Development and validation of a multimodal neuroimaging biomarker for electroconvulsive therapy outcome in depression: a multicenter machine learning analysis.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective intervention for patients with treatment resistant depression. A clinical decision support tool could guide patient selection to improve the overall response rate and avoid ineffective treatments with adverse effects. Initial small-scale, monocenter studies indicate that both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) biomarkers may predict ECT outcome, but it is not known whether those results can generalize to data from other centers. The objective of this study was to develop and validate neuroimaging biomarkers for ECT outcome in a multicenter setting. METHODS: Multimodal data (i.e. clinical, sMRI and resting-state fMRI) were collected from seven centers of the Global ECT-MRI Research Collaboration (GEMRIC). We used data from 189 depressed patients to evaluate which data modalities or combinations thereof could provide the best predictions for treatment remission (HAM-D score ⩽7) using a support vector machine classifier. RESULTS: Remission classification using a combination of gray matter volume and functional connectivity led to good performing models with average 0.82-0.83 area under the curve (AUC) when trained and tested on samples coming from the three largest centers (N = 109), and remained acceptable when validated using leave-one-site-out cross-validation (0.70-0.73 AUC). CONCLUSIONS: These results show that multimodal neuroimaging data can be used to predict remission with ECT for individual patients across different treatment centers, despite significant variability in clinical characteristics across centers. Future development of a clinical decision support tool applying these biomarkers may be feasible.

Age-related subtypes of late life depression and mortality: A prospective clinical cohort study.

OBJECTIVES: Late Life Depression (LLD) is associated with increased mortality rates, but it remains unclear which depressed patients are at increased risk. This study examined the mortality risk of previously identified subgroups of depressed older patients based on age-related clinical features (the presence of physical and cognitive frailty). METHODS: A six-year follow-up of a clinical cohort study including 375 depressed older patients and 132 non-depressed persons (NESDO). Depressed patients were diagnosed with the Composite International Diagnostic Interview (CIDI) according to DSM-IV criteria and classified by latent profile analysis on depressive symptom severity, cognitive domains and physical frailty. We estimated the hazard rate of mortality for the four depressed subgroups compared to non-depressed persons by applying Cox-regression analyses. Models were adjusted for age, sex and education as confounders and for explanatory variables per pathway in separate models: somatic burden, lifestyle characteristics, vascular burden or inflammation markers. RESULTS: A total of 61/375 (16.3%) depressed patients and 8/132 (6.1%) non-depressed persons died during the 6-year follow-up. Two of the four subgroups (n = 186/375 (50%) of the depressed sample) had a higher hazard rate (HR) for mortality compared to non-depressed participants, that is, frail-depressed patients (HR = 5.25, [95%-CI: 2.13-13.0]) and pure mild depressed patients (HR = 3.32 [95%-CI: 1.46-7.58]) adjusted for confounders. Adding possible underlying pathways did not explain these associations. CONCLUSIONS: Age-related features (the presence of physical and cognitive frailty) contribute to the increased mortality risk in late-life depression. Future studies in depressed older patients should study the additional value of a clinical geriatric assessment and integrated treatment aimed to at reduce frailty and ameliorate their mortality risk.

Genomics Research of Lifetime Depression in the Netherlands: The BIObanks Netherlands Internet Collaboration (BIONIC) Project.

In this cohort profile article we describe the lifetime major depressive disorder (MDD) database that has been established as part of the BIObanks Netherlands Internet Collaboration (BIONIC). Across the Netherlands we collected data on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) lifetime MDD diagnosis in 132,850 Dutch individuals. Currently, N = 66,684 of these also have genomewide single nucleotide polymorphism (SNP) data. We initiated this project because the complex genetic basis of MDD requires large population-wide studies with uniform in-depth phenotyping. For standardized phenotyping we developed the LIDAS (LIfetime Depression Assessment Survey), which then was used to measure MDD in 11 Dutch cohorts. Data from these cohorts were combined with diagnostic interview depression data from 5 clinical cohorts to create a dataset of N = 29,650 lifetime MDD cases (22%) meeting DSM-5 criteria and 94,300 screened controls. In addition, genomewide genotype data from the cohorts were assembled into a genomewide association study (GWAS) dataset of N = 66,684 Dutch individuals (25.3% cases). Phenotype data include DSM-5-based MDD diagnoses, sociodemographic variables, information on lifestyle and BMI, characteristics of depressive symptoms and episodes, and psychiatric diagnosis and treatment history. We describe the establishment and harmonization of the BIONIC phenotype and GWAS datasets and provide an overview of the available information and sample characteristics. Our next step is the GWAS of lifetime MDD in the Netherlands, with future plans including fine-grained genetic analyses of depression characteristics, international collaborations and multi-omics studies.

How sustainable is resilience? A mixed-methods study on the COVID-19-pandemic as a challenge to resilience resources of older adults who previously recovered from depression.

OBJECTIVES: Despite expanding knowledge about the internal and external resources that contribute to resilience among individuals who have experienced depression, the long-term accessibility and protectiveness of these resources across different stressors is unknown. We investigated whether and how the resilience resources of individuals who previously recovered from late-life depression remained protective during the COVID-19 pandemic. METHODS: We used a sequential explanatory mixed methods design. Quantitative data were derived from two psychiatric case-control cohorts and included twelve repeated measures during the COVID-19 pandemic (n = 465, aged ≥ 60). Qualitative data included two sequential interviews held in 2020 (n = 25) and 2021 (n = 19). We used thematic analysis to determine the protective resources after depression and during the COVID-19 pandemic and linear mixed models to examine the effect of these resources on change in depressive symptoms during the COVID-19 pandemic. RESULTS: While resources of 'Taking agency', 'Need for rest', 'Managing thought processes' and 'Learning from depression' remained accessible and protective during the pandemic, 'Social support' and 'Engaging in activities' did not. 'Negotiating with lockdown measures', 'changing social contact' and 'changing activities' were compensating strategies. Quantitative data confirmed the protectiveness of social contact, social cohesion, sense of mastery, physical activity, staying active and entertained and not following the media. CONCLUSION: Many of the resources that previously helped to recover from depression also helped to maintain good mental health during the COVID-19 pandemic. Where accessibility and protectiveness declined, compensatory strategies or new resources were used. Hence, the sustainability of resilience is enabled through adaptation and compensation processes.

The Cortisol Awakening Response as a Biomarker for Cognitive Side-Effects of Electroconvulsive Therapy.

OBJECTIVE: To test whether the cortisol awakening response (CAR) could be a biomarker for cognitive decline during electroconvulsive therapy (ECT). METHODS: We studied 50 older patients with depression who were treated with ECT from the MODECT cohort. We used linear regression analyses to examine the association between CAR and cognitive change, assessed by the change in Mini Mental State Examination scores between baseline and 1 week after ECT course. CAR was assessed by the area under the curve of cortisol levels, according to Pruessner's-formula. Associations were adjusted for putative confounders, based on previous literature and availability. RESULTS: We found no significant associations between the CAR and cognitive change during the ECT course in (un)adjusted models. CONCLUSION: Our results indicate that the CAR is not usable as a biomarker for ECT-induced cognitive decline during ECT course. Further research in cohorts with larger samples is needed.

The impact of personality traits on the course of frailty.

OBJECTIVES: Determinants of frailty are generally explored within context of somatic healthcare and/or lifestyle characteristics. To examine the impact of personality traits on change in frailty and the potential role of depression. METHODS: A 2-year follow-up study including 285 patients with a depressive disorder and 116 never-depressed controls. Multiple linear regression analyses were conducted to regress the Big Five personality traits (independent variables) on different frailty measures (dependent variables), including the Frailty Index, Frailty phenotype, gait speed, and handgrip strength. Analyses were adjusted for confounders (with and without depressive disorder) and baseline frailty severity. Interactions between personality traits and depressive disorder were examined. RESULTS: All personality traits were associated with change in at least one frailty marker over time. Over time, a higher level of neuroticism was associated with an accelerated increase of frailty, whereas a higher level of extraversion, agreeableness, conscientiousness and openness were associated with an attenuated increase of frailty. None of the associations were moderated by depression. Additional adjustment for depression decreased the strength of the association of neuroticism, extraversion and conscientiousness with frailty. CONCLUSIONS: Personality traits have impact on frailty trajectories in later life. CLINICAL IMPLICATIONS: Underlying pathways and potential modification by psychotherapy merit further study.

Association Between Personality Traits and Functional Limitations in Older Adults with Affective Disorders: A Cross Sectional Study.

OBJECTIVES: Personality traits and affective disorders are both related to functional limitations. It is unknown whether personality traits have an additional effect on functioning in older adults with affective disorders. We studied the association between personality traits and functioning within this group. METHODS: We performed a cross-sectional study of 180 older patients referred to outpatient specialized geriatric mental health care centers with a depressive, anxiety and/or somatic symptom disorder according to DSM-criteria. We studied the association between the Big Five personality traits and functional limitations assessed with the WHO-DAS II, adjusting for potential confounders, including the severity of various affective disorders. RESULTS: The 180 patients (57.1% female, mean age 69.2 years) had an average WHO-DAS II score of 31.3 (SD 15.1). Lower scores on Conscientiousness were associated with more overall functional limitations (p = .001), particularly limitations in self-care (p = .001) and household activities (p = .001). Lower Extraversion scores were associated with more limitations in getting along with others (p = .001). CONCLUSIONS: Personality traits are related to functional limitations independent of the severity of affective disorders in older adults. CLINICAL IMPLICATIONS: Personality traits may be used as predictive factors for functioning in older adults with affective disorders.

Impact of Inflammation on Cognitive Functioning After Electroconvulsive Therapy in Older Patients with Depression with and Without White Matter Hyperintensities.

OBJECTIVE: Should we treat older, patients with depression with white matter hyperintensities (WMH) with electroconvulsive therapy (ECT)? WMH, inflammation, depression and cognitive functioning are suggested to be intertwined. Hence, this study investigates whether the association between inflammation and cognition is different in patients with depression with or without WMH. METHODS: Cognitive functioning was assessed using the Mini-Mental State Examination during and after a course of ECT in 77 older patients with depression. Serum samples (C-reactive protein [CRP], interleukin-6 [IL-6], interleukin-10 [IL-10] and tumour necrosis factor-alpha [TNF-α]) and 3T magnetic resonance imaging were obtained prior to ECT. RESULTS: An interaction effect was found for IL-10, but not for CRP, IL-6 or TNF-α. CONCLUSION: In general, the association between inflammatory markers and cognition in patients with depression treated with ECT is not different in patients with WMH compared to patients without WMH.

Does Late-Life Depression Counteract the Beneficial Effect of Physical Activity on Cognitive Decline? Results From the NESDO Study.

OBJECTIVES: Depression both affects physical activity (PA) and cognition in older persons, yet its impact on the association between PA and cognitive decline is to be determined. We aimed to investigate the association between baseline PA and cognitive functioning over time, stratified for depression. METHODS: We used data of the Netherlands Study of Depression in Older persons (NESDO), a multi-site cohort study with 6-years follow-up. Patients with complete data on PA and cognitive functioning at baseline were included, yielding 394 participants for the analyses of whom 297 were depressed and 97 non-depressed. PA (continuous) was measured with the International Physical Activity Questionnaire. Linear mixed models were used to determine differential effects of baseline PA on the rate of decline of 5 standardized outcomes of cognitive functioning over 6-year follow-up. For this purpose, we examined the significance of the interaction-term (PA*time) in both basic and adjusted models. We also assessed the association between time and cognitive functioning. All analyses were stratified for depression. RESULTS: In both groups, no robust significant interactions of PA with time were found. Furthermore, only decline in working memory was significantly worse in the depressed compared to the non-depressed. CONCLUSION: At older age, the impact of a more inactive lifestyle on cognitive decline was shown to be limited, irrespective of depression that appeared to worsen age-related decline of working memory only. As a higher PA-level at older age has a positive effect on a multitude of other health outcomes, PA should still be encouraged in this population.

Network structure of time-varying depressive symptoms through dynamic time warp analysis in late-life depression.

OBJECTIVES: Late-life major depressive disorder (MDD) can be conceptualized as a complex dynamic system. However, it is not straightforward how to analyze the covarying depressive symptoms over time in case of sparse panel data. Dynamic time warping (DTW) analysis may yield symptom networks and dimensions both at the patient and group level. METHODS: In the Netherlands Study of Depression in Older People (NESDO) depressive symptoms were assessed every 6 months using the 30-item Inventory of Depressive Symptomatology (IDS) with up to 13 assessments per participant. Our sample consisted of 182 persons, aged ≥ 60 years, with an IDS total score of 26 or higher at baseline. Symptom networks dimensions, and centrality metrics were analyzed using DTW and Distatis analyses. RESULTS: The mean age was 69.8 years (SD 7.1), with 69.0% females, and a mean IDS score of 38.0 (SD = 8.7). DTW enabled visualization of an idiographic symptom network in a single NESDO participant. In the group-level nomothetic approach, four depressive symptom dimensions were identified: "core symptoms", "lethargy/somatic", "sleep", and "appetite/atypical". Items of the "internalizing symptoms" dimension had the highest centrality, whose symptom changes over time were most similar to those changes of other symptoms. CONCLUSIONS: DTW revealed symptom networks and dimensions based on the within-person symptom changes in older MDD patients. Its centrality metrics signal the most influential symptoms, which may aid personalized care.

The 5-year outcome of subjective quality of life in older schizophrenia patients.

PURPOSE: Subjective quality of life (SQOL) is increasingly valued as an important outcome in schizophrenia treatment. The current study aims to gain insight into changes in SQOL during 5-year follow-up in older persons with schizophrenia spectrum disorders (SSD). METHODS: The sample consisted of a catchment area-based group of 75 older Dutch patients (mean age 66.0 years) with schizophrenia or schizoaffective disorder. Factor analysis was used to identify subdomains of SQOL, measured with the Manchester Short Assessment of Quality of Life (MANSA). 5-Year course trajectories and putative predictors of changes in SQOL and subdomains were examined using multivariable regression analyses. RESULTS: 72% was stable in either a high or a low SQOL-status over time. When outcome was defined as change score, 36%, 20%, and 44% of participants, respectively, reported a clinically relevant improvement, deterioration, or no change of SQOL during follow-up. Three SQOL subdomains were identified with different course trajectories; 33% of participants reported an improvement in the subdomains satisfaction with 'daily life' and 'personal circumstances.' The largest number of declines (28%) was reported in the subdomain satisfaction with 'physical and mental health.' Predictors of positive total and subdomain SQOL-change scores were limited to a higher age of onset and higher baseline SQOL scores. CONCLUSION: In this cohort of older persons, it was demonstrated that SQOL might considerably change during 5-year follow-up. As course trajectories differed among subdomains, separate evaluation of these subdomains is clinically relevant. Improvement of SQOL is an attainable goal in older SSD patients despite deteriorating physical health.

Patterns of discordance of physical functioning in older persons; different associations for apathy and depression? Results from the NESDO-study.

OBJECTIVES: Discordance between self-reported functional limitations and performance-based physical functioning may have a negative impact in functional independence in older adults. We longitudinally examined baseline apathy- and depressive symptomatology as associates of discordance. METHOD: 469 participants from the multi-site cohort study NESDO were included. Self-reported functional limitations were assessed by two items derived from the WHO-Disability Assessment Schedule. Performance-based physical functioning included walking speed and handgrip-strength. Both measures were rescaled, with final sum-scores ranging from 0 to 6. Discordance-scores were computed by subtracting sum-scores on performance-based measures from self-reported functional limitations. Using latent growth curve analysis, we estimated individual trajectories of discordance at baseline, 2-and 6-years follow-up, consisting of the baseline discordance-score (intercept) and the yearly change of discordance-score (slope). We then estimated associations with apathy and depression indicators. RESULTS: At baseline, persons (mean age 70.48 years, 65% female, 73% depressed) on average overestimated their daily functioning compared to performance tests (b = 0.77, p < 0.001). The average discordance-scores yearly increased by 0.15 (p < 0.001). Only in models adjusted for several demographic and clinical characteristics, depression severity was negatively associated with discordance-scores at baseline (b=-0.01, p = 0.02), while apathy was not (b=-0.02, p = 0.21). No associations with change over time were found. CONCLUSION: In older persons, not indifference and diminished goal-directed activity, but negative emotions appear to underlie underestimation of one's physical capacity. Further research is needed to determine (1) to what extent targeting discordance results in actual preservation of physical functioning and (2) whether older persons with apathy and/or depression need different approaches for this purpose.

Transient Cognitive Impairment and White Matter Hyperintensities in Severely Depressed Older Patients Treated With Electroconvulsive Therapy.

BACKGROUND: Although electroconvulsive therapy (ECT) is a safe and effective treatment for patients with severe late life depression (LLD), transient cognitive impairment can be a reason to discontinue the treatment. The aim of the current study was to evaluate the association between structural brain characteristics and general cognitive function during and after ECT. METHODS: A total of 80 patients with LLD from the prospective naturalistic follow-up Mood Disorders in Elderly treated with Electroconvulsive Therapy study were examined. Magnetic resonance imaging scans were acquired before ECT. Overall brain morphology (white and grey matter) was evaluated using visual rating scales. Cognitive functioning before, during, and after ECT was measured using the Mini Mental State Examination (MMSE). A linear mixed-model analysis was performed to analyze the association between structural brain alterations and cognitive functioning over time. RESULTS: Patients with moderate to severe white matter hyperintensities (WMH) showed significantly lower MMSE scores than patients without severe WMH (F(1,75.54) = 5.42, p = 0.02) before, during, and post-ECT, however their trajectory of cognitive functioning was similar as no time × WMH interaction effect was observed (F(4,65.85) = 1.9, p = 0.25). Transient cognitive impairment was not associated with medial temporal or global cortical atrophy (MTA, GCA). CONCLUSION: All patients showed a significant drop in cognitive functioning during ECT, which however recovered above baseline levels post-ECT and remained stable until at least 6 months post-ECT, independently of severity of WMH, GCA, or MTA. Therefore, clinicians should not be reluctant to start or continue ECT in patients with severe structural brain alterations.

Are Apathy and Depressive Symptoms Related to Vascular White Matter Hyperintensities in Severe Late Life Depression?

OBJECTIVE: Apathy symptoms are defined as a lack of interest and motivation. Patients with late-life depression (LLD) also suffer from lack of interest and motivation and previous studies have linked apathy to vascular white matter hyperintensities (WMH) of the brain in depressed and nondepressed patients. The aim of this study was to investigate the relationship between apathy symptoms, depressive symptoms, and WMH in LLD. We hypothesize that late-onset depression (LOD; first episode of depression after 55 years of age) is associated with WMH and apathy symptoms. METHODS: Apathy scores were collected for 87 inpatients diagnosed with LLD. Eighty patients underwent brain magnetic resonance imaging. Associations between depressive and apathy symptoms and WMH were analyzed using linear regression. RESULTS: All 3 subdomains of the 10-item Montgomery-Åsberg Depression Rating Scale correlated significantly with the apathy scale score (all P < .05). In the total sample, apathy nor depressive symptoms were related to specific WMH. In LOD only, periventricular WMH were associated with depression severity (ß = 5.21, P = .04), while WMH in the left infratentorial region were associated with apathy symptoms (ß coefficient = 5.89, P = .03). CONCLUSION: Apathy and depressive symptoms are highly overlapping in the current cohort of older patients with severe LLD, leading to the hypothesis that apathy symptoms are part of depressive symptoms in the symptom profile of older patients with severe LLD. Neither apathy nor depressive symptoms were related to WMH, suggesting that radiological markers of cerebrovascular disease, such as WMH, may not be useful in predicting these symptoms in severe LLD.

A 6-year prospective clinical cohort study on the bidirectional association between frailty and depressive disorder.

INTRODUCTION: Depressive disorder has been conceptualised as a condition of accelerated biological ageing. We operationalised a frailty index (FI) as marker for biological ageing aimed to explore the bidirectional, longitudinal association between frailty and either depressive symptoms or depressive disorder. METHODS: A cohort study with 6-year follow-up including 377 older (≥60 years) outpatients with a DSM-IV-defined depressive disorder and 132 never-depressed controls. Site visits at baseline, 2 and 6-year follow-up were conducted and included the CIDI 2.0 to assess depressive disorder and relevant covariates. Depressive symptom severity and mortality were assessed every 6 months by mail and telephone. A 41-item FI was operationalised and validated against the 6-year morality rate by Cox regression (HRFI  = 1.04 [95% CI: 1.02-1.06]). RESULTS: Cox regression showed that a higher FI was associated with a lower chance of remission among depressed patients (HRFI  = 0.98 [95% CI: 0.97-0.99]). Nonetheless, this latter effect disappeared after adjustment for baseline depressive symptom severity. Linear mixed models showed that the FI increased over time in the whole sample (B[SE] = 0.94 (0.12), p < .001) with a differential impact of depressive symptom severity and depressive disorder. Higher baseline depressive symptom severity was associated with an attenuated and depressive disorder with an accelerated increase of the FI over time. CONCLUSIONS: The sum score of depression rating scales is likely confounded by frailty. Depressive disorder, according to DSM-IV criteria, is associated with accelerated biological ageing. This argues for the development of multidisciplinary geriatric care models incorporating frailty to improve the overall outcome of late-life depression.

A prospective study into change of vitamin D levels, depression and frailty among depressed older persons.

OBJECTIVES: While vitamin D is involved in frailty as well as depression, hardly any study has examined the course of vitamin D levels prospectively. The objective of this study is to examine whether a change of vitamin D in depressed older adults is associated with either depression course, course of frailty, or both. METHODS: The study population consisted of 232 of 378 older adults (60-93 years) with a DSM-IV defined depressive disorder participating in the Netherlands Study of Depression in Older persons, a prospective clinical cohort study. Baseline and 2-year follow-up data on depressive disorder (DSM-IV diagnosis), symptom severity (inventory of depressive symptoms), frailty phenotype (and its individual components) and vitamin D levels were obtained. Linear mixed models were used to study the association of change in vitamin D levels with depression course, course of frailty, and the combination. RESULTS: Vitamin D levels decreased from baseline to follow-up, independent from depression course. An increase in frailty was associated with a significantly sharper decrease of vitamin D levels over time. Post hoc analyses showed that this association with frailty might be driven by an increase of exhaustion over time and counteracted by an increase in walking speed. CONCLUSIONS: Our findings generate the hypothesis that vitamin D supplementation in late-life depression may improve frailty, which may partly explain inconsistent findings of randomised controlled trials evaluating the effect of vitamin D for depression. We advocate to consider frailty (components) as an outcome in future supplementation trials in late-life depression.

Why we need to evaluate long-term antidepressant use in older patients with depression.

In this commentary, we address current clinical practice of long-term antidepressant use in older adults with depression, and recommend improvements. Compared with younger adults, older adults more frequently use antidepressants in the long term, although they may not always benefit from them, and in spite of an increased risk for adverse events. Unfortunately, evaluations of long-term antidepressant use are sparse, especially in older age groups. To prevent and reduce inappropriate long-term use and adverse events, antidepressant use in older age groups should be regularly evaluated.

Five-year outcome of clinical recovery and subjective well-being in older Dutch patients with schizophrenia.

Outcome of schizophrenia in later life can be evaluated from different perspectives. The recovery concept has moved forward this evaluation, discerning clinical-based and patient-based definitions. Longitudinal data on measures of recovery in older individuals with schizophrenia are scant. This study evaluated the five-year outcome of clinical recovery and subjective well-being in a sample of 73 older Dutch schizophrenia patients (mean age 65.9 years; SD 5.4), employing a catchment-area based design that included both community living and institutionalized patients regardless of the age of onset of their disorder. At baseline (T1), 5.5% of participants qualified for clinical recovery, while at five-year follow-up (T2), this rate was 12.3% (p = 0.18; exact McNemar's test). Subjective well-being was reported by 20.5% of participants at T1 and by 27.4% at T2 (p = 0.27; exact McNemar's test). Concurrence of clinical recovery and subjective well-being was exceptional, being present in only one participant (1.4%) at T1 and in two participants (2.7%) at T2. Clinical recovery and subjective well-being were not correlated neither at T1 (p = 0.82; phi = 0.027) nor at T2 (p = 0.71; phi = -0.044). There was no significant correlation over time between clinical recovery at T1 and subjective well-being at T2 (p = 0.30; phi = 0.122) nor between subjective well-being at T1 and clinical recovery at T2 (p = 0.45; phi = -0.088). These results indicate that while reaching clinical recovery is relatively rare in older individuals with schizophrenia, it is not a prerequisite to experience subjective well-being.

Loneliness, social network size, and mortality in older adults and the role of cortisol.

BACKGROUND: Loneliness and social isolation have both been found to be associated with increased mortality in previous studies. One potential underlying mechanism is via the hypothalamic-pituitary-adrenal axis. OBJECTIVE: This study aimed to examine the association between social network size and cortisol, to analyze the associations between both loneliness and social network size and mortality, and to examine to what extent the association between network size and/or loneliness and mortality is mediated by cortisol. DESIGN: The study group consisted of 443 depressed and non-depressed participants of the Netherlands Study of Depression in the Elderly (NESDO). Cross-sectional analysis of the association between social network size and cortisol measures was followed by a survival analysis of the associations between both social network size and loneliness and mortality. RESULTS: There were no significant associations between social network size and cortisol measures. Loneliness and small social network size were not associated with mortality. Age and partner status were more important predictors of mortality. CONCLUSION: As people grow older the variety of factors that influence mortality risk increases, diminishing the effect of a single factor. Prevention of early morbidity and mortality in older adults should be tailored to specific needs and risks, instead of aiming at one specific factor.

Clinical characteristics of late-life depression predicting mortality.

OBJECTIVE: Depression has been associated with increased mortality rates, and modifying mechanisms have not yet been elucidated. We examined whether specific subtypes or characteristics of late-life depression predict mortality. METHODS: A cohort study including 378 depressed older patients according to DSM-IV criteria and 132 never depressed comparisons. The predictive value of depression subtypes and characteristics on the six-year mortality rate, as well as their interaction with somatic disease burden and antidepressant drug use, were studied by Cox proportional hazard analysis adjusted for demographic and lifestyle characteristics. RESULTS: Depressed persons had a higher mortality risk than non-depressed comparisons (HR = 2.95 [95% CI: 1.41-6.16], p = .004), which lost significance after adjustment for age, sex, education, smoking, alcohol, physical activity, number of prescribed medications and somatic comorbidity. Regarding depression subtypes and characteristics, only minor depression was associated with a higher mortality risk when adjusted for confounders (HR = 6.59 [95% CI: 1.79-24.2], p = .005). CONCLUSIONS: Increased mortality rates of depressed older persons seem best explained by unhealthy lifestyle characteristics and multiple drug prescriptions. The high mortality rate in minor depression, independent of these factors, might point to another, yet unknown, pathway towards mortality for this depression subtype. An explanation might be that minor depression in later life reflects depressive symptoms due to underlying aging-related processes, such as inflammation-based sickness behavior, frailty, and mild cognitive impairment, which have all been associated with increased mortality.