Depressive Symptoms and Plasma Markers of Alzheimer's Disease and Neurodegeneration: A Coordinated Meta-Analysis of 8 Cohort Studies.

BACKGROUND: Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD). There has been a recent emergence in plasma biomarkers for AD pathophysiology, such as amyloid-beta (Aß) and phosphorylated tau (p-tau), as well as for axonal damage (neurofilament light, NfL) and astrocytic activation (glial fibrillary acidic protein, GFAP). Hypothesizing that depressive symptoms may occur along the AD process, we investigated associations between plasma biomarkers of AD with depressive symptoms in individuals without dementia. METHODS: A two-stage meta-analysis was performed on 2 clinic-based and 6 population-based cohorts (N = 7210) as part of the Netherlands Consortium of Dementia Cohorts. Plasma markers (Aß42/40, p-tau181, NfL, and GFAP) were measured using Single Molecular Array (Simoa; Quanterix) assays. Depressive symptoms were measured with validated questionnaires. We estimated the cross-sectional association of each standardized plasma marker (determinants) with standardized depressive symptoms (outcome) using linear regressions, correcting for age, sex, education, and APOE ε4 allele presence, as well as subgrouping by sex and APOE ε4 allele. Effect estimates were entered into a random-effects meta-analysis. RESULTS: Mean age of participants was 71 years. The prevalence of clinically relevant depressive symptoms ranged from 1% to 22%. None of the plasma markers were associated with depressive symptoms in the meta-analyses. However, NfL was associated with depressive symptoms only in APOE ε4 carriers (ß 0.11; 95% CI: 0.05-0.17). CONCLUSIONS: Late-life depressive symptoms did not show an association to plasma biomarkers of AD pathology. However, in APOE ε4 allele carriers, a more profound role of neurodegeneration was suggested with depressive symptoms.

A taxonomy of threat and soothing influences in rheumatic and musculoskeletal diseases and central sensitivity syndromes / Una taxonomía de amenazas e influencias calmantes en enfermedades reumáticas y musculoesqueléticas y síndromes de sensibilidad central

Background: An imbalance in affect regulation, reflected by a hyperactive threat system and hypoactive soothing system, may impact physical symptoms in people with rheumatic and musculoskeletal diseases (RMD) and central sensitivity syndromes (CSS), including chronic fatigue syndrome, fibromyalgia, and irritable bowel syndrome. This study aimed to identify and structure comprehensive overviews of threat and soothing influences that may worsen or alleviate physical symptoms in people with RMD or CSS. Method: A concept mapping procedure was used. An online open-question survey (N = 686, 641 [93.4%] women) yielded comprehensive sets of 40 threats and 40 soothers that were individually sorted by people with RMD or CSS (N = 115, 112 [97.4%] women). Results: Hierarchical cluster analyses generated eight threat clusters: environmental stimuli, physical symptoms, food and drugs, inactivity, demands, effort, invalidation, and emotional stress. Ten soother clusters were identified: social emotional support, rest and balance, pleasant surroundings, illness understanding, positive mindset and autonomy, spirituality, leisure activity, wellness, treatment and care, and nutrition and treats. Conclusions: Our study provided a comprehensive taxonomy of threats and soothers in people with RMD or CSS. The results can be used in experimental research to label threat and soothing stimuli and in clinical practice to screen and monitor relevant treatment targets.(AU)

Plasma Markers of Alzheimer's Disease Pathology, Neuronal Injury, and Astrocytic Activation and MRI Load of Vascular Pathology and Neurodegeneration: The SMART-MR Study.

BACKGROUND: Two of the main causes for dementia are Alzheimer's disease (AD) and vascular pathology, with most patients showing mixed pathology. Plasma biomarkers for Alzheimer's disease-related pathology have recently emerged, including Aß (amyloid-beta), p-tau (phosphorylated tau), NfL (neurofilament light), and GFAP (glial fibrillary acidic protein). There is a current gap in the literature regarding whether there is an association between these plasma biomarkers with vascular pathology and neurodegeneration. METHODS AND RESULTS: Cross-sectional data from 594 individuals (mean [SD] age: 64 [8] years; 17% female) were included from the SMART-MR (Second Manifestations of Arterial Disease-Magnetic Resonance) study, a prospective cohort study of individuals with a history of arterial disease. Plasma markers were assessed using single molecular array assays (Quanterix). Magnetic resonance imaging markers included white matter hyperintensity volume, presence of infarcts (yes/no), total brain volume, and hippocampal volume assessed on 1.5T magnetic resonance imaging. Linear regressions were performed for each standardized plasma marker with white matter hyperintensity volume, total brain volume, and hippocampal volume as separate outcomes, correcting for age, sex, education, and intracranial volume. Logistic regressions were performed for the presence of lacunar and cortical infarcts. Higher p-tau181 was associated with larger white matter hyperintensity volume (b per SD increase=0.16 [95% CI, 0.06-0.26], P=0.015). Higher NfL (b=-5.63, [95% CI, -8.95 to -2.31], P=0.015) was associated with lower total brain volume and the presence of infarcts (odds ratio [OR], 1.42 [95% CI, 1.13-1.78], P=0.039). Higher GFAP levels were associated with cortical infarcts (OR, 1.45 [95% CI, 1.09-1.92], P=0.010). CONCLUSIONS: Plasma biomarkers that have been associated with tau pathology, axonal injury, and astrocytic activation are related to magnetic resonance imagingmarkers of vascular pathology and neurodegeneration in patients with manifest arterial disease.

Association of amyloid-beta with depression or depressive symptoms in older adults without dementia: a systematic review and meta-analysis.

Several lines of evidence have indicated that depression might be a prodromal symptom of Alzheimer's disease (AD). This systematic review and meta-analysis investigated the cross-sectional association between amyloid-beta, one of the key pathologies defining AD, and depression or depressive symptoms in older adults without dementia. A systematic search in PubMed yielded 689 peer-reviewed articles. After full-text screening, nine CSF studies, 11 PET studies, and five plasma studies were included. No association between amyloid-beta and depression or depressive symptoms were found using cerebrospinal fluid (CSF) (0.15; 95% CI: -0.08; 0.37), positron emission topography (PET) (Cohen's d: 0.09; 95% CI: -0.05; 0.24), or plasma (-0.01; 95% CI: -0.23; 0.22). However, subgroup analyses revealed an association in plasma studies of individuals with cognitive impairment. A trend of an association was found in the studies using CSF and PET. This systematic review and meta-analysis suggested that depressive symptoms may be part of the prodromal stage of dementia.

A taxonomy of threat and soothing influences in rheumatic and musculoskeletal diseases and central sensitivity syndromes.

Background: An imbalance in affect regulation, reflected by a hyperactive threat system and hypoactive soothing system, may impact physical symptoms in people with rheumatic and musculoskeletal diseases (RMD) and central sensitivity syndromes (CSS), including chronic fatigue syndrome, fibromyalgia, and irritable bowel syndrome. This study aimed to identify and structure comprehensive overviews of threat and soothing influences that may worsen or alleviate physical symptoms in people with RMD or CSS. Method: A concept mapping procedure was used. An online open-question survey (N = 686, 641 [93.4%] women) yielded comprehensive sets of 40 threats and 40 soothers that were individually sorted by people with RMD or CSS (N = 115, 112 [97.4%] women). Results: Hierarchical cluster analyses generated eight threat clusters: environmental stimuli, physical symptoms, food and drugs, inactivity, demands, effort, invalidation, and emotional stress. Ten soother clusters were identified: social emotional support, rest and balance, pleasant surroundings, illness understanding, positive mindset and autonomy, spirituality, leisure activity, wellness, treatment and care, and nutrition and treats. Conclusions: Our study provided a comprehensive taxonomy of threats and soothers in people with RMD or CSS. The results can be used in experimental research to label threat and soothing stimuli and in clinical practice to screen and monitor relevant treatment targets.

Positive future thinking without task-relevance increases anxiety and frontal stress regulation.

Negative anticipatory biases can affect the way we interpret and subjectively experience events. Through its role in emotion regulation, positive future thinking may provide an accessible way to attenuate these biases. However, it is unclear whether positive future thinking works ubiquitously, independent of contextual relevance. Here, we used a positive future thinking intervention (task-relevant; task-irrelevant and control condition) prior to a social stress task to adapt the way this task was experienced. We assessed subjective and objective stress measures and also recorded resting state electroencephalography (EEG) to assess intervention related differences in the level of frontal delta-beta coupling, which is considered a neurobiological substrate of stress regulation. Results show that the intervention reduced subjective stress and anxiety, and increased social fixation behavior and task performance, but only if future thinking was task-relevant. Paradoxically, task-irrelevant positive future thoughts enhanced negative perceptual biases and stress reactivity. This increase in stress reactivity was corroborated by elevated levels of frontal delta-beta coupling during event anticipation, which suggests an increased demand for stress regulation. Together, these findings show that positive future thinking can mitigate the negative emotional, behavioral and neurobiological consequences of a stressful event, but that it should not be applied indiscriminately.

Eye movement desensitization and reprocessing (EMDR) therapy or supportive counseling prior to exposure therapy in patients with panic disorder: study protocol for a multicenter randomized controlled trial (IMPROVE).

BACKGROUND: Exposure-based therapy is the treatment of choice for anxiety disorders, but many patients do not benefit sufficiently from it. Distressing images of threat related to the future or past may maintain the anxiety symptomatology or impede exposure therapy. An intervention that targets threat-related imagery is eye movement desensitization and reprocessing (EMDR) therapy. The main goal of this multicenter randomized controlled trial is to investigate whether EMDR therapy plus exposure therapy, relative to supportive counseling plus exposure therapy, improves treatment efficacy, tolerability, and adherence in patients with panic disorder. In addition, we will examine potential predictors of optimal treatment allocation, mechanisms of change as well as the long term effects of treatment. Finally, we will assess cost-effectiveness. METHODS: A multicenter randomized controlled trial mixed design will be conducted. Participants will be 50 patients, aged ≥ 18, diagnosed with a panic disorder. They will be randomly assigned to one of two conditions: EMDR therapy (i.e., flashforward strategy) or supportive counseling (each consisting of four weekly sessions of 90 min each) prior to exposure therapy (consisting of eight weekly sessions of 90 min each). Assessments will be made pre-treatment (T1), between-treatments (T2), post-treatment (T3), one month post-treatment (FU1) and six months post-treatment (FU2) by an assessor blind to treatment condition. The primary outcome measure is severity of panic-related symptoms. Secondary outcome measures are: tolerability of exposure therapy (initial avoidance, willingness to start exposure therapy, considered drop-out; no-show and drop-out), related symptomatology (generalized anxiety, depression), and functional impairment. DISCUSSION: The primary goals of this research are to compare the efficacy, tolerability, and adherence of EMDR therapy plus exposure therapy and supportive counseling plus exposure therapy and to identify predictors, moderators, and mediators for treatment success. This multi-center research aims to make a significant contribution to our understanding as to how treatment for patients with anxiety disorders can be optimized, and elucidate who can benefit most from this novel approach. TRIAL REGISTRATION: ISRCTN-ISRCTN29668369: Improving anxiety treatment by modifying emotional memories before real-life exposure. Registered 27 June 2022-retrospectively registered. ISRCTN-ISRCTN29668369.

Psychosocial factors and hippocampal subfields: The Medea-7T study.

Specific subfields within the hippocampus have shown vulnerability to chronic stress, highlighting the importance of looking regionally within the hippocampus to understand the role of psychosocial factors in the development of neurodegenerative diseases. A systematic review on psychosocial factors and hippocampal subfield volumes was performed and showed inconsistent results, highlighting the need for future studies to explore this relationship. The current study aimed to explore the association of psychosocial factors with hippocampal (subfield) volumes, using high-field 7T MRI. Data were from the Memory Depression and Aging (Medea)-7T study, which included 333 participants without dementia. Hippocampal subfields were automatically segmented from T2-weighted images using ASHS software. Generalized linear models accounting for correlated outcomes were used to assess the association between subfields (i.e., entorhinal cortex, subiculum, Cornu Ammonis [CA]1, CA2, CA3, dentate gyrus, and tail) and each psychosocial factor (i.e., depressive symptoms, anxiety symptoms, childhood maltreatment, recent stressful life events, and social support), adjusted for age, sex, and intracranial volume. Neither depression nor anxiety was associated with specific hippocampal (subfield) volumes. A trend for lower total hippocampal volume was found in those reporting childhood maltreatment, and a trend for higher total hippocampal volume was found in those who experienced a recent stressful life event. Among subfields, low social support was associated with lower volume in the CA3 (B = -0.43, 95% CI: -0.72; -0.15). This study suggests possible differential effects among hippocampal (subfield) volumes and psychosocial factors.

Late-life depression, allostatic load, and risk of dementia: The AGES-Reykjavik study.

BACKGROUND: The current study aimed to assess if the relation between depression and dementia could be explained by allostatic load (AL) profiles, as well as assessing their risk on incident all-cause dementia, Alzheimer's disease (AD), and non-AD dementias. METHODS: The study included individuals without dementia at baseline from the population-based AGES-Reykjavik Study. Depressive symptoms assessed with the Geriatric Depression Scale-15 and AL markers were collected at baseline. Latent profile analysis (LPA) was performed on the AL markers. Incident dementia was measured during 12-years of follow-up. Cox regressions adjusted for AL profiles were performed to evaluate if AL could explain the relation between depressive symptoms and incident dementia. Additional Cox regressions exploring the interaction with depressive symptoms and AL profiles were also performed. RESULTS: LPA revealed four profiles based on AL factors: 'Low cardiovascular dysregulation' (43 %), 'Average' (42 % prevalence), 'High cardiovascular dysregulation' (11 %), and 'Multisystem dysregulation' (4 %). Cox regression analyses found an increased risk for dementia in the 'Multisystem dysregulation' group (HR 1.72; 95 % CI 1.26-2.33), as well as for AD (HR 1.75; 95 % CI: 1.12-2.71) and non-AD dementias (HR 1.87; 95 % CI: 1.23-2.84). AL profiles did not mediate the risk of all-cause dementia with depressive symptoms; however, there was evidence of additive interaction with depressive symptoms and the 'Multisystem dysregulation' profile and all-cause dementia (RERI 0.15; 95 % CI 0.03-0.26). CONCLUSION: AL profiles and depressive symptoms were independently related to dementia. Individuals with multisystem dysregulation could be more susceptible to the negative effects of depressive symptomology on incident dementia.

Stable Anxiety and Depression Trajectories in Late Adolescence for Oral Contraceptive Users.

Background: The use of oral contraceptives (OCs) has been associated with increased incidences of anxiety and depression, for which adolescents seem to be particularly vulnerable. Rather than looking at singular outcomes, we examined whether OC use is associated with depressive and anxiety symptom trajectories from early adolescence into early adulthood. Materials and Methods: Data from 178 girls were drawn from the Research on Adolescent Development and Relationships (RADAR-Y) younger cohort study. We used assessments on 9 waves from age 13 until 24. Developmental trajectories of ratings on the Reynolds Adolescent Depression Scale (RADS-2) and the Screen for Child Anxiety Related Emotional Disorders (SCARED) were compared between never and ever users of OCs. Results: Never users showed increases in depressive and anxiety symptoms in late adolescence, whereas OC users showed a stable level of symptoms throughout adolescence. This effect remained after adjusting for baseline differences between groups in romantic relationships, sexual debut, educational level, smoking, drinking, and drug use. Age of OC use onset did not significantly predict symptom development. Conclusions: OC use in adolescence was related to an altered developmental trajectory of internalizing symptoms, in which OC users did not show an increase in depressive and anxiety symptoms in late adolescence, whereas never users did. The question remains whether this altered symptom trajectory can be considered a protective effect of OC use on psychopathology. Additional research is needed to improve our understanding of the long-term consequences of OC use on mental health.

Individual treatment goals and factors influencing goal attainment in patients with somatic symptom disorder from the perspective of clinicians: A concept mapping study.

OBJECTIVE: Overviews of treatment goals and influencing factors may support shared decision making and optimize customized treatment to the patient with somatic symptom disorder (SSD). The aim of this study was to identify and structure comprehensive sets of treatment goals and factors influencing goal attainment in patients with SSD from the perspective of clinicians. METHODS: Using a concept mapping procedure, clinicians participated in interviews (N = 17) and card sorting tasks comprising 55 treatment goals and 55 factors influencing goal attainment (N = 38). RESULTS: We identified four overarching categories (A to D) of nine clusters (1 to 9) of treatment goals: A. empowerment (A1. personal values, A2. committed action, A3. self-esteem), B. skill improvement (B4. interpersonal skills, B5. emotion and stress regulation), C. symptom reduction (C6. dysfunctional beliefs, C7. somatic symptoms, C8. psychological symptoms), and D9. active and structured lifestyle. Also, we identified four overarching categories (A to D) of nine clusters (1 to 9) of factors influencing goal attainment: A1. therapeutic alliance, B. social and everyday context (B2. [family] system, B3. meaningful daily schedule, B4. social and economic circumstances), C. ability to change (C5. externalizing tendency, C6. reflective and psychological skills, C7. perspective and motivation), and D. psychological vulnerability (D8. vulnerable personality, D9. [psychiatric] comorbidity). CONCLUSION: The overviews of treatment goals and factors influencing goal attainment reflect different paradigmatic backgrounds of clinicians. The results can be used, in combination with the perspective of the patient, to define treatment goals, and to monitor and evaluate change in outcomes.

Depression and Dementia: The Role of Cortisol and Vascular Brain Lesions. AGES-Reykjavik Study.

BACKGROUND: Late-life depression (LLD) is related to an increased risk of developing dementia; however, the biological mechanisms explaining this relationship remain unclear. OBJECTIVE: To determine whether the relationship between LLD and dementia can be best explained by the glucocorticoid cascade or vascular hypothesis. METHODS: Data are from 4,354 persons (mean age 76±5 years) without dementia at baseline from the AGES-Reykjavik Study. LLD was assessed with the MINI diagnostic interview (current and remitted major depressive disorder [MDD]) and the Geriatric Depression Scale-15. Morning and evening salivary cortisol were collected (glucocorticoid cascade hypothesis). White matter hyperintensities (WMH; vascular hypothesis) volume was assessed using 1.5T brain MRI. Using Cox proportional hazard models, we estimated the associations of LLD, cortisol levels, and WMH volume with incident all-cause dementia, AD, and non-AD dementia. RESULTS: During 8.8±3.2 years of follow-up, 843 persons developed dementia, including 397 with AD. Current MDD was associated with an increased risk of developing all-cause dementia (HR = 2.17; 95% CI 1.66-2.67), with risks similar for AD and non-AD, while remitted MDD was not (HR = 1.02; 95% CI 0.55-1.49). Depressive symptoms were also associated with increased risk of dementia, in particular non-AD dementias. Higher levels of evening cortisol increased risk of dementia, but this was independent of MDD. WMH partially explained the relation between current MDD and dementia risk but remained increased (HR = 1.71; 95% CI 1.34-2.08). CONCLUSION: The current study highlights the importance of LLD in developing dementia. However, neither the glucocorticoid cascade nor the vascular hypotheses fully explained the relation between depression and dementia.

Association of childhood maltreatment and cortisol with the severity and stability of depression symptoms.

BACKGROUND: Little is known about patterns of depression symptoms over time in older adults. This study aims to assess the association of childhood maltreatment and cortisol levels with latent classes of depression symptoms over ten years in older adults. METHODS: A total of 752 participants (mean age 61.7±9.5, female 18%) in the Second Manifestations of ARTerial disease-Memory, depression and aging (SMART-Medea) study provided up to twenty measures of depression symptoms over ten years based on the Patient Health Questionnaire-9 (PHQ-9). At baseline, salivary cortisol was measured, and childhood maltreatment was assessed. Responses to the PHQ-9 were indicators in a latent class analysis. Multinomial regression determined associations between class membership and cortisol and maltreatment, adjusting for age, sex, and education. RESULTS: Four distinct classes were identified; never depressed (n=275, 37%), energy/sleep difficulties (n=237, 32%), mild depression symptoms (n=152, 20%) and fluctuating severe depression (n=88, 12%). Childhood maltreatment was associated with mild depression symptoms (OR=1.95, 95% CI: 1.17-3.25) and fluctuating severe depression (OR=3.50, 95% CI: 1.99-6.15). Blunted morning cortisol was associated with energy/sleep difficulties (OR=0.98, 95% CI: 0.95-1.00) and fluctuating severe depression (OR=0.96, 95% CI: 0.92-0.99). There was no evidence for interaction between maltreatment and cortisol. LIMITATIONS: There is limited generalizability due to the cohort consisting of participants with atherosclerosis and being mostly male. This study utilizes retrospective self-reporting of childhood maltreatment. CONCLUSION: Childhood maltreatment and blunted morning cortisol independently contribute to a worse depression course. Blunted morning cortisol may contribute to sub-clinical depression symptoms, specifically difficulties with energy levels and sleep.

Depressive symptom profiles predict dementia onset and brain pathology in older persons. The AGES-Reykjavik study.

Late-life depression (LLD) increases risk for dementia and brain pathology, but possibly this is only true for one or more symptom profiles of LLD. In 4354 participants (76 ± 5 years; 58% female) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we identified five LLD symptom profiles, based on the Geriatric Depression Scale-15 (no LLD (57%); apathy (31%); apathy with emptiness (2%), mild LLD (8%) and severe LLD (2%)). Cox regression analyses showed that severe LLD, mild LLD and apathy increased risk of dementia up to 12 years, compared to no LLD. Additionally, hippocampal volume loss and white matter lesion increase, were assessed on 1.5 T MR images, at baseline and after 5 years follow-up. Only severe LLD showed increased WML volume over time, but not on hippocampal volume loss. WML increase over time mediated partially the relation between mild LLD and dementia but not for the other symptom profiles. It appears that hippocampal atrophy and LLD are independent predictors for dementia incidence, whereas for mild LLD the risk for dementia is partially mediated by WML changes.

Forgetting the Future: Emotion Improves Memory for Imagined Future Events in Healthy Individuals but Not Individuals With Anxiety.

Negative thoughts about future events are a central aspect of anxiety disorders. It is important to gain a deeper understanding of how these imagined events are retained over time when considering the impact of negative future thoughts on anxiety. Prior research indicates that emotional intensity fades faster for negative than positive memories in healthy individuals. This so-called fading-affect bias could extend to recall of imagined future events. Furthermore, several studies have suggested that this bias may be reversed in individuals with high levels of anxiety. In the current study, we examined whether individuals with high anxiety (n = 23), relative to individuals with low anxiety (n = 30), showed faster decay for positive than negative future-event simulations. The results show that emotion facilitated cued recall for imagined future events in the low-anxiety group but not in the high-anxiety group. In addition, individuals with high anxiety showed decreased episodic specificity during recall across all emotional conditions.

Fear of the coronavirus (COVID-19): Predictors in an online study conducted in March 2020.

Fear is an adaptive response in the presence of danger. However, when threat is uncertain and continuous, as in the current coronavirus disease (COVID-19) pandemic, fear can become chronic and burdensome. To identify predictors of fear of the coronavirus, we conducted an online survey (N = 439) three days after the World Health Organization declared the coronavirus outbreak a pandemic (i.e., between March 14 and 17, 2020). Fear of the coronavirus was assessed with the newly developed Fear of the Coronavirus Questionnaire (FCQ) consisting of eight questions pertaining to different dimensions of fear (e.g., subjective worry, safety behaviors, preferential attention), and an open-ended question. The predictors included psychological vulnerability factors (i.e., intolerance of uncertainty, worry, and health anxiety), media exposure, and personal relevance (i.e., personal health, risk for loved ones, and risk control). We found four predictors for the FCQ in a simultaneous regression analysis: health anxiety, regular media use, social media use, and risks for loved ones (R2 = .37). Furthermore, 16 different topics of concern were identified based participants' open-ended responses, including the health of loved ones, health care systems overload, and economic consequences. We discuss the relevance of our findings for managing people's fear of the coronavirus.

The Association of Individual Changes in Stressful Life Events and Telomere Length Over Time in Twins 50 Years and Older.

OBJECTIVE: Exposure to adverse stressors has been associated with shortening of leukocyte telomere length (LTL). The present longitudinal study investigates the time course of exposure to life events and LTL to determine whether increases in exposure to life events are related to subsequent accelerated LTL shortening. METHODS: In the Swedish Adoption/Twin Study of Aging, we assessed late-life stressful events and LTL in 543 individual participants (mean age = 68.4 years, 40% men, including 48 complete monozygotic twin pairs and 167 complete dizygotic twin pairs) in up to five separate measurements over a period of 25 years. LTL was measured using quantitative polymerase chain reaction. Longitudinal analyses were conducted using time-varying mixed modeling, corrected for life-style factors and depressive symptoms. RESULTS: When adjusting for differences in genetic makeup by looking only in monozygotic twins, we found that an increase in life stressors within an individual was related to decreased LTL over time (B = -0.02; 95% confidence interval = -0.04 to 0.01; p = .002). None of the findings were significant when only looking at dizygotic twins (all, p > .05). CONCLUSIONS: Our findings in an older population show a causal relation between increase in life stress and accelerated LTL shortening by using intraindividual time-varying analysis.

Prospective biomarkers of major depressive disorder: a systematic review and meta-analysis.

Leading biological hypotheses propose that biological changes may underlie major depressive disorder onset and relapse/recurrence. Here, we investigate if there is prospective evidence for biomarkers derived from leading theories. We focus on neuroimaging, gastrointestinal factors, immunology, neurotrophic factors, neurotransmitters, hormones, and oxidative stress. Searches were performed in Pubmed, Embase and PsychInfo for articles published up to 06/2019. References and citations of included articles were screened to identify additional articles. Inclusion criteria were having an MDD diagnosis as outcome, a biomarker as predictor, and prospective design search terms were formulated accordingly. PRISMA guidelines were applied. Meta-analyses were performed using a random effect model when three or more comparable studies were identified, using a random effect model. Our search resulted in 67,464 articles, of which 75 prospective articles were identified on: Neuroimaging (N = 24), Gastrointestinal factors (N = 1), Immunology (N = 8), Neurotrophic (N = 2), Neurotransmitters (N = 1), Hormones (N = 39), Oxidative stress (N = 1). Meta-analyses on brain volumes and immunology markers were not significant. Only cortisol (N = 19, OR = 1.294, p = 0.024) showed a predictive effect on onset/relapse/recurrence of MDD, but not on time until MDD onset/relapse/recurrence. However, this effect disappeared when studies including participants with a baseline clinical diagnosis were removed from the analyses. Other studies were too heterogeneous to compare. Thus, there is a lack of evidence for leading biological theories for onset and maintenance of depression. Only cortisol was identified as potential predictor for MDD, but results are influenced by the disease state. High-quality (prospective) studies on MDD are needed to disentangle the etiology and maintenance of MDD.

Long-term glucocorticoid levels measured in hair in patients with depressive and anxiety disorders.

BACKGROUND: Depressive and anxiety disorders have been linked to a dysregulated hypothalamus-pituitary-adrenal (HPA)-axis. Hair cortisol levels (HairF) reflect integrated long-term cortisol regulation and are therefore promising endocrine markers of chronic (psychological and physical) stress. Our aim was to assess hair cortisol levels in persons with a depressive and/or anxiety disorder and to compare their levels with that of persons in remission and healthy controls. METHODS: Data from 1166 participants of the Netherlands Study of Depression and Anxiety (NESDA) were used, including 266 participants with a recent (1-month) diagnosis of a depressive and/or anxiety disorder, 655 participants with a diagnosis in remission, and 245 healthy controls. HairF was measured in the proximal three cm of scalp hair, using LC-MS/MS. RESULTS: Compared to the healthy controls no differences on HairF or HairE levels were found for depressive and anxiety disorders alone. However the presence of a comorbid depressive and anxiety disorder was significantly associated with increased HairF levels (ß = 0.07; p = .031), as was the severity of depressive symptoms (ß = 0.06; p = .029), but no differences were found on HairE nor the HairF:HairE ratio. CONCLUSIONS: Persons with current diagnosis of comorbid depression and anxiety show moderately higher levels of cortisol than patients with only depression or anxiety, or patients in remission and healthy controls, which may be indicative of a chronic state of hyperactivation of the HPA axis.