss of interest. Compared with the melancholic class, the severe atypical class had the highest prevalence of females, the lowest mean age, the highest BMI, and highest prevalence of both cardiovascular disease, and metabolic syndrome. LIMITATIONS: The strongest distinguishing symptoms, appetite and weight, could be correlated. Further, only longitudinal studies could demonstrate whether the identified classes are stable on the long term. DISCUSSION: In older persons with depressive disorders, three distinct subtypes were identified, similar to subtypes found in younger adults. The strongest distinguishing features were appetite and weight; moreover, classes differed strongly on prevalence of metabolic syndrome and cardiovascular disease. These findings suggest differences in the involvement of metabolic pathways across classes, which should be considered when investigating the pathogenesis and (eventually) treatment of depression in older persons.

The Use of Antidepressants, Anxiolytics, and Hypnotics in People with Type 2 Diabetes and Patterns Associated with Use: The Hoorn Diabetes Care System Cohort.

Objective. With depression being present in approximately 20% of people with type 2 diabetes mellitus (T2DM), we expect equally frequent prescription of antidepressants, anxiolytics, and hypnotics. Nevertheless, prescription data in people with T2DM is missing and the effect of depression on glycaemic control is contradictory. The aim of this study was to assess the prevalence of antidepressants, anxiolytics, and/or hypnotics use in a large, managed, primary care system cohort of people with T2DM and to determine the sociodemographic characteristics, comorbidities, T2DM medication, and metabolic control associated with its use. Method. The prevalence of antidepressants, anxiolytics, and/or hypnotics use in the years 2007-2012 was assessed in the Hoorn Diabetes Care System Cohort from the Netherlands. Results. From the 7016 people with T2DM, 500 people (7.1%) used antidepressants only, 456 people (6.5%) used anxiolytics and/or hypnotics only, and 254 people (3.6%) used a combination. Conclusion. We conclude that in our managed, primary care system 17% of all people with T2DM used antidepressants, anxiolytics, and/or hypnotics. Users of antidepressants, anxiolytics, and/or hypnotics were more often female, non-Caucasian, lower educated, and more often treated with insulin.

Big Five personality characteristics are associated with depression subtypes and symptom dimensions of depression in older adults.

OBJECTIVE: This study examined the associations of personality characteristics with both subtypes and symptom dimensions of depression in older adults. METHODS: Three hundred and seventy-eight depressed older adults participated in the Netherlands Study of Depression in Older Persons. Personality characteristics were assessed by the NEO-Five Factor Inventory. Subtypes and symptom dimensions of depression were determined using the Composite International Diagnostic Interview and the Inventory of Depressive Symptomatology (IDS). Multinomial logistic regression analyses were performed to examine the associations between personality and atypical, melancholic, and unspecified subtypes of major depression. Linear regression analyses examined the associations between personality and the IDS mood, somatic, and motivation symptom dimensions. The analyses were adjusted for confounders and additionally adjusted for depression severity. RESULTS: Neuroticism, Extraversion, Conscientiousness, and Agreeableness were associated with specified (atypical or melancholic) major depression compared with unspecified major depression in the bivariate analyses but lost their significance after adjustments for functional limitations and severity of depression. Neuroticism was positively associated with the IDS mood and motivation symptom dimensions, also in the adjusted models. Further, Extraversion and Agreeableness were negatively associated with the IDS mood symptom dimension, and Extraversion and Conscientiousness were negatively associated with the IDS motivation symptom dimension. None was associated with the IDS somatic symptom dimension. CONCLUSIONS: This study demonstrated the association of personality characteristics with mood and motivational symptoms of late-life depression. The lacking ability of personality to differentiate between melancholic and atypical depression seems to be largely explained by severity of depressive symptoms. Copyright © 2017 John Wiley & Sons, Ltd.

Complete Regression of Psoriatic Arthritis After Belatacept Conversion in a Highly HLA-Sensitized Kidney Transplant Patient.

Costimulatory inhibitors (i.e. abatacept and belatacept) effectively abrogate T lymphocyte activation and proliferation and have been shown to be effective for disease control in certain autoimmune disorders as well as in preventing allograft rejection in kidney transplantation. Whether such immunomodulatory agents may be useful for the control of autoimmune flares and allograft acceptance, while avoiding the need of additional strong immunosuppressants, has not been shown. Here, we report the first case of a 47-year-old man affected by a serious debilitating form of psoriatic arthritis that presented during the course of a third, high immunological-risk kidney transplantation. Three years after transplantation, the patient benefited by switching from tacrolimus- to belatacept-based therapy, without additional immunosuppression, by showing complete regression of the arthritic symptoms as well as no progression of severe radiological lesions, which leaded to the recovery of disability and functional impairment. Remarkably, the treatment with belatacept in association with mycophenolate mofetil and steroids also provided a stable normal allograft function over time and abrogated the development of de novo circulating donor-specific alloantibodies after 4 years of follow-up.

Influence of Small Vessel Disease and Microstructural Integrity on Neurocognitive Functioning in Older Individuals: The DANTE Study Leiden.

BACKGROUND AND PURPOSE: Small vessel disease is a major cause of neurocognitive dysfunction in the elderly. Small vessel disease may manifest as white matter hyperintensities, lacunar infarcts, cerebral microbleeds, and atrophy, all of which are visible on conventional MR imaging or as microstructural changes determined by diffusion tensor imaging. This study investigated whether microstructural integrity is associated with neurocognitive dysfunction in older individuals, irrespective of the conventional features of small vessel disease. MATERIALS AND METHODS: The study included 195 participants (75 years of age or older) who underwent conventional 3T MR imaging with DTI to assess fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. Cognitive tests were administered to assess cognitive domains, and the Geriatric Depression Scale-15 and Apathy Scale of Starkstein were used to assess symptoms of depression and apathy, respectively. The association between DTI measures and neurocognitive function was analyzed by using linear regression models. RESULTS: In gray matter, a lower fractional anisotropy and higher mean diffusivity, axial diffusivity, and radial diffusivity were associated with worse executive function, psychomotor speed, and overall cognition and, in white matter, also with memory. Findings were independent of white matter hyperintensities, lacunar infarcts, and cerebral microbleeds. However, after additional adjustment for normalized brain volume, only lower fractional anisotropy in white and gray matter and higher gray matter radial diffusivity remained associated with executive functioning. DTI measures were not associated with scores on the Geriatric Depression Scale-15 or the Apathy Scale of Starkstein. CONCLUSIONS: Microstructural integrity was associated with cognitive but not psychological dysfunction. Associations were independent of the conventional features of small vessel disease but attenuated after adjusting for brain volume.

The effect of pain on presence and severity of depressive disorders in older persons: The role of perceived control as mediator.

BACKGROUND: The relation between pain and depression is reported repeatedly. It is suggested that pain by itself is not sufficient for the development of depression. We aim to study the role of perceived control as mediating factor in the relation between pain and depressive disorders at old age. METHODS: Baseline data of the Netherlands Study of Depression in Older Persons (NESDO) were used, including 345 persons with DSM-IV depressive disorders (CIDI) and 125 control persons without depressive disorders, aged 60 years and over. Measures included severity of depression (Inventory of Depressive Symptomatology), presence and intensity of pain and pain-related disability (Chronic Graded Pain scale), and a general measure of perceived control over life (Pearlin Mastery Scale). In mediation analyses direct and indirect effects were estimated. RESULTS: Older persons with depressive disorders reported pain more frequently with higher intensity than controls. After controlling for confounding, the direct effect of pain intensity and the indirect effect through perceived control on depression were OR=1.10 (CI 95% .98;1.25) and OR=1.24 (1.15;1.35). For pain-related disability these were OR=1.14 (1.02;1.29) and OR=1.21 (1.13;1.29). In depressed persons there was a strong direct effect of pain intensity and disability and a smaller indirect effect through perceived control on severity of depressive symptoms. LIMITATIONS: This cross-sectional study cannot give evidence on causal direction. CONCLUSIONS: Perceived control plays an important role as mediator in the association between pain and presence of depression. In depressed persons however, the direct role of pain seems more important in the association with depression severity.

Cerebrovascular involvement and clinical presentation of late-life depression, findings from the NESDO study.

OBJECTIVES: The vascular depression hypothesis, which supposes a causal relation of vascular risk factors and vascular disease with depression, has not been definitively accepted. Inconsistent findings may be due to different clinical presentations of depression in older people with and without a clear history of stroke. We therefore aimed to investigate the association between vascular pathology, with and without previous stroke, and different symptom domains of depression. METHOD: For our study, we used baseline data of 378 people aged 60 years and older with a current depression who participated in the Netherlands Study of Depression in Older persons (NESDO), an observational (multicentre) cohort study. Using all information on vascular pathology and risk factors, three classes were operationalized: a first class of depressed older people with previous stroke; a second class of depressed older people with cardiovascular and peripheral arterial diseases, but without stroke; and a third class of depressed older people with no vascular disease. RESULTS: The depressed older people with previous stroke were characterized by more 'motivational' symptoms, which distinguished them from other depressed older people. Inclusion in this stroke group was also associated with having increased prevalence of hypertension, smoking more cigarettes, and lower alcohol consumption. CONCLUSIONS: Our findings suggest that the 'vascular depression' connotation should be reserved for depressed (older) patients with vascular pathology and evident cerebral involvement.

In depressed older persons higher blood pressure is associated with symptoms of apathy. The NESDO study.

BACKGROUND: In older persons, a relationship between both higher and lower blood pressure and depression has inconsistently been reported. Blood pressure may be differentially associated with distinct symptom domains of depression. We examined the cross-sectional relation of current systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) with different depressive symptom domains among depressed older persons. METHODS: In the Netherlands Study of Depression in Older Persons (NESDO), 270 participants aged 60 years and above were diagnosed with depression in the past month. Using the three corresponding subscales of the Inventory of Depressive Symptoms-Self Report (IDS-SR), motivational, mood and somatic symptom domains were assessed. Additionally, symptoms of apathy were determined with the Apathy Scale. Multiple linear regression was used to examine the cross-sectional relationship between current SBP, DBP and MAP with both IDS-SR subscale and Apathy Scale scores. Unstandardized betas were calculated per 10 mmHg increase in blood pressure measures. RESULTS: Mean age of participants was 70.4 years (standard deviation 7.3). Higher SBP (Beta 0.33, t (254) = 2.01, p = 0.045), higher DBP (Beta 0.68, t (254) = 2.15, p = 0.03) and higher MAP (Beta 0.63, t (254) = 2.33, p = 0.02) were associated with higher Apathy Scale scores in the fully adjusted model. Furthermore, a higher SBP was associated with higher IDS-SR mood subscale scores (Beta 0.25, t (254) = 2.13, p = 0.03). CONCLUSIONS: Depressed older people with higher blood pressure measures had particularly more symptoms of apathy. To disentangle the relationship of blood pressure with late-life depression, it is important to pay attention to the role of apathy symptoms.

Hypothalamic-pituitary-adrenal axis functioning in Huntington's disease and its association with depressive symptoms and suicidality.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in Huntington's disease (HD). In non-HD populations, alterations in HPA axis activity have been associated with depression and suicidality. The present study aims to compare HPA axis activity between HD mutation carriers and controls, and examine its association with depressive symptoms and suicidality. To this end, salivary cortisol concentrations at seven time points, as well as depressive symptoms and suicidality, were assessed in 49 pre-motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow-up combined. Differences in parameters of HPA axis activity between these three groups, and their associations with depressive symptoms and suicidality in HD mutation carriers, were analysed using multilevel regression analyses. There were no differences in parameters of HPA axis activity between mutation carriers and controls, whereas pre-motor symptomatic mutation carriers had a significantly higher area under the curve to the increase (AUCi ) compared to motor symptomatic mutation carriers. In the entire HD cohort, HPA axis activity was not associated with depressive symptoms or suicidality. After stratifying mutation carriers into pre-motor, early and advanced disease stages, ß values differed between these groups. Remarkably, a higher AUCi was significantly associated with depressive symptoms in pre-motor and early disease stage mutation carriers, with a reverse nonsignificant association in advanced disease stage mutation carriers. The lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre-motor, early and advanced disease stages could possibly be explained by exhaustion of the HPA axis after prolonged stress-induced HPA axis hyperactivity and deserves further longitudinal study.