Temporal Directionality Between Symptoms During Treatment of Depressed Inpatients: A Dynamic Time Warp Network Analysis.

BACKGROUND: Depression is generally perceived from the perspective of the common-cause disease model. However, the network perspective assumes mutual influence of individual symptoms and stresses the importance of investigating symptom dynamics. Gaining a better understanding of symptom dynamics within individuals might contribute to more effective treatments. METHODS: Current exploratory longitudinal research studied the associations and directionality between 43 symptoms from the generic questionnaire Symptom Questionnaire-48 (SQ-48) using dynamic time warp (DTW) analyses, in which trajectories with similar time-dependent patterns can be identified. Data from individuals were analysed first, yielding distance matrices for all symptom trajectories, after which the data were aggregated. RESULTS: The 148 included patients were all admitted for the treatment of their clinical depression. Undirected DTW analyses of three patients with longer time series but otherwise randomly chosen showed large variability among individuals. Group-level undirected DTW analyses showed numerous significant edges between symptoms, largely clustering symptoms according to the eight pre-existing subscales of the SQ-48. Group-level directed DTW analyses showed five symptoms with significant outstrength: 'hopeless', 'restless', 'down/depressed', 'feeling tense' and 'no enjoyment', meaning that change in these key symptoms preceded change in other symptoms. LIMITATIONS: The 43 included symptoms of the SQ-48 primarily focus on internalizing problems in severely depressed inpatients, potentially limiting generalizability. CONCLUSIONS: DTW networks provided us with five key symptoms based on the dynamics of symptom scores. Future studies could explore whether process-based therapy targeted at symptoms with high outstrength might result in more effectivity as part of personalized treatment.

Symptoms of Posttraumatic Stress Disorder Among Japanese Peacekeepers Deployed in South Sudan.

Importance: Peacekeepers in United Nations missions experience potentially traumatic events, resulting in increased risk for posttraumatic stress disorder (PTSD). Understanding the course and risk factors of PTSD symptom severity is crucial to ensure personnel safety. Objective: To investigate the incidence of PTSD, symptom severity trajectories, and potential risk factors associated with adverse trajectories among Japanese peacekeepers deployed in South Sudan. Design, Setting, and Participants: Data for this 6-year prospective cohort study were collected from December 2011 to December 2018 from Japan Ground Self-Defense Force personnel deployed at the United Nations Mission in South Sudan, corresponding to before and up to 78 months after deployment. Of 3799 potential participants, 80 were excluded because of multiple deployments and 757 because of missing data, incomplete responses, or not providing informed consent. Therefore, 2962 participants were included in the analysis. Data analysis was performed from February 2022 to February 2024. Exposure: The participants were deployed to United Nations Mission in South Sudan for 6 months. Main Outcomes and Measures: The 22-item Impact of Event Scale-Revised was used to assess PTSD symptoms, with 25 or more points indicating probable PTSD (p-PTSD). Sociodemographic data were collected, and the 30-item General Health Questionnaire was administered before deployment to identify risk factors for PTSD symptom severity. Results: In the 2962 participants studied (2901 [97.9%] male; mean [SD] age, 33.9 [7.2] years), the incidence of p-PTSD was 3.95%. Latent growth mixture models identified 4 symptom severity trajectories: resilient (2143 [72.3%]), recovery (479 [16.2%]), protracted (182 [6.1%]), and delayed (158 [5.3%]). Multinomial logistic regression showed that sleep disturbance was a common risk factor for the 2 most severe trajectories (protracted: odds ratio [OR], 1.29; 95% CI, 1.08-1.54; delayed: OR, 1.26; 95% CI, 1.03-1.53), whereas older age (OR, 1.25; 95% CI, 1.06-1.48), anxiety and dysphoria (OR, 1.45; 95% CI, 1.20-1.75), and general illness (OR, 1.30; 95% CI, 1.06-1.59) were associated with the protracted trajectory. Conclusions and Relevance: This cohort study found that approximately 4% of the participants developed p-PTSD and identified 4 distinct PTSD symptom trajectories. The findings suggest that addressing sleep disturbance and general health issues could effectively prevent PTSD symptoms among peacekeepers.

Temporal dynamics of depressive symptoms and cognitive decline in the oldest old: dynamic time warp analysis of the Leiden 85-plus study.

BACKGROUND: The prevalence of depressive symptoms and cognitive decline increases with age. We investigated their temporal dynamics in individuals aged 85 and older across a 5-year follow-up period. METHODS: Participants were selected from the Leiden 85-plus study and were eligible if at least three follow-up measurements were available (325 of 599 participants). Depressive symptoms were assessed at baseline and at yearly assessments during a follow-up period of up to 5 years, using the 15-item Geriatric Depression Scale (GDS-15). Cognitive decline was measured through various tests, including the Mini Mental State Exam, Stroop test, Letter Digit Coding test and immediate and delayed recall. A novel method, dynamic time warping analysis, was employed to model their temporal dynamics within individuals, in undirected and directed time-lag analyses, to ascertain whether depressive symptoms precede cognitive decline in group-level aggregated results or vice versa. RESULTS: The 325 participants were all 85 years of age at baseline; 68% were female, and 45% received intermediate to higher education. Depressive symptoms and cognitive functioning significantly covaried in time, and directed analyses showed that depressive symptoms preceded most of the constituents of cognitive impairment in the oldest old. Of the GDS-15 symptoms, those with the strongest outstrength, indicating changes in these symptoms preceded subsequent changes in other symptoms, were worthlessness, hopelessness, low happiness, dropping activities/interests, and low satisfaction with life (all P's < 0.01). CONCLUSION: Depressive symptoms preceded cognitive impairment in a population based sample of the oldest old.

Network dynamics of self-compassion, anxiety, and depression during eating disorder therapy.

BACKGROUND: Recovery processes during residential treatment for eating disorders, especially in patients with a history of maltreatment, are insufficiently understood. This study aimed to explore the temporal relationships among comorbid factors, including depression, anxiety, and self-compassion, with the influence of childhood maltreatment. METHOD: Using Dynamic Time Warp (DTW), weekly scores from the Symptom Checklist-5, Eating Disorder Examination, and Self-Compassion Scale were analysed over 12 weeks. The study generated undirected and directed networks to identify influential symptoms in a transdiagnostic sample, comparing patients with and without childhood maltreatment. RESULTS: The study included 124 patients with eating disorders (ED) (97% women), mean age of 30.9 years (SD = 9.7, range 18-61 years). Diagnoses included anorexia nervosa (26%), bulimia nervosa (38%), and other specified feeding and eating disorders (36%). The directed DTW network showed that hopelessness, worrying, and restlessness had the highest out-strength, predicting changes in self-compassion and ED behaviour. In maltreatment cases, hopelessness and low acceptance predicted changes, while worry, restlessness, and nervousness were predictive in non-maltreatment cases. CONCLUSION: Temporal network analyses suggest that a change in hopelessness, worrying, and restlessness drives symptom improvement in ED behaviour and the development of self-compassion during residential treatment. These processes vary between patients with and without a history of childhood maltreatment separately, indicating the need for further analyses.

Borderline personality features in relationship to childhood trauma in unipolar depressive and bipolar disorders.

BACKGROUND: Childhood trauma, including emotional neglect, emotional abuse, physical abuse, and sexual abuse, may contribute to borderline personality features like affective instability, identity problems, negative relationships, and self-harm. This study aims to explore how different types of childhood trauma affect these features in bipolar versus unipolar depressive disorders. METHODS: We included 839 participants of the Netherlands Study of Depression and Anxiety (NESDA) with a lifetime diagnosis of major depressive disorder single episode (MDDS; N = 443), recurrent major depressive disorder (MDD-R; N = 331), or bipolar disorder (BD; N = 65). Multivariate regression was used to analyze data from the Childhood Trauma Interview and borderline features (from the self-report Personality Assessment Inventory). RESULTS: On average, participants were 48.6 years old (SD: 12.6), with 69.2 % being women, and 50.3 % of participants assessed positive for childhood trauma. Adjusted analyses revealed that participants diagnosed with BD, followed by MDD-R, exhibited the highest number of borderline personality features. Additionally, within the entire group, a strong association was found between childhood trauma, especially emotional neglect, and the presence of borderline personality features. CONCLUSION: Given the high prevalence of childhood trauma and borderline personality features, screening for these factors in individuals with mood disorders is crucial. Identifying these elements can inform and enhance the management of the often fluctuating and complex nature of these comorbid conditions, leading to more effective and tailored treatment strategies.

Symptoms of a feather flock together? An exploratory secondary dynamic time warp analysis of 11 single case time series of suicidal ideation and related symptoms.

Suicidal ideation fluctuates over time, as does its related risk factors. Little is known about the difference or similarities of the temporal patterns. The current exploratory secondary analysis examines which risk symptoms have similar time dynamics using a mathematical algorithm called dynamic time warping (DTW). Ecological momentary assessment data was used of 11 depressed psychiatric outpatients with suicidal ideation who answered three daytime surveys at semi-random sampling points for a period of three to six months. Patients with 45 assessments or more were included. Results revealed significant inter-individual variability in symptom dynamics and clustering, with certain symptoms often clustering due to similar temporal patterns, notably feeling sad, hopelessness, feeling stuck, and worrying. The directed network analyses shed light on the temporal order, highlighting entrapment and worrying as symptoms strongly related to suicide ideation. Still, all patients also showed unique directed networks. While for some patients changes in entrapment directly preceded change in suicide ideation, the reverse temporal ordering was also found. Relatedly, within some patients, perceived burdensomeness played a pivotal role, whereas in others it was unconnected to other symptoms. The study underscores the individualized nature of symptom dynamics and challenges linear models of progression, advocating for personalized treatment strategies.

Experience sampling of suicidality, religiosity and spirituality in depression: Network analyses using dynamic time warping.

BACKGROUND: Suicidality is a clinically important and multifaceted phenomenon, frequently present in depressed subjects. Religiosity and spirituality (R/S) can have an attenuating as well as a reinforcing effect on suicidality. METHODS: From two Dutch mental health care settings, a sample of 31 depressed and in- and outpatients with suicidal ideation, self-identifying as being religious or spiritual, was selected by convenience sampling. Using an experience sampling method (ESM) mobile application, during six days (mean of 42 assessments per subject), the association between symptoms of depression, suicidality, and specific positive-supportive affective R/S and positive psychology variables. For 28 participants symptom network plots on a group level, and on an individual level, were analyzed using dynamic time warping (DTW). RESULTS: Participants were on average 35.7 years old, and 65 % were women. In the group-level undirected network, R/S variables were linked to positive psychology variables via a bridge function of inner peace. Changes in the experience of inner peace and enjoying a physical activity preceded changes of several other symptoms. A network dynamic appeared with a dense cluster of 'positive psychology' items. LIMITATIONS: Only a limited number of R/S variables were included. CONCLUSION: The results of this study suggest that religiosity and spirituality function as meaningful factors in depression and suicidality in religiously or spiritually engaged persons. Experienced inner peace has a positive association with reasons to live. Experience sampling method data can be effectively analyzed using dynamic time warping. Exploring individual religious or spiritual engagement can prove important in treating suicidality and depression.

The clinical effectiveness of a self-management intervention for patients with persistent depressive disorder and their partners/caregivers: results from a multicenter, pragmatic randomized controlled trial.

BACKGROUND: Persistent depressive disorder (PDD) is prevalent and debilitating. For patients with PDD, psychiatric rehabilitation using self-management interventions is advised as the next therapeutic step after multiple unsuccessful treatment attempts. The "Patient and Partner Education Program for All Chronic Diseases" (PPEP4All) is a brief, structured self-management program that focuses on functional recovery for patients and their partners/caregivers. In chronic somatic disorder populations, PPEP4All has already been shown to be clinically effective. We examined whether PPEP4All adapted for PDD (PPEP4All-PDD, nine weekly group or individual sessions) is also clinically effective for adults/elderly with PDD and their partners/caregivers compared to care-as-usual (CAU) in specialized mental healthcare. METHODS: In this mixed-method multicenter pragmatic randomized controlled trial, 70 patients with PDD and 14 partners/caregivers were allocated to either PPEP4All-PDD (patients, n = 37; partners/caregivers, n = 14) or CAU (patients, n = 33; partners/caregivers, not included) and completed questionnaires at 0, 3, 6, and 12 months regarding depressive symptoms, psychopathology, psychosocial burden, mental resilience, and happiness/well-being. Qualitative data were collected regarding treatment satisfaction. Data were analyzed using mixed model analyses and an intention-to-treat (ITT) approach. RESULTS: There was no statistically significant difference in any outcome regarding clinical effectiveness between PPEP4All-PDD and CAU. Subgroup analysis for depressive symptoms did not show any interaction effect for any subgroup. Although 78% of participants recommended PPEP4All-PDD, there was no difference in treatment satisfaction between PPEP4All-PDD (score = 6.6; SD = 1.7) and CAU (score = 7.6; SD = 1.2), p = 0.06. CONCLUSION: Although depressive symptoms did not improve relative to CAU, this only confirmed that treatment for patients with treatment-resistant PDD should move from symptom reduction to functional recovery. Also, functional recovery may be reflected in other outcomes than psychosocial burden, such as self-empowerment, in patients with treatment-resistant PDD. Future research on PPEP4All-PDD could focus on a longer-term program and/or online program that may also be offered earlier in the treatment process as an empowerment intervention.  TRIAL REGISTRATION: Netherlands Trial Register Identifier NL5818. Registered on 20 July 2016 https://clinicaltrialregister.nl/nl/trial/20302.

Metabolic syndrome after childhood trauma: a 9-year longitudinal analysis.

BACKGROUND: Childhood trauma (CT) has been cross-sectionally associated with metabolic syndrome (MetS), a group of biological risk factors for cardiometabolic disease. Longitudinal studies, while rare, would clarify the development of cardiometabolic dysregulations over time. Therefore, we longitudinally investigated the association of CT with the 9-year course of MetS components. METHODS: Participants (N = 2958) from the Netherlands Study of Depression and Anxiety were assessed four times across 9 years. The CT interview retrospectively assessed childhood emotional neglect and physical, emotional, and sexual abuse. Metabolic outcomes encompassed continuous MetS components (waist circumference, triglycerides, high-density lipoprotein [HDL] cholesterol, blood pressure [BP], and glucose) and count of clinically elevated MetS components. Mixed-effects models estimated sociodemographic- and lifestyle-adjusted longitudinal associations of CT with metabolic outcomes over time. Time interactions evaluated change in these associations. RESULTS: CT was reported by 49% of participants. CT was consistently associated with increased waist (b = 0.32, s.e. = 0.10, p = 0.001), glucose (b = 0.02, s.e. = 0.01, p < 0.001), and count of MetS components (b = 0.04, s.e. = 0.01, p < 0.001); and decreased HDL cholesterol (b = -0.01, s.e.<0.01, p = .020) and systolic BP (b = -0.33, s.e. = 0.13, p = 0.010). These associations were mainly driven by severe CT and unaffected by lifestyle. Only systolic BP showed a CT-by-time interaction, where CT was associated with lower systolic BP initially and with higher systolic BP at the last follow-up. CONCLUSIONS: Over time, adults with CT have overall persistent poorer metabolic outcomes than their non-maltreated peers. Individuals with CT have an increased risk for cardiometabolic disease and may benefit from monitoring and early interventions targeting metabolism.

Breaking the cycle: Identifying key symptom pathways of eating disorders and the influence of childhood maltreatment.

BACKGROUND: Most network analyses on central symptoms in eating disorders (EDs) have been cross-sectional. Longitudinal within-person analyses of therapy processes are scarce. Our aim was to investigate central change processes in therapy in a transdiagnostic sample, considering the influence of childhood maltreatment. METHOD: We employed dynamic time warping analyses to identify clusters of symptoms that tended to change similarly across therapy on a within-person level. Symptoms were measured by a 28-item Eating Disorder Examination Questionnaire (EDE-Q). Furthermore, we examined the temporal direction of symptom change to identify symptoms that tended to precede and predict other symptoms. Finally, we estimated two directed, temporal networks in patients with and without a history of childhood maltreatment. RESULTS: Our analysis included 122 ED patients (mean age = 30.9, SD = 9.7; illness duration = 14.2 years, SD = 8.9; prior treatment = 5.6 years, SD = 5.1). The initial network revealed three robust clusters of symptoms over time: (1) ED behavior, (2) inhibition, and (3) cognitions and feelings about body and weight. Overvaluation of shape had the highest out-strength preceding and predicting other symptoms. Dissatisfaction with weight preceded and predicted other symptoms in the maltreatment network. The non-maltreatment network showed a similar structure to the transdiagnostic network. CONCLUSION: Targeting and monitoring feelings and cognitions related to shape may be crucial for achieving lasting symptom improvement in a transdiagnostic sample. Furthermore, our findings highlight the need for further investigation into the different processes driving EDs based on maltreatment status. PUBLIC SIGNIFICANCE: There is limited understanding of the processes that occur for patients with eating disorders between admission and discharge in therapy, especially for patients with a history of childhood maltreatment. Our analyses suggest that changes in cognitions regarding shape precede and predict changes in cognitions about weight. Different processes may be driving the eating disorder according to maltreatment status, which might further illuminate the riddle of dropout and relapse in therapy for patients with a history of childhood maltreatment. These findings suggest the need for further investigation into the specific dynamics occurring during therapy for individuals with a history of childhood maltreatment.

Lithium in bipolar depression: A review of the evidence.

BACKGROUND: Lithium is widely used as treatment of acute mania and as prophylactic therapy for bipolar disorder. International and national guidelines also consider lithium as a possible treatment of acute bipolar depression. Research on the use of lithium in bipolar depression, however, seems to be limited compared to the data available for its efficacy in the other phases of bipolar disorder. OBJECTIVE: To provide a systematic review of the evidence for lithium in the treatment of acute bipolar depression and provide directions for further research. METHOD: A systematic review of clinical studies investigating the use of lithium in bipolar depression was performed using preferred reporting items for systematic reviews and meta-analyses guidelines in Pubmed, Embase and Psychinfo using the medical subjects headings and free text terms "lithium," "bipolar depression," "dosage," "serum concentration" and "bipolar disorders." RESULTS: This review included 15 studies with a total of 1222 patients, between the age of 18 and 65, suffering from bipolar depression of which 464 were treated with lithium. There are currently only limited and low-quality data on the efficacy of lithium as a treatment of bipolar depression. It appears that there have been no placebo controlled randomized controlled trials with lithium concentrations that are considered to be therapeutic. The older studies suffered from limitations such as small sample sizes, insufficient treatment lengths, and insufficient monitoring of serum concentrations. CONCLUSION: In contrast to data for the treatment of mania and prophylaxis, robust data on the efficacy of lithium in bipolar depression is currently lacking, making it impossible to make conclusions regarding efficacy or inefficacy, for which further research is needed.

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

The impact of COVID-19-pandemic-related adversity on mental health: longitudinal study in Dutch populations with and without mental health disorders.

BACKGROUND: Despite growing concerns about mental health during the COVID-19 pandemic, particularly in people with pre-existing mental health disorders, research has shown that symptoms of depression and anxiety were generally quite stable, with modest changes in certain subgroups. However, individual differences in cumulative exposure to COVID-19 stressors have not been yet considered. AIMS: We aimed to quantify and investigate the impact of individual-level cumulative exposure to COVID-19-pandemic-related adversity on changes in depressive and anxiety symptoms and loneliness. In addition, we examined whether the impact differed among individuals with various levels of pre-pandemic chronicity of mental health disorders. METHOD: Between April 2020 and July 2021, 15 successive online questionnaires were distributed among three psychiatric case-control cohorts that started in the 2000s (N = 1377). Outcomes included depressive and anxiety symptoms and loneliness. We developed a COVID-19 Adversity Index (CAI) summarising up to 15 repeated measures of COVID-19-pandemic-related exposures (e.g. exposure to COVID-19 infection, negative economic impact and quarantine). We used linear mixed linear models to estimate the effects of COVID-19-related adversity on mental health and its interaction with pre-pandemic chronicity of mental health disorders and CAI. RESULTS: Higher CAI scores were positively associated with higher increases in depressive symptoms, anxiety symptoms and loneliness. Associations were not statistically significantly different between groups with and without (chronic) pre-pandemic mental health disorders. CONCLUSIONS: Individual differences in cumulative exposure to COVID-19-pandemic-related adversity are important predictors of mental health, but we found no evidence for higher vulnerability among people with (chronic) pre-pandemic mental health disorders.

Temporal associations between salivary cortisol and emotions in clinically depressed individuals and matched controls: A dynamic time warp analysis.

Depression can be understood as a complex dynamic system where depressive symptoms interact with one another. Cortisol is suggested to play a major role in the pathophysiology of depression, but knowledge on the temporal interplay between cortisol and depressive symptoms is scarce. We aimed to analyze the temporal connectivity between salivary cortisol and momentary affective states in depressed individuals and controls. Thirty pair-matched depressed and non-depressed participants completed questionnaires on momentary positive (PA) and negative (NA) affect and collected saliva three times a day for 30 days. The association between cortisol and affect was analyzed by dynamic time warp (DTW) analyses. These analyses involved lag-1 backward to lag-1 forward undirected analyses and lag-0 and lag-1 forward directed analyses. Large inter- and intra-individual variability in the networks were found. At the group level, with undirected analysis PA and NA were connected in the networks in depressed individuals and in controls. Directed analyses indicated that increases in cortisol preceded specific NA items in controls, but tended to follow upon specific affect items increase in depressed individuals. To conclude, at group level, changes in cortisol levels in individuals diagnosed with a depression may be a result of changes in affect, rather than a cause.

PTSD Symptom dynamics after the great east japan earthquake: mapping the temporal structure using Dynamic Time Warping.

Background: After the Great East Japan Earthquake [GEJE], approximately 70,000 Japan Ground Self Defense Force [JGSDF] personnel were deployed, risking Post-Traumatic Stress Disorder [PTSD]. The network approach to psychopathology suggests that symptoms may cause and exacerbate each other, resulting in the emergence and maintenance of disorders, including PTSD. It is therefore important to further explore the temporal interplay between symptoms. Most studies assessing the factor structure of the Impact of Event Scale-Revised [IES-R] have used cross-sectional designs. In this study, the structure of the IES-R was re-evaluated while incorporating the temporal interplay between symptoms.Methods: Using Dynamic Time Warping [DTW] the distances between PTSD symptoms on the IES-R were modelled in 1120 JGSDF personnel. Highly correlated symptoms were clustered at the group level using Distatis three-way principal component analyses of the distance matrices. The resulting clusters were compared to the original three subscales of the IES-R using a Confirmatory Factor Analysis (CFA).Results: The DTW analysis yielded four symptom clusters: Intrusion (five items), Hyperarousal (six items), Avoidance (six items), and Dissociation (five items). CFA yielded better fit estimates for this four-factor solution (RMSEA = 0.084, CFI = 0.918, TLI = 0.906), compared to the original three subscales of the IES-R (RMSEA = 0.103, CFI = 0.873, TLI = 0.858).Conclusions: DTW offers a new method of modelling the temporal relationships between symptoms. It yielded four IES-R symptom clusters, which may facilitate understanding of PTSD as a complex dynamic system.

Personnel from the Japan Ground Self-Defense Force responded to the aftermath of the 2011 Great East Japan Earthquake, putting them at increased risk of developing symptoms of Post-Traumatic Stress Disorder.In recent years, psychological research has focused increasingly on methods to map the ways in which symptoms of psychopathology cause and exacerbate each other.The Dynamic Time Warping algorithm seems to be an appropriate and useful tool to analyse the interaction between post-traumatic stress symptoms over time, especially if these are not instantaneous or linear. This can improve our understanding of psychopathology and help move towards personalized medicine.

Weighing poor immunometabolic health in relatives for severity of affective symptoms: A study of patients with depressive and anxiety disorders and their siblings.

BACKGROUND: Affective (i.e. depressive and anxiety) disorders often co-occur with immunometabolic diseases and related biological pathways. Although many large population-based and meta-analytic studies have confirmed this link in community and clinical samples, studies in at-risk samples of siblings of persons with affective disorders are lacking. Furthermore, this somatic-mental co-occurrence may be partially explained by familial clustering of the conditions. First, we examined whether the association between a wide range of immunometabolic diseases and related biomarker based risk-profiles with psychological symptoms replicates in at-risk siblings of probands with affective disorders. Second, leveraging on a sibling-pair design, we disentangled and quantified the effect of probands' immunometabolic health on siblings' psychological symptoms and on the association between immunometabolic health and these symptoms in siblings. METHODS: The sample included 636 participants (Mage = 49.7; 62.4% female) from 256 families, each including a proband with lifetime depressive and/or anxiety disorders and at least one of their sibling(s) (N = 380 proband-sibling pairs). Immunometabolic health included cardiometabolic and inflammatory diseases, body mass index (BMI), and composite metabolic (based on the five metabolic syndrome components) and inflammatory (based on interleukin-6 and C-reactive protein) biomarker indices. Overall affective symptoms and specific atypical, energy-related depressive symptoms were derived from self-report questionnaires. Mixed-effects analyses were used to model familial clustering. RESULTS: In siblings, inflammatory disease (γ = 0.25, p = 0.013), higher BMI (γ = 0.10, p = 0.033) and metabolic index (γ = 0.28, p < 0.001) were associated with higher affective symptoms, with stronger associations for atypical, energy-related depressive symptoms (additionally associated with cardiometabolic disease; γ = 0.56, p = 0.048). Immunometabolic health in probands was not independently associated with psychological symptoms in siblings nor did it moderate the association between immunometabolic health and psychological symptoms estimated in siblings. CONCLUSIONS: Our findings demonstrate that the link between later life immunometabolic health and psychological symptoms is consistently present also in adult siblings at high risk for affective disorders. Familial clustering did not appear to have a substantial impact on this association. Instead, individual lifestyle, rather than familial factors, may have a relatively higher impact in the clustering of later life immunometabolic conditions with psychological symptoms in at-risk adult individuals. Furthermore, results highlighted the importance of focusing on specific depression profiles when investigating the overlap with immunometabolic health.

Metabolomics signatures of depression: the role of symptom profiles.

Depression shows a metabolomic signature overlapping with that of cardiometabolic conditions. Whether this signature is linked to specific depression profiles remains undetermined. Previous research suggested that metabolic alterations cluster more consistently with depressive symptoms of the atypical spectrum related to energy alterations, such as hyperphagia, weight gain, hypersomnia, fatigue and leaden paralysis. We characterized the metabolomic signature of an "atypical/energy-related" symptom (AES) profile and evaluated its specificity and consistency. Fifty-one metabolites measured using the Nightingale platform in 2876 participants from the Netherlands Study of Depression and Anxiety were analyzed. An 'AES profile' score was based on five items of the Inventory of Depressive Symptomatology (IDS) questionnaire. The AES profile was significantly associated with 31 metabolites including higher glycoprotein acetyls (ß = 0.13, p = 1.35*10-12), isoleucine (ß = 0.13, p = 1.45*10-10), very-low-density lipoproteins cholesterol (ß = 0.11, p = 6.19*10-9) and saturated fatty acid levels (ß = 0.09, p = 3.68*10-10), and lower high-density lipoproteins cholesterol (ß = -0.07, p = 1.14*10-4). The metabolites were not significantly associated with a summary score of all other IDS items not included in the AES profile. Twenty-five AES-metabolites associations were internally replicated using data from the same subjects (N = 2015) collected at 6-year follow-up. We identified a specific metabolomic signature-commonly linked to cardiometabolic disorders-associated with a depression profile characterized by atypical, energy-related symptoms. The specific clustering of a metabolomic signature with a clinical profile identifies a more homogenous subgroup of depressed patients at higher cardiometabolic risk, and may represent a valuable target for interventions aiming at reducing depression's detrimental impact on health.

A network analysis of depressive symptoms and metabolomics.

BACKGROUND: Depression is associated with metabolic alterations including lipid dysregulation, whereby associations may vary across individual symptoms. Evaluating these associations using a network perspective yields a more complete insight than single outcome-single predictor models. METHODS: We used data from the Netherlands Study of Depression and Anxiety (N = 2498) and leveraged networks capturing associations between 30 depressive symptoms (Inventory of Depressive Symptomatology) and 46 metabolites. Analyses involved 4 steps: creating a network with Mixed Graphical Models; calculating centrality measures; bootstrapping for stability testing; validating central, stable associations by extra covariate-adjustment; and validation using another data wave collected 6 years later. RESULTS: The network yielded 28 symptom-metabolite associations. There were 15 highly-central variables (8 symptoms, 7 metabolites), and 3 stable links involving the symptoms Low energy (fatigue), and Hypersomnia. Specifically, fatigue showed consistent associations with higher mean diameter for VLDL particles and lower estimated degree of (fatty acid) unsaturation. These remained present after adjustment for lifestyle and health-related factors and using another data wave. CONCLUSIONS: The somatic symptoms Fatigue and Hypersomnia and cholesterol and fatty acid measures showed central, stable, and consistent relationships in our network. The present analyses showed how metabolic alterations are more consistently linked to specific symptom profiles.

Association Between the Fronto-Limbic Network and Cognitive and Emotional Functioning in Individuals With Bipolar Disorder: A Systematic Review and Meta-analysis.

Importance: Individuals with bipolar disorder (BD) experience cognitive and emotional dysfunctions. Various brain circuits are implicated in BD but have not been investigated in a meta-analysis of functional magnetic resonance imaging (fMRI) studies. Objective: To investigate the brain functioning of individuals with BD compared with healthy control individuals in the domains of emotion processing, reward processing, and working memory. Data Sources: All fMRI experiments on BD published before March 2020, as identified in a literature search of PubMed, Embase, Web of Science, Cochrane Library, PsycInfo, Emcare, Academic Search Premier, and ScienceDirect. The literature search was conducted on February 21, 2017, and March 2, 2020, and data were analyzed from January 2021 to January 2022. Study Selection: fMRI experiments comparing adult individuals with BD and healthy control individuals were selected if they reported whole-brain results, including a task assessing at least 1 of the domains. In total, 2320 studies were screened, and 253 full-text articles were evaluated. Data Extraction and Synthesis: A total of 49 studies were included after selection procedure. Coordinates reporting significant activation differences between individuals with BD and healthy control individuals were extracted. Differences in brain region activity were tested using the activation likelihood estimation method. Main Outcomes and Measures: A whole-brain meta-analysis evaluated whether reported differences in brain activation in response to stimuli in 3 cognitive domains between individuals with BD and healthy control individuals were different. Results: The study population included 999 individuals with BD (551 [55.2%] female) and 1027 healthy control individuals (532 [51.8%] female). Compared with healthy control individuals, individuals with BD showed amygdala and hippocampal hyperactivity and hypoactivation in the inferior frontal gyrus during emotion processing (20 studies; 324 individuals with BD and 369 healthy control individuals), hyperactivation in the orbitofrontal cortex during reward processing (9 studies; 195 individuals with BD and 213 healthy control individuals), and hyperactivation in the ventromedial prefrontal cortex and subgenual anterior cingulate cortex during working memory (20 studies; 530 individuals with BD and 417 healthy control individuals). Limbic hyperactivation was only found during euthymia in the emotion and reward processing domains; abnormalities in frontal cortex activity were also found in individuals with BD with mania and depression. Conclusions and Relevance: This systematic review and meta-analysis revealed evidence for activity disturbances in key brain areas involved in cognitive and emotion processing in individuals with BD. Most of the regions are part of the fronto-limbic network. The results suggest that aberrations in the fronto-limbic network, present in both euthymic and symptomatic individuals, may be underlying cognitive and emotional dysfunctions in BD.