BackgroundA recent hypothesis postulates the existence of an ‘immune-metabolic depression’ (IMD) dimension characterized by metabolic dysregulations. Combining data on metabolomics and depressive... Show moreBackgroundA recent hypothesis postulates the existence of an ‘immune-metabolic depression’ (IMD) dimension characterized by metabolic dysregulations. Combining data on metabolomics and depressive symptoms, we aimed to identify depressions associated with an increased risk of adverse metabolic alterations.MethodClustering data were from 1094 individuals with major depressive disorder in the last 6 months and measures of 149 metabolites from a 1H-NMR platform and 30 depressive symptoms (IDS-SR30). Canonical correlation analyses (CCA) were used to identify main independent metabolite-symptom axes of variance. Then, for the replication, we examined the association of the identified dimensions with metabolites from the same platform and cardiometabolic diseases in an independent population-based cohort (n = 6572).ResultsCCA identified an overall depression dimension and a dimension resembling IMD, in which symptoms such as sleeping too much, increased appetite, and low energy level had higher relative loading. In the independent sample, the overall depression dimension was associated with lower cardiometabolic risk, such as (i.e. per s.d.) HOMA-1B −0.06 (95% CI −0.09 – −0.04), and visceral adipose tissue −0.10 cm2 (95% CI −0.14 – −0.07). In contrast, the IMD dimension was associated with well-known cardiometabolic diseases such as higher visceral adipose tissue 0.08 cm2 (95% CI 0.04–0.12), HOMA-1B 0.06 (95% CI 0.04–0.09), and lower HDL-cholesterol levels −0.03 mmol/L (95% CI −0.05 – −0.01).ConclusionsCombining metabolomics and clinical symptoms we identified a replicable depression dimension associated with adverse metabolic alterations, in line with the IMD hypothesis. Patients with IMD may be at higher cardiometabolic risk and may benefit from specific treatment targeting underlying metabolic dysregulations. Show less
Background Cognitive impairment is a core feature of Huntington's disease (HD), however, the onset and rate of cognitive decline is highly variable. Apathy is the most common neuropsychiatric... Show moreBackground Cognitive impairment is a core feature of Huntington's disease (HD), however, the onset and rate of cognitive decline is highly variable. Apathy is the most common neuropsychiatric symptom of HD, and is associated with cognitive impairment. The aim of this study was to investigate apathy as a predictor of subsequent cognitive decline over 2 years in premanifest and early HD, using a prospective, longitudinal design. Methods A total of 118 premanifest HD gene carriers, 111 early HD and 118 healthy control participants from the multi-centre TRACK-HD study were included. Apathy symptoms were assessed at baseline using the apathy severity rating from the Short Problem Behaviours Assessment. A composite of 12 outcome measures from nine cognitive tasks was used to assess cognitive function at baseline and after 24 months. Results In the premanifest group, after controlling for age, depression and motor signs, more apathy symptoms predicted faster cognitive decline over 2 years. In contrast, in the early HD group, more motor signs, but not apathy, predicted faster subsequent cognitive decline. In the control group, only older age predicted cognitive decline. Conclusions Our findings indicate that in premanifest HD, apathy is a harbinger for cognitive decline. In contrast, after motor onset, in early diagnosed HD, motor symptom severity more strongly predicts the rate of cognitive decline. Show less
Background This study aimed to develop, validate and compare the performance of models predicting post-treatment outcomes for depressed adults based on pre-treatment data. Methods Individual... Show moreBackground This study aimed to develop, validate and compare the performance of models predicting post-treatment outcomes for depressed adults based on pre-treatment data. Methods Individual patient data from all six eligible randomised controlled trials were used to develop (k = 3, n = 1722) and test (k = 3, n = 918) nine models. Predictors included depressive and anxiety symptoms, social support, life events and alcohol use. Weighted sum scores were developed using coefficient weights derived from network centrality statistics (models 1-3) and factor loadings from a confirmatory factor analysis (model 4). Unweighted sum score models were tested using elastic net regularised (ENR) and ordinary least squares (OLS) regression (models 5 and 6). Individual items were then included in ENR and OLS (models 7 and 8). All models were compared to one another and to a null model (mean post-baseline Beck Depression Inventory Second Edition (BDI-II) score in the training data: model 9). Primary outcome: BDI-II scores at 3-4 months. Results Models 1-7 all outperformed the null model and model 8. Model performance was very similar across models 1-6, meaning that differential weights applied to the baseline sum scores had little impact. Conclusions Any of the modelling techniques (models 1-7) could be used to inform prognostic predictions for depressed adults with differences in the proportions of patients reaching remission based on the predicted severity of depressive symptoms post-treatment. However, the majority of variance in prognosis remained unexplained. It may be necessary to include a broader range of biopsychosocial variables to better adjudicate between competing models, and to derive models with greater clinical utility for treatment-seeking adults with depression. Show less
Kendler, K.S.; Aggen, S.H.; Werner, M.; Fried, E.I. 2020
Background: Few factor analyses and no network analyses have examined the structure of DSM phobic fears or tested the specificity of the relationship between panic disorder and agoraphobic fears.... Show moreBackground: Few factor analyses and no network analyses have examined the structure of DSM phobic fears or tested the specificity of the relationship between panic disorder and agoraphobic fears. Methods: Histories of 21 lifetime phobic fears, coded as four-level ordinal variables (no fear to fear with major interference) were assessed at personal interview in 7514 adults from the Virginia Twin Registry. We estimated Gaussian Graphical Models on individual phobic fears; compared network structures of women and men using the Network Comparison Test; used community detection to determine the number and nature of groups in which phobic fears hang together; and validated the anticipated specific relationship between panic disorder and agoraphobia. Results: All networks were densely and positively inter-connected; networks of women and men were structurally similar. Our most frequent and stable solution identified four phobic clusters: (i) blood-injection, (ii) social-agoraphobia, (iii) situational, and (iv) animal-disease. Fear of public restrooms and of diseases clustered with animal and not, respectively, social and blood-injury phobias. When added to the network, the three strongest connections with lifetime panic disorder were all agoraphobic fears: being in crowds, going out of the house alone, and being in open spaces Conclusions: Using network analyses applied to a large epidemiologic twin sample, we broadly validated the DSM-IV typography but did not entirely support the distinction of agoraphobic and social phobic fears or the DSM placements for fears of public restrooms and diseases. We found strong support for the specificity of the relationship between panic disorder and agoraphobic fears. Show less
Huneke, N.T.M.; Wee, N. van der; Garner, M.; Baldwin, D.S. 2020
Placebos are not inert, but exert measurable biological effects. The placebo response in psychiatric illness is important and clinically relevant, but remains poorly understood. In this paper, we... Show morePlacebos are not inert, but exert measurable biological effects. The placebo response in psychiatric illness is important and clinically relevant, but remains poorly understood. In this paper, we review current knowledge about the placebo response in psychiatric medicine and identify research directions for the future. We argue that more research is needed into the placebo response in psychiatric medicine for three broad reasons. First, awareness of factors that cause placebo response, for whom, and when, within clinical trials will allow us to better evidence efficacy of new treatments. Second, by understanding how placebo mechanisms operate in the clinic, we can take advantage of these to optimise the effects of current treatments. Finally, exploring the biological mechanisms of placebo effects might reveal tractable targets for novel treatment development. Show less
Background The importance of the hippocampus and amygdala for disrupted emotional memory formation in depression is well-recognized, but it remains unclear whether functional abnormalities are... Show moreBackground The importance of the hippocampus and amygdala for disrupted emotional memory formation in depression is well-recognized, but it remains unclear whether functional abnormalities are state-dependent and whether they are affected by the persistence of depressive symptoms. Methods Thirty-nine patients with major depressive disorder and 28 healthy controls were included from the longitudinal functional magnetic resonance imaging (fMRI) sub-study of the Netherlands Study of Depression and Anxiety. Participants performed an emotional word-encoding and -recognition task during fMRI at baseline and 2-year follow-up measurement. At baseline, all patients were in a depressed state. We investigated state-dependency by relating changes in brain activation over time to changes in symptom severity. Furthermore, the effect of time spent with depressive symptoms in the 2-year interval was investigated. Results Symptom change was linearly associated with higher activation over time of the left anterior hippocampus extending to the amygdala during positive and negative word-encoding. Especially during positive word encoding, this effect was driven by symptomatic improvement. There was no effect of time spent with depression in the 2-year interval on change in brain activation. Results were independent of medication- and psychotherapy-use. Conclusion Using a longitudinal within-subjects design, we showed that hippocampal-amygdalar activation during emotional memory formation is related to depressive symptom severity but not persistence (i.e. time spent with depression or 'load'), suggesting functional activation patterns in depression are not subject to functional 'scarring' although this hypothesis awaits future replication. Show less
Background Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are... Show moreBackground Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age. Methods Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer. Results CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions. Conclusions Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind. Show less
BackgroundInterpersonal difficulties in borderline personality disorder (BPD) could be related to the disturbed self-views of BPD patients. This study investigates affective and neural responses to... Show moreBackgroundInterpersonal difficulties in borderline personality disorder (BPD) could be related to the disturbed self-views of BPD patients. This study investigates affective and neural responses to positive and negative social feedback (SF) of BPD patients compared with healthy (HC) and low self-esteem (LSE) controls and how this relates to individual self-views.MethodsBPD (N = 26), HC (N = 32), and LSE (N = 22) performed a SF task in a magnetic resonance imaging scanner. Participants received 15 negative, intermediate and positive evaluative feedback words putatively given by another participant and rated their mood and applicability of the words to the self.ResultsBPD had more negative self-views than HC and felt worse after negative feedback. Applicability of feedback was a less strong determinant of mood in BPD than HC. Increased precuneus activation was observed in HC to negative compared with positive feedback, whereas in BPD, this was similarly low for both valences. HC showed increased temporoparietal junction (TPJ) activation to positive v. negative feedback, while BPD showed more TPJ activation to negative feedback. The LSE group showed a different pattern of results suggesting that LSE cannot explain these findings in BPD.ConclusionsThe negative self-views that BPD have, may obstruct critically examining negative feedback, resulting in lower mood. Moreover, where HC focus on the positive feedback (based on TPJ activation), BPD seem to focus more on negative feedback, potentially maintaining negative self-views. Better balanced self-views may make BPD better equipped to deal with potential negative feedback and more open to positive interactions. Show less
BackgroundInterpersonal difficulties in borderline personality disorder (BPD) could be related to the disturbed self-views of BPD patients. This study investigates affective and neural responses to... Show moreBackgroundInterpersonal difficulties in borderline personality disorder (BPD) could be related to the disturbed self-views of BPD patients. This study investigates affective and neural responses to positive and negative social feedback (SF) of BPD patients compared with healthy (HC) and low self-esteem (LSE) controls and how this relates to individual self-views.MethodsBPD (N = 26), HC (N = 32), and LSE (N = 22) performed a SF task in a magnetic resonance imaging scanner. Participants received 15 negative, intermediate and positive evaluative feedback words putatively given by another participant and rated their mood and applicability of the words to the self.ResultsBPD had more negative self-views than HC and felt worse after negative feedback. Applicability of feedback was a less strong determinant of mood in BPD than HC. Increased precuneus activation was observed in HC to negative compared with positive feedback, whereas in BPD, this was similarly low for both valences. HC showed increased temporoparietal junction (TPJ) activation to positive v. negative feedback, while BPD showed more TPJ activation to negative feedback. The LSE group showed a different pattern of results suggesting that LSE cannot explain these findings in BPD.ConclusionsThe negative self-views that BPD have, may obstruct critically examining negative feedback, resulting in lower mood. Moreover, where HC focus on the positive feedback (based on TPJ activation), BPD seem to focus more on negative feedback, potentially maintaining negative self-views. Better balanced self-views may make BPD better equipped to deal with potential negative feedback and more open to positive interactions. Show less
Background Antidepressant medications (ADMs) are widely used and long-term use is increasing. Given this extensive use and recommendation of ADMs in guidelines, one would expect ADMs to be... Show moreBackground Antidepressant medications (ADMs) are widely used and long-term use is increasing. Given this extensive use and recommendation of ADMs in guidelines, one would expect ADMs to be universally considered effective. Surprisingly, that is not the case; fierce debate on their benefits and harms continues. This editorial seeks to understand why the controversy continues and how consensus can be achieved. Methods 'Position' paper. Critical analysis and synthesis of relevant literature. Results Advocates point at ADMs impressive effect size (number needed to treat, NNT = 6-8) in acute phase treatment and continuation/maintenance ADM treatment prevention relapse/recurrence in acute phase ADM responders (NNT = 3-4). Critics point at the limited clinically significant surplus value of ADMs relative to placebo and argue that effectiveness is overstated. We identified multiple factors that fuel the controversy: certainty of evidence is low to moderate; modest efficacy on top of strong placebo effects allows critics to focus on small net efficacy and advocates on large gross efficacy; ADM withdrawal symptoms masquerade as relapse/recurrence; lack of association between ADM treatment and long-term outcome in observational databases. Similar problems affect psychological treatments as well, but less so. We recommend four approaches to resolve the controversy: (1) placebo-controlled trials with relevant long-term outcome assessments, (2) inventive analyses of observational databases, (3) patient cohort studies including effect moderators to improve personalized treatment, and (4) psychological treatments as universal first-line treatment step. Conclusions Given the public health significance of depression and increased long-term ADM usage, new approaches are needed to resolve the controversy. Show less
BackgroundResearch in depression has progressed rapidly over the past four decades. Yet depression rates are not subsiding and treatment success is not improving. We examine the extent to which the... Show moreBackgroundResearch in depression has progressed rapidly over the past four decades. Yet depression rates are not subsiding and treatment success is not improving. We examine the extent to which the gap between science and practice is associated with the level of integration in how depression is considered in research and stakeholder-relevant documents.MethodsWe used a network-science perspective to analyze similar uses of depression relevant terms in the Google News corpus (approximately 1 billion words) and the Web of Science database (120 000 documents).ResultsThese analyses yielded consistent pictures of insular modules associated with: (1) patient/providers, (2) academics, and (3) industry. Within academia insular modules associated with psychology, general medical, and psychiatry/neuroscience/biology were also detected.ConclusionsThese analyses suggest that the domain of depression is fragmented, and that advancements of relevance to one stakeholder group (academics, industry, or patients) may not translate to the others. We consider potential causes and associated responses to this fragmentation that could help to unify and advance translation from research on depression to the clinic, largely involving harmonizing employed language, bridging conceptual domains, and increasing communication across stakeholder groups. Show less
BackgroundStudies investigating the link between depressive symptoms and inflammation have yielded inconsistent results, which may be due to two factors. First, studies differed regarding the... Show moreBackgroundStudies 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.MethodsWe 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.ResultsThe 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.ConclusionsWe 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. Show less
