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Cluster analyses have become popular tools for data-driven classification in biological psychiatric research. However, these analyses are known to be sensitive to the chosen methods and/or modelling options, which may hamper generalizability and replicability of findings. To gain more insight into this problem, we used Specification-Curve Analysis (SCA) to investigate the influence of methodological variation on biomarker-based cluster-analysis results.
Proteomics data (31 biomarkers) were used from patients (n = 688) and healthy controls (n = 426) in the Netherlands Study of Depression and Anxiety. In SCAs, consistency of results was evaluated across 1200 k-means and hierarchical clustering analyses, each with a unique combination of the clustering algorithm, fit-index, and distance metric. Next, SCAs were run in simulated datasets with varying cluster numbers and noise/outlier levels to evaluate the effect of data properties on SCA outcomes.
The real data SCA showed no robust patterns of biological clustering in either the MDD or a combined MDD/healthy dataset. The simulation results showed that the correct number of clusters could be identified quite consistently across the 1200 model specifications, but that correct cluster identification became harder when the number of clusters and noise levels increased.
SCA can provide useful insights into the presence of clusters in biomarker data. However, SCA is likely to show inconsistent results in real-world biomarker datasets that are complex and contain considerable levels of noise. Here, the number and nature of the observed clusters may depend strongly on the chosen model-specification, precluding conclusions about the existence of biological clusters among psychiatric patients.
This paper develops the idea that nosological reform is ultimately a matter of finding homogeneous groups of patients that are maximally distinct from each other. The focus lies on the statistical properties of patients, so that the problem of classification coincides with the problem of the reference class from the philosophy of science. It is argued that specific statistical methods – model selection and causal modeling – can assist in finding good classifications. An important advantage of these statistical methods is that they do not favor any particular explanatory level or vocabulary. Whether or not we should include some patient characteristic in our classification scheme is an empirical issue, to be settled entirely by its contribution to the performance of the scheme in predictions and intervention decisions. For this reason the paper adopts a so-called a-reductionist perspective: we do not need a principled discussion on reductionism.
Major depressive disorder (MDD) is a common mood disorder, with a heritability of around 34%. Molecular genetic studies made significant progress and identified genetic markers associated with the risk of MDD; however, progress is slowed down by substantial heterogeneity as MDD is assessed differently across international cohorts. Here, we used a standardized online approach to measure MDD in multiple cohorts in the Netherlands and evaluated whether this approach can be used in epidemiological and genetic association studies of depression.
Within the Biobank Netherlands Internet Collaboration (BIONIC) project, we collected MDD data in eight cohorts involving 31 936 participants, using the online Lifetime Depression Assessment Self-report (LIDAS), and estimated the prevalence of current and lifetime MDD in 22 623 unrelated individuals. In a large Netherlands Twin Register (NTR) twin-family dataset (n ≈ 18 000), we estimated the heritability of MDD, and the prediction of MDD in a subset (n = 4782) through Polygenic Risk Score (PRS).
Estimates of current and lifetime MDD prevalence were 6.7% and 18.1%, respectively, in line with population estimates based on validated psychiatric interviews. In the NTR heritability estimates were 0.34/0.30 (s.e. = 0.02/0.02) for current/lifetime MDD, respectively, showing that the LIDAS gives similar heritability rates for MDD as reported in the literature. The PRS predicted risk of MDD (OR 1.23, 95% CI 1.15–1.32, R2 = 1.47%).
By assessing MDD status in the Netherlands using the LIDAS instrument, we were able to confirm previously reported MDD prevalence and heritability estimates, which suggests that this instrument can be used in epidemiological and genetic association studies of depression.
Network models block reductionism about psychiatric disorders only if models are interpreted in a realist manner – that is, taken to represent “what psychiatric disorders really are.” A flexible and more instrumentalist view of models is needed to improve our understanding of the heterogeneity and multifactorial character of psychiatric disorders.
Improvement in depression within the first 2 weeks of antidepressant treatment predicts good outcomes, but non-improvers can still respond or remit, whereas improvers often do not.
We aimed to investigate whether early improvement of individual depressive symptoms better predicts response or remission.
We obtained individual patient data of 30 trials comprising 2184 placebo-treated and 6058 antidepressant-treated participants. Primary outcome was week 6 response; secondary outcomes were week 6 remission and week 12 response and remission. We compared models that only included improvement in total score by week 2 (total improvement model) with models that also included improvement in individual symptoms.
For week 6 response, the area under the receiver operating characteristic curve and negative and positive predictive values of the total improvement model were 0.73, 0.67 and 0.74 compared with 0.77, 0.70 and 0.71 for the item improvement model. Model performance decreased for week 12 outcomes. Of predicted non-responders, 29% actually did respond by week 6 and 43% by week 12, which was decreased from the baseline (overall) probabilities of 51% by week 6 and 69% by week 12. In post hoc analyses with continuous rather than dichotomous early improvement, including individual items did not enhance model performance.
Examining individual symptoms adds little to the predictive ability of early improvement. Additionally, early non-improvement does not rule out response or remission, particularly after 12 rather than 6 weeks. Therefore, our findings suggest that routinely adapting pharmacological treatment because of limited early improvement would often be premature.
Major depression (MD) occurs about twice as often in women as in men, but it is unclear whether sex differences subsist after disease onset. This study aims to elucidate potential sex differences in rates and risk factors for MD recurrence, in order to improve prediction of course of illness and understanding of its underlying mechanisms.
We used prospective data from a general population sample (n = 653) that experienced a recent episode of MD. A diverse set of potential risk factors for recurrence of MD was analyzed using Cox models subject to elastic net regularization for males and females separately. Accuracy of the prediction models was tested in same-sex and opposite-sex test data. Additionally, interactions between sex and each of the risk factors were investigated to identify potential sex differences.
Recurrence rates and the impact of most risk factors were similar for men and women. For both sexes, prediction models were highly multifactorial including risk factors such as comorbid anxiety, early traumas, and family history. Some subtle sex differences were detected: for men, prediction models included more risk factors concerning characteristics of the depressive episode and family history of MD and generalized anxiety, whereas for women, models included more risk factors concerning early and recent adverse life events and socioeconomic problems.
No prominent sex differences in risk factors for recurrence of MD were found, potentially indicating similar disease maintaining mechanisms for both sexes. Course of MD is a multifactorial phenomenon for both males and females.
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