The association between persistent cognitive difficulties and depression and functional outcomes in people with major depressive disorder.

BACKGROUND: Cognitive symptoms are common during and following episodes of depression. Little is known about the persistence of self-reported and performance-based cognition with depression and functional outcomes. METHODS: This is a secondary analysis of a prospective naturalistic observational clinical cohort study of individuals with recurrent major depressive disorder (MDD; N = 623). Participants completed app-based self-reported and performance-based cognitive function assessments alongside validated measures of depression, functional disability, and self-esteem every 3 months. Participants were followed-up for a maximum of 2-years. Multilevel hierarchically nested modelling was employed to explore between- and within-participant variation over time to identify whether persistent cognitive difficulties are related to levels of depression and functional impairment during follow-up. RESULTS: 508 individuals (81.5%) provided data (mean age: 46.6, s.d.: 15.6; 76.2% female). Increasing persistence of self-reported cognitive difficulty was associated with higher levels of depression and functional impairment throughout the follow-up. In comparison to low persistence of objective cognitive difficulty (<25% of timepoints), those with high persistence (>75% of timepoints) reported significantly higher levels of depression (B = 5.17, s.e. = 2.21, p = 0.019) and functional impairment (B = 4.82, s.e. = 1.79, p = 0.002) over time. Examination of the individual cognitive modules shows that persistently impaired executive function is associated with worse functioning, and poor processing speed is particularly important for worsened depressive symptoms. CONCLUSIONS: We replicated previous findings of greater persistence of cognitive difficulty with increasing severity of depression and further demonstrate that these cognitive difficulties are associated with pervasive functional disability. Difficulties with cognition may be an indicator and target for further treatment input.

The usability of daytime and night-time heart rate dynamics as digital biomarkers of depression severity.

BACKGROUND: Alterations in heart rate (HR) may provide new information about physiological signatures of depression severity. This 2-year study in individuals with a history of recurrent major depressive disorder (MDD) explored the intra-individual variations in HR parameters and their relationship with depression severity. METHODS: Data from 510 participants (Number of observations of the HR parameters = 6666) were collected from three centres in the Netherlands, Spain, and the UK, as a part of the remote assessment of disease and relapse-MDD study. We analysed the relationship between depression severity, assessed every 2 weeks with the Patient Health Questionnaire-8, with HR parameters in the week before the assessment, such as HR features during all day, resting periods during the day and at night, and activity periods during the day evaluated with a wrist-worn Fitbit device. Linear mixed models were used with random intercepts for participants and countries. Covariates included in the models were age, sex, BMI, smoking and alcohol consumption, antidepressant use and co-morbidities with other medical health conditions. RESULTS: Decreases in HR variation during resting periods during the day were related with an increased severity of depression both in univariate and multivariate analyses. Mean HR during resting at night was higher in participants with more severe depressive symptoms. CONCLUSIONS: Our findings demonstrate that alterations in resting HR during all day and night are associated with depression severity. These findings may provide an early warning of worsening depression symptoms which could allow clinicians to take responsive treatment measures promptly.

Efficacy of celecoxib add-on treatment for immuno-metabolic depression: Protocol of the INFLAMED double-blind placebo-controlled randomized controlled trial.

Introduction: As the role of (neuro)inflammation in depression pathophysiology is emerging, augmentation of antidepressant treatments with anti-inflammatory drugs have shown beneficial results, but not consistently across all studies. Inconsistencies may be due to depression biological and clinical heterogeneity. Immuno-Metabolic Depression (IMD) has been put forward as a form of depression characterized by the clustering of low-grade inflammation, metabolic dysregulations and atypical, energy-related symptoms (overeating, weight gain, hypersomnia, fatigue and leaden paralysis). IMD features are present in ∼30% of patients with Major Depressive Disorder (MDD). By selecting these specific patients, directly targeting inflammation may reduce depressive symptoms. Methods: and analysis INFLAMED is a double-blind randomized controlled trial. 140 MDD patients with IMD characteristics (MDD with Inventory of Depressive Symptomatology (IDS) ≥ 26, IDS atypical, energy related symptoms ≥6, C-Reactive Protein (CRP) > 1 mg/L) will receive either 400 mg celecoxib per day or matching placebo for a period of 12 weeks. Biological, physical and interview data will be collected after 2, 6 and 12 weeks of starting the intervention. Questionnaires will be sent out bi-weekly during the study period. The main study outcome is the IDS (30-item self-report) total score during 12-week follow-up. Secondary study outcomes include response, remission, adverse side effects, symptom profiles (atypical, energy-related symptoms), fatigue, food craving, sleep, anxiety symptoms, functioning, pain, and optionally, microbiome composition. Explorative analyses will be performed on the role of CRP, IL-6, TNF-α, cholesterol, triglycerides, glucose, BMI, waist and hip circumference. Ethics and dissemination: This protocol has been approved by the Medical Ethics Review Board of the Amsterdam UMC, location VUmc (2022.0015) on 2-6-2022, as well as by the competent authority in The Netherlands: CCMO, on 3-8-2022. Registration details: Trail registration numbers NCT05415397, EudraCT 2021-003850-21.

Predictors of engagement with remote sensing technologies for symptom measurement in Major Depressive Disorder.

BACKGROUND: Remote sensing for the measurement and management of long-term conditions such as Major Depressive Disorder (MDD) is becoming more prevalent. User-engagement is essential to yield any benefits. We tested three hypotheses examining associations between clinical characteristics, perceptions of remote sensing, and objective user engagement metrics. METHODS: The Remote Assessment of Disease and Relapse - Major Depressive Disorder (RADAR-MDD) study is a multicentre longitudinal observational cohort study in people with recurrent MDD. Participants wore a FitBit and completed app-based assessments every two weeks for a median of 18 months. Multivariable random effects regression models pooling data across timepoints were used to examine associations between variables. RESULTS: A total of 547 participants (87.8% of the total sample) were included in the current analysis. Higher levels of anxiety were associated with lower levels of perceived technology ease of use; increased functional disability was associated with small differences in perceptions of technology usefulness and usability. Participants who reported higher system ease of use, usefulness, and acceptability subsequently completed more app-based questionnaires and tended to wear their FitBit activity tracker for longer. All effect sizes were small and unlikely to be of practical significance. LIMITATIONS: Symptoms of depression, anxiety, functional disability, and perceptions of system usability are measured at the same time. These therefore represent cross-sectional associations rather than predictions of future perceptions. CONCLUSIONS: These findings suggest that perceived usability and actual use of remote measurement technologies in people with MDD are robust across differences in severity of depression, anxiety, and functional impairment.

Individual placement and support and employment in personality disorders: a registry based cohort study.

BACKGROUND: To explore the relative impact of Individual Placement and Support (IPS) in patients with personality disorders (PDs) as compared to patients with other mental disorders. METHODS: Data from the Dutch Employee Insurance Agency of participants enrolled in a national IPS trajectory between 2008 and 2018 were linked to corresponding data on employment outcomes, diagnostic and sociodemographic information from Statistics Netherlands. This resulted in a sample of 335 participants with PDs who could be compared with 1073 participants with other mental disorders. RESULTS: Participants with PD just as often found competitive employment as participants with other mental disorders (37.6% vs. 38.0%, ORadjusted = 0.97, 95% confidence interval (CI) 0.74 to 1.27). The median time to gaining employment for those gaining employment (37.9%) was 195.5 days (mean number of days 252.5) in the PD group and 178.5 days (mean number of days 234.6) in the other mental disorders group (HRadjusted = 0.95, 95% CI 0.77 to 1.18). Also, total number of hours paid for competitive employment did not differ significantly between groups (median hours 686.5 vs 781.5, IRRadjusted = 0.85 95% CI 0.69 to 1.05). CONCLUSIONS: Based on this study, which includes the largest sample of patients with PDs in any published IPS study, IPS seems to result in an equal percentage of patients with PDs and other mental disorders, gaining and maintaining employment. Although future studies should determine whether PD-specific adaptations to IPS are useful, our findings indicate that IPS could be an effective way to increase employment outcomes in PDs. This is important because the enormous societal costs of PDs are largely driven by loss of economic productivity, and because clinical recovery in PDs is suggested to be enhanced when patients are employed.

Chronotype, daily affect and social contact: An ecological momentary assessment study.

Eveningness is associated with lower daily positive affect (PA). The relationship between negative affect (NA) and chronotype, however, is less consistent in the literature. Eveningness may be further characterized by increased social isolation, which could explain the associations between chronotype and PA/NA. In the present longitudinal study, we used ecological momentary assessment (EMA) to investigate the associations of chronotype with daily PA, NA, and social contact in individuals with current and remitted major depressive disorder (MDD) and healthy controls. As part of the Netherlands Study of Depression and Anxiety (NESDA), 279 participants (n = 49 depressed, n = 172 remitted, n = 58 controls) monitored daily PA, NA, and social contact (i.e., being alone vs. with others) for two weeks, five times per day. Overall, eveningness was associated with less social contact. This effect became nonsignificant, however, after accounting for sociodemographics (gender, age, education, living situation). Chronotype was not related to PA or NA. Less social contact was associated with lower PA and higher NA independent of chronotype. In conclusion, we could not replicate the finding of lower PA among evening types, but found social contact to associate with both daily PA and NA.

Affect fluctuations examined with ecological momentary assessment in patients with current or remitted depression and anxiety disorders.

BACKGROUND: There is increasing interest in day-to-day affect fluctuations of patients with depressive and anxiety disorders. Few studies have compared repeated assessments of positive affect (PA) and negative affect (NA) across diagnostic groups, and fluctuation patterns were not uniformly defined. The aim of this study is to compare affect fluctuations in patients with a current episode of depressive or anxiety disorder, in remitted patients and in controls, using affect instability as a core concept but also describing other measures of variability and adjusting for possible confounders. METHODS: Ecological momentary assessment (EMA) data were obtained from 365 participants of the Netherlands Study of Depression and Anxiety with current (n = 95), remitted (n = 178) or no (n = 92) DSM-IV defined depression/anxiety disorder. For 2 weeks, five times per day, participants filled-out items on PA and NA. Affect instability was calculated as the root mean square of successive differences (RMSSD). Tests on group differences in RMSSD, within-person variance, and autocorrelation were performed, controlling for mean affect levels. RESULTS: Current depression/anxiety patients had the highest affect instability in both PA and NA, followed by remitters and then controls. Instability differences between groups remained significant when controlling for mean affect levels, but differences between current and remitted were no longer significant. CONCLUSIONS: Patients with a current disorder have higher instability of NA and PA than remitted patients and controls. Especially with regard to NA, this could be interpreted as patients with a current disorder being more sensitive to internal and external stressors and having suboptimal affect regulation.

Employment in Personality Disorders and the Effectiveness of Individual Placement and Support: Outcomes from a Secondary Data Analysis.

Purpose Personality disorders (PDs) are associated with severe functional impairment and subsequent high societal costs, increasing the need to improve occupational functioning in PD. Individual placement and support (IPS) is an effective, evidence-based method of supported employment, which so far has been tested in various mixed patient populations with severe mental illness (SMI, including PDs). However, the effectiveness of IPS for PDs per se remains uninvestigated. Methods Data from the SCION trial were used, including 31 SMI patients with PDs and 115 SMI patients with other primary diagnoses (primarily psychotic disorders). First, the interaction effect of diagnosis (PD vs other SMI) and intervention (IPS vs traditional vocational rehabilitation) was studied. Second, in the IPS condition, difference between diagnostic groups in time to first job was studied. Results We did not find evidence of a moderating effect of PD diagnosis on the primary effect of IPS (proportion who started in regular employment) (OR = 0.592, 95% CI 0.80-4.350, p = 0.606) after 30 months. Also, PD diagnosis did not moderate the effect of time until first job in IPS. Conclusions From the present explorative analysis we did not find evidence for a moderating effect of PD diagnosis on the effectiveness of IPS among PD participants. This indicates that IPS could be as effective in gaining employment in participants with PD as it is in participants with other SMI. Future studies, implementing larger numbers, should confirm whether IPS is equally effective in PDs and study whether augmentations or alterations to the standard IPS model might be beneficiary for PD.

Using network analysis to examine links between individual depressive symptoms, inflammatory markers, and covariates.

BACKGROUND: Studies investigating the link between depressive symptoms and inflammation have yielded inconsistent results, which may be due to two factors. First, studies differed regarding the specific inflammatory markers studied and covariates accounted for. Second, specific depressive symptoms may be differentially related to inflammation. We address both challenges using network psychometrics. METHODS: We estimated seven regularized Mixed Graphical Models in the Netherlands Study of Depression and Anxiety (NESDA) data (N = 2321) to explore shared variances among (1) depression severity, modeled via depression sum-score, nine DSM-5 symptoms, or 28 individual depressive symptoms; (2) inflammatory markers C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α); (3) before and after adjusting for sex, age, body mass index (BMI), exercise, smoking, alcohol, and chronic diseases. RESULTS: The depression sum-score was related to both IL-6 and CRP before, and only to IL-6 after covariate adjustment. When modeling the DSM-5 symptoms and CRP in a conceptual replication of Jokela et al., CRP was associated with 'sleep problems', 'energy level', and 'weight/appetite changes'; only the first two links survived covariate adjustment. In a conservative model with all 38 variables, symptoms and markers were unrelated. Following recent psychometric work, we re-estimated the full model without regularization: the depressive symptoms 'insomnia', 'hypersomnia', and 'aches and pain' showed unique positive relations to all inflammatory markers. CONCLUSIONS: We found evidence for differential relations between markers, depressive symptoms, and covariates. Associations between symptoms and markers were attenuated after covariate adjustment; BMI and sex consistently showed strong relations with inflammatory markers.

Remote assessment of disease and relapse in major depressive disorder (RADAR-MDD): a multi-centre prospective cohort study protocol.

BACKGROUND: There is a growing body of literature highlighting the role that wearable and mobile remote measurement technology (RMT) can play in measuring symptoms of major depressive disorder (MDD). Outcomes assessment typically relies on self-report, which can be biased by dysfunctional perceptions and current symptom severity. Predictors of depressive relapse include disrupted sleep, reduced sociability, physical activity, changes in mood, prosody and cognitive function, which are all amenable to measurement via RMT. This study aims to: 1) determine the usability, feasibility and acceptability of RMT; 2) improve and refine clinical outcome measurement using RMT to identify current clinical state; 3) determine whether RMT can provide information predictive of depressive relapse and other critical outcomes. METHODS: RADAR-MDD is a multi-site prospective cohort study, aiming to recruit 600 participants with a history of depressive disorder across three sites: London, Amsterdam and Barcelona. Participants will be asked to wear a wrist-worn activity tracker and download several apps onto their smartphones. These apps will be used to either collect data passively from existing smartphone sensors, or to deliver questionnaires, cognitive tasks, and speech assessments. The wearable device, smartphone sensors and questionnaires will collect data for up to 2-years about participants' sleep, physical activity, stress, mood, sociability, speech patterns, and cognitive function. The primary outcome of interest is MDD relapse, defined via the Inventory of Depressive Symptomatology- Self-Report questionnaire (IDS-SR) and the World Health Organisation's self-reported Composite International Diagnostic Interview (CIDI-SF). DISCUSSION: This study aims to provide insight into the early predictors of major depressive relapse, measured unobtrusively via RMT. If found to be acceptable to patients and other key stakeholders and able to provide clinically useful information predictive of future deterioration, RMT has potential to change the way in which depression and other long-term conditions are measured and managed.

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.

Metabolic and inflammatory markers: associations with individual depressive symptoms.

BACKGROUND: Literature has shown that obesity, metabolic syndrome and inflammation are associated with depression, however, evidence suggests that these associations are specific to atypical depression. Which of the atypical symptoms are driving associations with obesity-related outcomes and inflammation is unknown. We evaluated associations between individual symptoms of depression (both atypical and non-atypical) and body mass index (BMI), metabolic syndrome components and inflammatory markers. METHODS: We included 808 persons with a current diagnosis of depression participating in the Netherlands Study of Depression and Anxiety (67% female, mean age 41.6 years). Depressive symptoms were derived from the Composite International Diagnostic Interview and the Inventory of Depressive Symptomatology. Univariable and multivariable regression analyses adjusting for sex, age, educational level, depression severity, current smoking, physical activity, anti-inflammatory medication use, and statin use were performed. RESULTS: Increased appetite was positively associated with BMI, number of metabolic syndrome components, waist circumference, C-reactive protein and tumor necrosis factor-α. Decreased appetite was negatively associated with BMI and waist circumference. Psychomotor retardation was positively associated with BMI, high-density lipoprotein cholesterol and triglycerides, and insomnia with number of metabolic syndrome components. CONCLUSION: Increased appetite - in the context of a depressive episode - was the only symptom that was associated with both metabolic as well as inflammatory markers, and could be a key feature of an immuno-metabolic form of depression. This immuno-metabolic depression should be considered in clinical trials evaluating effectiveness of compounds targeting metabolic and inflammatory pathways or lifestyle interventions.

Dysregulation of objectively assessed 24-hour motor activity patterns as a potential marker for bipolar I disorder: results of a community-based family study.

There has been a growing number of studies that have employed actigraphy to investigate differences in motor activity in mood disorders. In general, these studies have shown that people with bipolar disorders (BPDs) tend to exhibit greater variability and less daytime motor activity than controls. The goal of this study was to examine whether patterns of motor activity differ in euthymic individuals across the full range of mood disorder subtypes (Bipolar I (BPI), Bipolar II (BPII) and major depression (MDD)) compared with unaffected controls in a community-based family study of mood spectrum disorders. Minute-to-minute activity counts derived from actigraphy were collected over a 2-week period for each participant. Prospective assessments of the level, timing and day-to-day variability of physical activity measures were compared across diagnostic groups after controlling for a comprehensive list of potential confounding factors. After adjusting for the effects of age, sex, body mass index (BMI) and medication use, the BPI group had lower median activity intensity levels across the second half of the day and greater variability in the afternoon compared with controls. Those with a history of BPII had increased variability during the night time compared with controls, indicating poorer sleep quality. No differences were found in the average intensity, variability or timing of activity in comparisons between other mood disorder subgroups and controls. Findings confirm evidence from previous studies that BPI may be a manifestation of a rhythm disturbance that is most prominent during the second half of the day. The present study is the largest study to date that included the full range of mood disorder subgroups in a nonclinical sample that increases the generalizability of our findings to the general community. The manifestations of activity patterns outside of acute episodes add to the accumulating evidence that dysregulation of patterns of activity may constitute a potential biomarker for BPD.

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.

Sit, step, sweat: longitudinal associations between physical activity patterns, anxiety and depression.

BACKGROUND: Physical inactivity has been identified as a risk factor for depression and, less often, as a long-term consequence of depression. Underexplored is whether similar bi-directional longitudinal relationships are observed for anxiety disorders, particularly in relation to three distinct indicators of activity levels - sports participation, general physical activity and sedentary behavior. METHOD: Participants were from the Netherlands Study of Depression and Anxiety (NESDA; N = 2932, 18-65 years old; 57% current anxiety or depressive disorder, 21% remitted disorder, 22% healthy controls). At baseline, 2, 4, and 6 years, participants completed a diagnostic interview and self-report questionnaires assessing psychopathology symptom severity, physical activity indicators, and sociodemographic and health covariates. RESULTS: Consistently across assessment waves, people with anxiety and/or depressive disorders had lower sports participation and general physical activity compared to healthy controls. Greater anxiety or depressive symptoms were associated with lower activity according to all three indicators. Over time, a diagnosis or greater symptom severity at one assessment was associated with poorer sports participation and general physical activity 2 years later. In the opposite direction, only low sports participation was associated with greater symptom severity and increased odds of disorder onset 2 years later. Stronger effects were observed for chronicity, with lower activity according to all indicators increasing the odds of disorder chronicity after 2 years. CONCLUSIONS: Over time, there seems to a mutually reinforcing, bidirectional relationship between psychopathology and lower physical activity, particularly low sports participation. People with anxiety are as adversely affected as those with depression.

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.

Age-related variability in the presentation of symptoms of major depressive disorder.

BACKGROUND: The heterogeneous aetiology of major depressive disorder (MDD) might affect the presentation of depressive symptoms across the lifespan. We examined to what extent a range of mood, cognitive, and somatic/vegetative depressive symptoms were differentially present depending on patient's age. METHOD: Data came from 1404 participants with current MDD (aged 18-88 years) from two cohort studies: the Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Study of Depression in Older Persons (NESDO). Associations between age (per 10 years) and 30 depressive symptoms as well as three symptom clusters (mood, cognitive, somatic/vegetative) were assessed using logistic and linear regression analyses. RESULTS: Depression severity was found to be stable with increasing age. Nevertheless, 20 (67%) out of 30 symptoms were associated with age. Most clearly, with ageing there was more often early morning awakening [odds ratio (OR) 1.47, 95% confidence interval (CI) 1.36-1.60], reduced interest in sex (OR 1.42, 95% CI 1.31-1.53), and problems sleeping during the night (OR 1.33, 95% CI 1.24-1.43), whereas symptoms most strongly associated with younger age were interpersonal sensitivity (OR 0.72, 95% CI 0.66-0.79), feeling irritable (OR 0.73, 95% CI 0.67-0.79), and sleeping too much (OR 0.75, 95% CI 0.68-0.83). The sum score of somatic/vegetative symptoms was associated with older age (B = 0.23, p < 0.001), whereas the mood and cognitive sum scores were associated with younger age (B = -0.20, p < 0.001; B = -0.04, p = 0.004). CONCLUSIONS: Depression severity was found to be stable across the lifespan, yet depressive symptoms tend to shift with age from being predominantly mood-related to being more somatic/vegetative. Due to the increasing somatic presentation of depression with age, diagnoses may be missed.

Serum proteomic profiles of depressive subtypes.

Depression is a highly heterogeneous disorder. Accumulating evidence suggests biological and genetic differences between subtypes of depression that are homogeneous in symptom presentation. We aimed to evaluate differences in serum protein profiles between persons with atypical and melancholic depressive subtypes, and compare these profiles with serum protein levels of healthy controls. We used the baseline data from the Netherlands Study of Depression and Anxiety on 414 controls, 231 persons with a melancholic depressive subtype and 128 persons with an atypical depressive subtype for whom the proteomic data were available. Depressive subtypes were previously established using a data-driven analysis, and 171 serum proteins were measured on a multi-analyte profiling platform. Linear regression models were adjusted for several covariates and corrected for multiple testing using false discovery rate q-values. We observed differences in analytes between the atypical and melancholic subtypes (9 analytes, q<0.05) and between atypical depression and controls (23 analytes, q<0.05). Eight of the nine markers differing between the atypical and melancholic subtype overlapped with markers from the comparison between atypical subtype and controls (mesothelin, leptin, IGFBP1, IGFBP2, FABPa, insulin, C3 and B2M), and were mainly involved in cellular communication and signal transduction, and immune response. No markers differed significantly between the melancholic subtype and controls. To conclude, although some uncertainties exist in our results as a result of missing data imputation and lack of proteomic replication samples, many of the identified analytes are inflammatory or metabolic markers, which supports the notion of atypical depression as a syndrome characterized by metabolic disturbances and inflammation, and underline the importance and relevance of subtypes of depression in biological and genetic research, and potentially in the treatment of depression.

Six-year longitudinal course and outcomes of subtypes of depression.

BACKGROUND: Clinical and aetiological heterogeneity have impeded our understanding of depression. AIMS: To evaluate differences in psychiatric and somatic course between people with depression subtypes that differed clinically (severity) and aetiologically (melancholic v. atypical). METHOD: Data from baseline, 2-, 4- and 6-year follow-up of The Netherlands Study of Depression and Anxiety were used, and included 600 controls and 648 people with major depressive disorder (subtypes: severe melancholic n = 308; severe atypical n = 167; moderate n = 173, established using latent class analysis). RESULTS: Those with the moderate subtype had a significantly better psychiatric clinical course than the severe melancholic and atypical subtype groups. Suicidal thoughts and anxiety persisted longer in those with the melancholic subtype. The atypical subtype group continued to have the highest body mass index and highest prevalence of metabolic syndrome during follow-up, although differences between groups became less pronounced over time. CONCLUSIONS: Course trajectories of depressive subtypes mostly ran parallel to each other, with baseline severity being the most important differentiator in course between groups.

Polygenic dissection of major depression clinical heterogeneity.

The molecular mechanisms underlying major depressive disorder (MDD) are largely unknown. Limited success of previous genetics studies may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the polygenic features of MDD and two common clinical subtypes (typical and atypical) defined by symptom profiles in a large sample of adults with established diagnoses. Data were from 1530 patients of the Netherlands Study of Depression and Anxiety (NESDA) and 1700 controls mainly from the Netherlands Twin Register (NTR). Diagnoses of MDD and its subtypes were based on DSM-IV symptoms. Genetic overlap of MDD and subtypes with psychiatric (MDD, bipolar disorder, schizophrenia) and metabolic (body mass index (BMI), C-reactive protein, triglycerides) traits was evaluated via genomic profile risk scores (GPRS) generated from meta-analysis results of large international consortia. Single nucleotide polymorphism (SNP)-heritability of MDD and subtypes was also estimated. MDD was associated with psychiatric GPRS, while no association was found for GPRS of metabolic traits. MDD subtypes had differential polygenic signatures: typical was strongly associated with schizophrenia GPRS (odds ratio (OR)=1.54, P=7.8e-9), while atypical was additionally associated with BMI (OR=1.29, P=2.7e-4) and triglycerides (OR=1.21, P=0.006) GPRS. Similar results were found when only the highly discriminatory symptoms of appetite/weight were used to define subtypes. SNP-heritability was 32% for MDD, 38% and 43% for subtypes with, respectively, decreased (typical) and increased (atypical) appetite/weight. In conclusion, MDD subtypes are characterized by partially distinct polygenic liabilities and may represent more homogeneous phenotypes. Disentangling MDD heterogeneity may help the psychiatric field moving forward in the search for molecular roots of depression.