Detecting impending symptom transitions using early warning signals in individuals receiving treatment for depression

Background: The path to depressive symptom improvement during therapy is often complex, as many individuals experience periods of instability and discontinuous symptom change. If the process of remission follows complex dynamic systems principles, early warning signals (EWS) may precede such depressive symptom transitions. Aims: We aimed to test whether EWS, in the form of rises in lag-1 autocorrelation and variance, occur in momentary affect time series preceding transitions towards lower levels of depressive symptoms during therapy. We also investigated the presence of EWS in patients without symptom transitions. Methods: In a sample of 41 depressed individuals who were starting psychological treatment, positive affect and negative affect (high and low arousal) were measured five times a day using ecological momentary assessments (EMA) for four months (521 observations per individual on average; yielding 25,197 observations in total), and depressive symptoms were assessed weekly over six months. We used a moving window method and time-varying autoregressive generalized additive modeling (TV-AR GAM) to determine whether EWS occurred in these momentary affect measures, within-persons. Results: For the moving-window autocorrelation, 89% of individuals with transitions showed at least one EWS in one of the variables (versus 62.5% in the no-transition group), and the proportion of EWS in the separate variables was consistently higher (~44% across affect measures) than for individuals without transitions (~27%). Rising variance was found for few individuals, both preceding transitions (~11%) and for individuals without a transition (~12%). Conclusions: The process of symptom remission showed critical slowing down in at least part of our sample. Our findings indicate that EWS are not generic across all affect measures and may have limited value as a personalized prediction method

On the transience of stability of subthreshold psychopathology

Symptoms of psychopathology lie on a continuum ranging from mental health to psychiatric disorders. Although much research has focused on progression along this continuum, for most individuals, subthreshold symptoms do not escalate into full-blown disorders. This study investigated how the stability of psychopathological symptoms (attractor strength) varies across severity levels (homebase). Data were retrieved from the TRAILS TRANS-ID study, where 122 at-risk young adults (mean age 23.6 years old, 57% males) monitored their mental states daily for a period of six months (± 183 observations per participant). We estimated each individual’s homebase and attractor strength using generalized additive mixed models. Regression analyses showed no association between homebases and attractor strengths (linear model: B = 0.02, p = 0.47, R(2) < 0.01; polynomial model: B < 0.01, p = 0.61, R(2) < 0.01). Sensitivity analyses where we (1) weighed estimates according to their uncertainty and (2) removed individuals with a DSM-5 diagnosis from the analyses did not change this finding. This suggests that stability is similar across severity levels, implying that subthreshold psychopathology may resemble a stable state rather than a transient intermediate between mental health and psychiatric disorder. Our study thus provides additional support for a dimensional view on psychopathology, which implies that symptoms differ in degree rather than kind

Can we predict the direction of sudden shifts in symptoms?:Transdiagnostic implications from a complex systems perspective on psychopathology

Recently, there has been renewed interest in the application of assumptions from complex systems theory in the field of psychopathology. One assumption, with high clinical relevance, is that sudden transitions in symptoms may be anticipated by rising instability in the system, which can be detected with early warning signals (EWS). Empirical studies support the idea that this principle also applies to the field of psychopathology. The current manuscript discusses whether assumptions from complex systems theory can additionally be informative with respect to the specific symptom dimension in which such a transition will occur (e.g. whether a transition towards anxious, depressive or manic symptoms is most likely). From a complex systems perspective, both EWS measured in single symptom dynamics and network symptom dynamics at large are hypothesized to provide clues regarding the direction of the transition. Challenging research designs are needed to provide empirical validation of these hypotheses. These designs should be able to follow sudden transitions 'live' using frequent observations of symptoms within individuals and apply a transdiagnostic approach to psychopathology. If the assumptions proposed are supported by empirical studies then this will signify a large improvement in the possibility for personalized estimations of the course of psychiatric symptoms. Such information can be extremely useful for early intervention strategies aimed at preventing specific psychiatric problems

The Associations of Affection and Rejection During Adolescence with Interpersonal Functioning in Young Adulthood:A Macro- and Micro-Level Investigation Using the TRAILS TRANS-ID Study

Affection and rejection in close relationships during adolescence are thought to impact adult interpersonal functioning, but few studies focused on how the quality of adolescents' relationships with different people (e.g. parents, peers, and teachers) impacts the daily, micro-level social experiences as well as general, macro-level interpersonal functioning in young adulthood. The present study investigated the associations between: (i) parental, teacher and peer affection and rejection during adolescence and macro-level (over several months) interpersonal functioning as well as different patterns (i.e. mean, variability and inertia) of micro-level (daily social experiences) during young adulthood; (ii) macro-level interpersonal functioning and the patterns of micro-level social experiences during young adulthood. The sample consisted of N = 122 (43% female) youth. At 11.2 +/- 0.4 and 16.0 +/- 0.6 years old, self- and other-reported parental, peer and teacher affection and rejection were assessed. At 23.7 +/- 0.6 years old, participants reported daily social experiences and interpersonal functioning across six months. The results suggested that: (i) higher teacher-reported peer rejection was associated with lower macro-level interpersonal functioning, higher means and higher variability in negative social experiences during adulthood; (ii) higher macro-level interpersonal functioning during young adulthood was associated with higher means and lower inertia in positive and lower variability in negative daily social experiences. These findings indicate that the affection and rejection during adolescence impact interpersonal functioning at macro- and micro-level during adulthood. The present study also shows distinct associations between macro-level interpersonal functioning and dynamics in daily social experiences

Anticipating Transitions in Mental Health in At-Risk Youths:A 6-Month Daily Diary Study Into Early-Warning Signals

If psychopathology behaves like a complex dynamic system, sudden onset or worsening of symptoms may be preceded by early-warning signals (EWSs). EWSs could thus reflect personalized warning signals for impending psychopathology. We empirically investigated this hypothesis in at-risk youths (N = 122, mean age = 23.6 ± 0.7 years, 57% males) from the clinical cohort of Tracking Adolescents’ Individual Lives Survey (TRAILS-CC), who provided daily emotion assessments for 6 months. We analyzed whether EWSs (rising autocorrelations and standard deviations in emotions) preceded transitions toward psychopathology. Across indicators and a range of analytical options, EWSs had low sensitivity (M = 26%, SD = 11%) and moderate specificity (M = 75%, SD = 14%). Thus, in the present sample, the proposed generic nature and clinical utility of EWSs could not be substantiated. Given this finding, we call for a more nuanced view on the application of complex-dynamic-systems principles to psychopathology and lay out key questions to be addressed in the future

Anticipating manic and depressive transitions in patients with bipolar disorder using early warning signals

Background In bipolar disorder treatment, accurate episode prediction is paramount but remains difficult. A novel idiographic approach to prediction is to monitor generic early warning signals (EWS), which may manifest in symptom dynamics. EWS could thus form personalized alerts in clinical care. The present study investigated whether EWS can anticipate manic and depressive transitions in individual patients with bipolar disorder. Methods Twenty bipolar type I/II patients (with >= 2 episodes in the previous year) participated in ecological momentary assessment (EMA), completing five questionnaires a day for four months (Mean = 491 observations per person). Transitions were determined by weekly completed questionnaires on depressive (Quick Inventory for Depressive Symptomatology Self-Report) and manic (Altman Self-Rating Mania Scale) symptoms. EWS (rises in autocorrelation at lag-1 and standard deviation) were calculated in moving windows over 17 affective and symptomatic EMA states. Positive and negative predictive values were calculated to determine clinical utility. Results Eleven patients reported 1-2 transitions. The presence of EWS increased the probability of impending depressive and manic transitions from 32-36% to 46-48% (autocorrelation) and 29-41% (standard deviation). However, the absence of EWS could not be taken as a sign that no transition would occur in the near future. The momentary states that indicated nearby transitions most accurately (predictive values: 65-100%) were full of ideas, worry, and agitation. Large individual differences in the utility of EWS were found. Conclusions EWS show theoretical promise in anticipating manic and depressive transitions in bipolar disorder, but the level of false positives and negatives, as well as the heterogeneity within and between individuals and preprocessing methods currently limit clinical utility

Lower emotional complexity as a prospective predictor of psychopathology in adolescents from the general population

Emotional complexity (EC) involves the ability to distinguish between distinct emotions (differentiation) and the experience of a large range of emotions (diversity). Lower EC has been related to psychopathology in cross-sectional studies. This study aimed to investigate (a) whether EC prospectively predicts psychopathology and (b) whether this effect is contingent on stressful life events. To further explore EC, we compared the effects of differentiation and diversity. Adolescents from the general population (N = 401) rated 8 negatively valenced emotions 10 times a day for 6 consecutive days. Further, they completed the Symptom Checklist-90 (baseline and 1-year follow-up) and a questionnaire on past year's life events at follow-up. Logistic regression analyses tested whether EC-reflected by emotion differentiation (intraclass correlation coefficient [ICC]) and diversity (diversity index [DI])-predicted prognosis (good: remitting or lacking symptoms vs. bad: worsening or persisting symptoms). EC predicted prognoses but only when based on the ICC (OREC.ICC = 1.42, p = .02). An ECICC 1 SD above average increased the probability of good prognosis from .67 to .74. This effect was not related to stressful life events (OREC × Life events = 1.03, p = .86) and disappeared when emotion intensity (mean level) was taken into account (OREC = 1.20, p = .20). Predicting future prognosis does not necessitate complex measures of emotional experience (ICC, DI) but rather might be achieved through simpler indices (mean). The discrepant effects of the ICC and DI on prognosis suggest that impaired emotion representation (ICC) plays a more important role in vulnerability to mental ill health than does low diversity of emotions (DI)

Early warning signals in psychopathology:what do they tell?

BACKGROUND: Despite the increasing understanding of factors that might underlie psychiatric disorders, prospectively detecting shifts from a healthy towards a symptomatic state has remained unattainable. A complex systems perspective on psychopathology implies that such symptom shifts may be foreseen by generic indicators of instability, or early warning signals (EWS). EWS include, for instance, increasing variability, covariance, and autocorrelation in momentary affective states-of which the latter was studied. The present study investigated if EWS predict (i) future worsening of symptoms as well as (ii) the type of symptoms that will develop, meaning that the association between EWS and future symptom shifts would be most pronounced for congruent affective states and psychopathological domains (e.g., feeling down and depression). METHODS: A registered general population cohort of adolescents (mean age 18 years, 36% male) provided ten daily ratings of their affective states for 6 consecutive days. The resulting time series were used to compute EWS in feeling down, listless, anxious, not relaxed, insecure, suspicious, and unwell. At baseline and 1-year follow-up, symptom severity was assessed by the Symptom Checklist-90 (SCL-90). We selected four subsamples of participants who reported an increase in one of the following SCL-90 domains: depression (N = 180), anxiety (N = 192), interpersonal sensitivity (N = 184), or somatic complaints (N = 166). RESULTS: Multilevel models showed that EWS in feeling suspicious anticipated increases in interpersonal sensitivity, as hypothesized. EWS were absent for other domains. While the association between EWS and symptom increases was restricted to the interpersonal sensitivity domain, post hoc analyses showed that symptom severity at baseline was related to heightened autocorrelations in congruent affective states for interpersonal sensitivity, depression, and anxiety. This pattern replicated in a second, independent dataset. CONCLUSIONS: The presence of EWS prior to symptom shifts may depend on the dynamics of the psychopathological domain under consideration: for depression, EWS may manifest only several weeks prior to a shift, while for interpersonal sensitivity, EWS may already occur 1 year in advance. Intensive longitudinal designs where EWS and symptoms are assessed in real-time are required in order to determine at what timescale and for what type of domain EWS are most informative of future psychopathology

Cerebral small vessel disease and perihematomal edema formation in spontaneous intracerebral hemorrhage

ObjectiveBlood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of cerebral small vessel disease (cSVD)-related intracerebral hemorrhage (ICH). The formation of perihematomal edema (PHE) is presumed to reflect acute BBB permeability following ICH. We aimed to assess the association between cSVD burden and PHE formation in patients with spontaneous ICH.MethodsWe selected patients with spontaneous ICH who underwent 3T MRI imaging within 21 days after symptom onset from a prospective observational multicenter cohort study. We rated markers of cSVD (white matter hyperintensities, enlarged perivascular spaces, lacunes and cerebral microbleeds) and calculated the composite score as a measure of the total cSVD burden. Perihematomal edema formation was measured using the edema extension distance (EED). We assessed the association between the cSVD burden and the EED using a multivariable linear regression model adjusting for age, (log-transformed) ICH volume, ICH location (lobar vs. non-lobar), and interval between symptom onset and MRI.ResultsWe included 85 patients (mean age 63.5 years, 75.3% male). Median interval between symptom onset and MRI imaging was 6 days (IQR 1–19). Median ICH volume was 17.0 mL (IQR 1.4–88.6), and mean EED was 0.54 cm (SD 0.17). We found no association between the total cSVD burden and EED (B = −0.003, 95% CI −0.003–0.03, p = 0.83), nor for any of the individual radiological cSVD markers.ConclusionWe found no association between the cSVD burden and PHE formation. This implies that mechanisms other than BBB dysfunction are involved in the pathophysiology of PHE

Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF):a randomised, open-label, phase 2 trial

Background In patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial. Methods APACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7-90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2.5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites. Findings Between Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73-83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21-74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1.9 years (IQR 1.0-3.1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12.6% [95% CI 6.7-21.5]) and in 12 (24%) allocated to avoid anticoagulation (11.9% [95% CI 6.2-20.8]; adjusted hazard ratio 1.05 [95% CI 0.48-2.31]; p=0.90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation. Interpretation Patients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous. Copyright (C) 2021 Elsevier Ltd. All rights reserved