Individuals with depression also present with comorbidity, and this could present an issue for depression treatment. Understanding how symptoms influence one another across traditional diagnostic boundaries, and how they influence important outcomes, may provide insights relevant to the assessment and treatment of mood disorders. In this study, we initially examined the differential impact of individual symptoms on prognosis and assessed whether individual symptoms offer predictive value above sum scores. The item level models of outcomes post-treatment and the sum score models were similarly associated with outcomes at 3–4 and 6–8 months but explained considerably more variance at 9–12 months. Pessimism was consistently the most important predictor of future outcomes (independent of its mean), indicating that experiencing pessimism rather than severity of the symptom is responsible for this association. Secondly, we explored the functional relations among comorbid symptoms of depression and anxiety disorders using network analysis. The symptom network comprised of three communities clearly clustering into anxiety items, depressive cognitions, and depressive physical symptoms. The primary bridge symptoms between communities were sadness; pessimism; and indecision. The most central symptoms across both centrality metrics were sadness and failure/worthless. Finally, we analysed differences in the symptom networks at study entry for patients that remitted vs. those whose depression persisted, after treatment. Network comparison revealed no overall differences in connectivity. Together, the present findings suggest the utility of item-level analysis in informing the content of assessments and consideration of individual items over and above scale scores when predicting prognosis.
Findings in context
Exploring the associations with treatment outcomes revealed that item-level prediction methods performed similarly to sum scores and outperformed sum score models at the 9–12-month endpoint. It is not clear why there is a difference at this time point; while it was not due to attrition between endpoints, it could be due to random variation. It may also reflect the course of depression following intervention, or the cyclical nature of depression such that individual items are better at predicting the relapse or maintenance of symptoms after benefits of treatment have faded, or where an amelioration of symptoms occurred due to further treatment post randomisation. There is an ongoing debate in the field whether central items derived from network models offer predictive utility beyond other items [
71‐
73]. Pessimism was not only the best predictor across outcomes; it was a central item (ranked 2nd on PC/PR and 6th on EI centrality) that acted as a bridge between communities and showed strong associations with sadness and failure/worthlessness. Sadness, comparatively, did not predict well across time points. It is worth noting that sadness falls within the physical symptom community and pessimism within the cognitive community. The amenability to act on an emotion (sadness) is understandably less than that of a cognition (pessimism), a target of cognitive therapy, while pessimism in association with a sense of failure/worthlessness may negatively impact treatment engagement (i.e. the motivation to sustain goal pursuit in the face of obstacles) [
74]. Given the central role and prognostic value of pessimism, we might speculate that it is associated with treatment factors, where pessimism hinders some people making progress and may not be directly addressed by some psychological treatments.
Symptoms of anxiety and depression clustered into separate communities with certain symptoms acting as bridges between communities. The bridge symptoms are statistically relevant and theoretically linked: indecision is a symptom in the classifications of both depression and generalised anxiety disorder, pessimism overlaps with worry [
75] and the strong cross-community edge of sadness to worry was similar to findings in other studies [
32,
76]. The results therefore provide evidence that these bridging symptoms may be important in the emergence of comorbidity between anxiety disorders and depression.
Planned comparisons of networks at study entry for those whose depression would persist versus those who would be in remission revealed no overall difference in connectivity, in contrast to Van Borkulo et al. [
77], but similar to Schweren et al. [
78].
Overall, we found no correlation between centrality metrics and Shapley values. This extends prior work on the association between centrality and the prognostic utility of items [
71]. Failure/worthlessness was predictively important at 3–4 months, displayed high centrality and is suggested to be a key symptom in depression and anxiety [
30]. The predictive utility of health anxiety and somatic concerns may be considered alongside the observation from the network comparison where there was a difference in centrality with somatic concerns more connected in the remitter network. Health anxiety was in the upper quintile of variable importance across time points, but relatively unimportant in terms of centrality. Not surprisingly, given the conceptual overlap, with health anxiety, the strongest edge was with somatic concerns. As such, the degree of concern for one’s health, or attention to somatic symptoms, whilst not playing a significant role within the maintenance of depression, may act as a motivational spur to engage with treatment (in this way enabling rather than disabling the individual). The absence of this anxiety may reflect an apathy about one’s health which is not captured by the motivational item in the BDI. While the predictive modelling did consider the influence of each item independent of the other items, modelling the predictive value of individual items may be improved by examining the association between the changes at symptom level and the overall network [
79,
80].
The network derived in this study provides empirical phenomena that can be explained by principles of network theory. This requires interpreting the network as a causal system, even though we cannot infer temporal relationship between symptoms and there is an absence of causal mechanisms within the external field (e.g. environmental factors) [
29]. These limitations apply to most of the findings in the network literature, although overinterpretation is common [
81]. Holding this in mind, we can consider possible pathways and mediating role of symptoms through the network. For example, taking suicidal ideation as a clinically severe symptom, we can identify the shortest path from worry [
82] passing through sadness (bridge), and from loss of pleasure/interest [
83] to suicidal thoughts, passed through pessimism (bridge). It is possible that any causal effect between these connections may be part of a longer pathway within the network highlighting a need for greater attention to be given to symptom interactions.
The statistical model investigates a symptom level, transdiagnostic conceptualization of the symptom interactions for individuals diagnosed with depression participating in RCTs. These interventions are based on biological or psychological theories, most notably Beck’s cognitive of theory of depression [
84]. Clinically, pragmatism trumps theoretical completeness; simple interventions which achieve rapid change do not require a detailed appreciation of the potential underlying mechanisms. However, oversimplified theories may restrict the ability to identify causal patterns, and gaps emerge in practice where the model is suggested to not fit the patient [
85]. More process-driven interventions targeting shared features of disorders have been developed [
86,
87], yet there is no unifying theory. The findings presented may help bridge the gap between disorder-specific theories and more transdiagnostic theories. Considering how symptoms may interact can help clinicians and researchers to understand underlying processes and in turn to conceptualise their patients’ difficulties in a way that supplements existing knowledge. A functional analysis which integrates the association between sadness and worry does not need to conceptualise the individual as having two disorders, but can consider how, for the individual, this interaction is being fuelled and may be contributing to their distress.
The journey to develop models that provide both explanatory and predictive utility will lead to greater understanding of psychopathology [
88]. While the analysis presented is primarily exploratory, it sets up clear testable hypotheses. These can be derived by examining the central structures within the network, formulating hypotheses and testing on an independent sample [
89]. For instance, whether the bridge edges belonging to pessimism, sadness, and indecisiveness re-emerge in an independent sample or whether a discrete intervention targeting pessimism would alter the network structure and lead to improved outcome. These statistical methods may help inform how identifying pathways and targets may lead to improved treatments all dependent on better assessment of symptoms.
Strengths and limitations
This study has clear strengths, making use of a large sample of individuals participating in RCTs for depression in primary care. The use of same assessment measures at study entry removed the need to harmonise data across different measures for the network. While this is less true of outcomes where issues of measurement errors arise from the use of PROMIS T-Score, the sensitivity analyses provided confidence in the results.
The demographic balance across samples may affect generalisability; however, five of the six trials were pragmatic trials more closely representative of patient populations. Most cases of depression are treated in primary care, and the studies being set in primary care, improve the potential generalisability to patients seen in this setting [
90].
This study was limited to the use of aggregate/group level findings to inform within person processes. However, the presence of an RCT outcome variable affords us the ability to detect changes from one state (e.g. depressed) to another (e.g. remitted), which is typically not the case with idiographic research studies that collect cross-sectional data. Exploring the prognostics value of networks on deterioration of symptoms would extend the utility of network analysis. This would however require generating idiographic networks, where reliable estimation necessitates many time points (low sensitivity at 100 time points [
91].
The accuracy of the network is limited by the items included and those omitted. The network does not cover the breadth of comorbidity of symptoms across psychopathology and is missing other environmental variables. Social adversity is associated with worse treatment outcomes for some patients with depression; it can be important to assess for and address these issues in clinic, where possible, to mitigate the risks of poor prognoses [
92]. There is also the possibility that the centrality of sadness particularly represents a strong association with a latent variable rather than a specific role within the network [
93].
The network models adjusted for duration of depression and anxiety, and a sensitivity analysis assessed for the influence of between study variability, adding robustness to the findings. While RCTs are used in the analysis, treatment arms were not factored in and treated as equivalent when estimating outcome. This may make the findings generalizable where findings are applicable regardless of treatment offered especially as the treatments included reflect those commonly available in primary care. Controlling for treatment group within the outcome modelling and controlling for relevant covariates (e.g. age, gender and social economic status) would also have improved the robustness of the findings. Such adjustments would have been fitting where the emphasis was on developing the best predictive model, instead of comparing the predictive ability of symptoms vs. total scores. More comprehensive prediction modelling using the Dep-GP dataset has been conducted [
94]. Additionally, our modelling did not include train/test split, as the whole sample was used in estimation of the network models. While a true out-of-sample ‘holdout’ dataset would have provided an unbiased evaluation of model fit, and is the preferred method for evaluating such models [
95], the internal cross-fold validation employed in the symptom level model offers a layer of robustness supporting the final model estimates (where overfitting presents an issue). This study focussed on item-level analysis in comparison to sum-scores, future comparisons with models which may measure latent constructs in other ways, could be informative.
Single item symptom measurement will have unknown reliability and construct validity. Equally, the restricted range (e.g. a four-point scale) may not adequately capture the range of symptom variance occurring in the sample. Symptom measurement on a broader scale may improve the prediction of changes over time.