Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL.

ABSTRACT: Distinct diagnostic entities within BCR::ABL1-positive acute lymphoblastic leukemia (ALL) are currently defined by the International Consensus Classification of myeloid neoplasms and acute leukemias (ICC): "lymphoid only", with BCR::ABL1 observed exclusively in lymphatic precursors, vs "multilineage", where BCR::ABL1 is also present in other hematopoietic lineages. Here, we analyzed transcriptomes of 327 BCR::ABL1-positive patients with ALL (age, 2-84 years; median, 46 years) and identified 2 main gene expression clusters reproducible across 4 independent patient cohorts. Fluorescence in situ hybridization analysis of fluorescence-activated cell-sorted hematopoietic compartments showed distinct BCR::ABL1 involvement in myeloid cells for these clusters (n = 18/18 vs n = 3/16 patients; P < .001), indicating that a multilineage or lymphoid BCR::ABL1 subtype can be inferred from gene expression. Further subclusters grouped samples according to cooperating genomic events (multilineage: HBS1L deletion or monosomy 7; lymphoid: IKZF1-/- or CDKN2A/PAX5 deletions/hyperdiploidy). A novel HSB1L transcript was highly specific for BCR::ABL1 multilineage cases independent of HBS1L genomic aberrations. Treatment on current German Multicenter Study Group for Adult ALL (GMALL) protocols resulted in comparable disease-free survival (DFS) for multilineage vs lymphoid cluster patients (3-year DFS: 70% vs 61%; P = .530; n = 91). However, the IKZF1-/- enriched lymphoid subcluster was associated with inferior DFS, whereas hyperdiploid cases showed a superior outcome. Thus, gene expression clusters define underlying developmental trajectories and distinct patterns of cooperating events in BCR::ABL1-positive ALL with prognostic relevance.

Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study.

BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial. METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry. RESULTS: In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry. CONCLUSIONS: These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03043872.

A structured evaluation of genome-scale constraint-based modeling tools for microbial consortia.

Harnessing the power of microbial consortia is integral to a diverse range of sectors, from healthcare to biotechnology to environmental remediation. To fully realize this potential, it is critical to understand the mechanisms behind the interactions that structure microbial consortia and determine their functions. Constraint-based reconstruction and analysis (COBRA) approaches, employing genome-scale metabolic models (GEMs), have emerged as the state-of-the-art tool to simulate the behavior of microbial communities from their constituent genomes. In the last decade, many tools have been developed that use COBRA approaches to simulate multi-species consortia, under either steady-state, dynamic, or spatiotemporally varying scenarios. Yet, these tools have not been systematically evaluated regarding their software quality, most suitable application, and predictive power. Hence, it is uncertain which tools users should apply to their system and what are the most urgent directions that developers should take in the future to improve existing capacities. This study conducted a systematic evaluation of COBRA-based tools for microbial communities using datasets from two-member communities as test cases. First, we performed a qualitative assessment in which we evaluated 24 published tools based on a list of FAIR (Findability, Accessibility, Interoperability, and Reusability) features essential for software quality. Next, we quantitatively tested the predictions in a subset of 14 of these tools against experimental data from three different case studies: a) syngas fermentation by C. autoethanogenum and C. kluyveri for the static tools, b) glucose/xylose fermentation with engineered E. coli and S. cerevisiae for the dynamic tools, and c) a Petri dish of E. coli and S. enterica for tools incorporating spatiotemporal variation. Our results show varying performance levels of the best qualitatively assessed tools when examining the different categories of tools. The differences in the mathematical formulation of the approaches and their relation to the results were also discussed. Ultimately, we provide recommendations for refining future GEM microbial modeling tools.

Impairments in Cognitive and Emotional Empathy as Markers of General versus Specific Personality Pathology.

INTRODUCTION: The alternative model for personality disorders (AMPD) of the Diagnostic and Statistical Manual of Mental Disorders - 5th edition (DSM-5) considers impairments in empathy a basic feature of personality disorders (PDs). In contrast, the AMPD pathological personality trait model and the categorical DSM-5 Section II PD model associate deficits in empathy to specific forms of personality pathology. The present study investigated to what extent impairments in cognitive and emotional empathy are markers of general versus specific personality pathology. METHODS: In a clinical sample (n = 119), the Multifaceted Empathy Test was used to assess cognitive empathy, emotional empathy for positive emotions, and emotional empathy for negative emotions. Personality functioning, pathological personality traits, and DSM-5 Section II PDs were assessed via interviews and self-reports. Confirmatory factor analyses were applied to associate the three empathy facets with the three personality pathology approaches, each modeled with general personality pathology (common factor) and specific personality pathology (residuals of indicators). RESULTS: Impairments in cognitive empathy and emotional empathy for positive emotions were significantly correlated with general personality pathology. All three empathy facets were also correlated to specific personality pathology when controlling for general personality pathology, respectively. Impairments in cognitive empathy were incrementally associated with identity and empathy (personality functioning), psychoticism (pathological personality traits), and paranoid and dependent PD (DSM-5 Section II PDs). Deficits in emotional empathy for positive emotions were incrementally associated with self-direction and intimacy (personality functioning) and detachment (pathological personality traits). Impairments in emotional empathy for negative emotions were incrementally associated with antagonism (pathological personality traits) and antisocial PD (DSM-5 Section II PDs). CONCLUSION: The results suggest that impairments in cognitive empathy and emotional empathy for positive emotions, but not for negative emotions, are markers of general personality pathology, while deficits in the three empathy facets are also markers for specific personality pathology.

Phosphoproteomics Profiling Defines a Target Landscape of the Basophilic Protein Kinases AKT, S6K, and RSK in Skeletal Myotubes.

Phosphorylation-dependent signal transduction plays an important role in regulating the functions and fate of skeletal muscle cells. Central players in the phospho-signaling network are the protein kinases AKT, S6K, and RSK as part of the PI3K-AKT-mTOR-S6K and RAF-MEK-ERK-RSK pathways. However, despite their functional importance, knowledge about their specific targets is incomplete because these kinases share the same basophilic substrate motif RxRxxp[ST]. To address this, we performed a multifaceted quantitative phosphoproteomics study of skeletal myotubes following kinase inhibition. Our data corroborate a cross talk between AKT and RAF, a negative feedback loop of RSK on ERK, and a putative connection between RSK and PI3K signaling. Altogether, we report a kinase target landscape containing 49 so far unknown target sites. AKT, S6K, and RSK phosphorylate numerous proteins involved in muscle development, integrity, and functions, and signaling converges on factors that are central for the skeletal muscle cytoskeleton. Whereas AKT controls insulin signaling and impinges on GTPase signaling, nuclear signaling is characteristic for RSK. Our data further support a role of RSK in glucose metabolism. Shared targets have functions in RNA maturation, stability, and translation, which suggests that these basophilic kinases establish an intricate signaling network to orchestrate and regulate processes involved in translation.

Evaluating the role of maladaptive personality traits in schema therapy and cognitive behavioural therapy for depression.

BACKGROUND: Advancements in the treatment of depression are pivotal due to high levels of non-response and relapse. This study evaluated the role of personality pathology in the treatment of depression by testing whether maladaptive personality traits (1) predict changes in depression over treatment or vice versa, (2) change themselves over treatment, (3) change differentially depending on treatment with schema therapy (ST) or cognitive behavioural therapy (CBT), and (4) moderate the effectiveness of these treatments. METHODS: We included 193 depressed inpatients (53.4% women, Mage = 42.9, SD = 13.4) participating in an assessor-blind randomized clinical trial and receiving a 7-week course of ST or CBT. The research questions were addressed using multiple indicator latent change score models as well as multigroup structural equation models implemented in EffectLiteR. RESULTS: Maladaptive traits did not predict changes in depressive symptoms at post-treatment, or vice versa. However, maladaptive trait domains decreased over treatment (standardized Δµ range: -0.38 to -0.89), irrespective of treatment with ST or CBT. Maladaptive traits at baseline did not moderate the effectiveness of these treatments. CONCLUSIONS: Self-reported maladaptive personality traits can change during treatment of depression, but may have limited prognostic or prescriptive value, at least in the context of ST or CBT. These results need to be replicated using follow-up data, larger and more diverse samples, and informant-rated measures of personality pathology.

Evaluating a multimodal, clinical and work-directed intervention (RTW-PIA) to support sustainable return to work among employees with mental disorders: study protocol of a multicentre, randomised controlled trial.

BACKGROUND: Mental disorders (MDs) are one of the leading causes for workforce sickness absence and disability worldwide. The burden, costs and challenges are enormous for the individuals concerned, employers and society at large. Although most MDs are characterised by a high risk of relapse after treatment or by chronic courses, interventions that link medical-psychotherapeutic approaches with work-directed components to facilitate a sustainable return to work (RTW) are rare. This protocol describes the design of a study to evaluate the (cost-)effectiveness and implementation process of a multimodal, clinical and work-directed intervention, called RTW-PIA, aimed at employees with MDs to achieve sustainable RTW in Germany. METHODS: The study consists of an effectiveness, a health-economic and a process evaluation, designed as a two-armed, multicentre, randomised controlled trial, conducted in German psychiatric outpatient clinics. Sick-listed employees with MDs will receive either the 18-month RTW-PIA treatment in conjunction with care as usual, or care as usual only. RTW-PIA consists of a face-to-face individual RTW support, RTW aftercare group meetings, and web-based aftercare. Assessments will be conducted at baseline and 6, 12, 18 and 24 months after completion of baseline survey. The primary outcome is the employees´ achievement of sustainable RTW, defined as reporting less than six weeks of working days missed out due to sickness absence within 12 months after first RTW. Secondary outcomes include health-related quality of life, mental functioning, RTW self-efficacy, overall job satisfaction, severity of mental illness and work ability. The health-economic evaluation will be conducted from a societal and public health care perspective, as well as from the employer's perspective in a cost-benefit analysis. The design will be supplemented by a qualitative effect evaluation using pre- and post-interviews, and a multimethod process evaluation examining various predefined key process indicators from different stakeholder perspectives. DISCUSSION: By applying a comprehensive, multimethodological evaluation design, this study captures various facets of RTW-PIA. In case of promising results for sustainable RTW, RTW-PIA may be integrated into standard care within German psychiatric outpatient clinics. TRIAL REGISTRATION: The study was prospectively registered with the German Clinical Trials Register ( DRKS00026232 , 1 September 2021).

Evaluating the Psychometric Properties of the German Self and Interpersonal Functioning Scale (SIFS).

The Self and Interpersonal Functioning Scale (SIFS) is a 24-item self-report questionnaire assessing personality functioning according to the alternative DSM-5 model for personality disorders. We evaluated the German SIFS version in a total sample of 886 participants from Germany and Switzerland. Its factor structure was investigated with confirmatory factor analysis comparing bifactor models with two specific factors (self- and interpersonal functioning) and four specific factors (identity, self-direction, empathy, and intimacy). The SIFS sum and domain scores were tested for reliability and convergent validity with self-report questionnaires and interviews for personality functioning, -organization, -traits, -disorder categories, and well-being. None of the bifactor models yielded good model fit, even after excluding two items with low factor loadings and including a method factor for reverse-keyed items. Based on a shortened 22-item SIFS version, models suggested that the g-factor explained 52.9-59.6% of the common variance and that the SIFS sum score measured the g-factor with a reliability of .68-.81. Even though the SIFS sum score showed large test-retest reliability and correlated strongly with well-established self-report questionnaires and interviews, the lack of structural validity appears to be a serious disadvantage of the SIFS compared to existing self-reports questionnaires of personality functioning.

Exploring the Latent Structure and Convergent and Incremental Validity of the Metacognition Assessment Scale - Abbreviated in a Sample of Patients with Non-Affective Psychosis.

Synthetic metacognition is a heterogeneous construct related to psychotic disorders. One important tool to assess this construct is the Metacognition Assessment Scale - Abbreviated (MAS-A). In this study, we investigated the latent structure as well as the interrater reliability and convergent and incremental validity of the MAS-A in a sample of patients with non-affective psychosis. Analyses indicated that the scale might be one-dimensional. Interrater reliability of the MAS-A total score was good. In terms of convergent validity, correlational analyses showed significant associations of MAS-A metacognition with the Operationalized Psychodynamic Diagnosis Level of Structural Integration Axis (OPD-LSIA) and the Levels of Emotional Awareness Scale (LEAS). In terms of construct validity, a significant association was observed between MAS-A metacognition and a short version of the International Classification of Functioning, Disability and Health (MINI-ICF), which persisted after self-report measures of impairments in structural capacities (Structure Questionnaire of Operationalized Psychodynamic Diagnosis [OPD-SQS]) and mentalizing abilities (Mentalization Questionnaire [MZQ]) were included as covariates, but not after symptom dimensions were included. There was a significant correlation with the current living situation, but not with other external criteria like diagnosis or duration of illness. Future studies should explore alternative outcomes and replicate results in longitudinal designs.

Intuition and meaning in life in persons with varying level of depressive symptoms and impairments in personality functioning.

OBJECTIVES: The current research explored the interplay between intuition, meaning in life, and psychopathology. Specifically, we investigated whether experiential and reflective components of meaning in life are associated with depressive symptoms and personality pathology, whether intuition is related to the experience of meaning, and whether psychopathology has disruptive effects on intuition as well as on the link between intuition and the experience of meaning. METHODS: We tested our preregistered hypotheses in two independent studies. In Study 1, N = 448 participants completed self-report instruments assessing the experiential and the reflective dimensions of meaning in life, depressive symptoms, and impairments in personality functioning. Intuition was operationalized as the ability to intuitively detect semantic coherence in an experimental task. Additionally, self-reported confidence in intuition was assessed. In Study 2, we aimed to replicate our findings and hypotheses that emerged from Study 1 with a new sample of N = 1189 participants. RESULTS: In both studies, participants with more depressive symptoms or higher levels of personality pathology experienced life as less meaningful but reflected significantly more about meaning in life. The intuitive ability to discriminate between coherence and incoherence in the experimental task was neither related to the experience of meaning in life nor to psychopathology, but more confidence in intuition was associated with experiencing life as more meaningful and with less psychopathological symptoms. It was tentatively supported that the association between meaning in life and intuition was moderated by psychopathology. CONCLUSION: The findings are discussed in terms of their clinical implications and regarding the cognitive-affective processes potentially underlying people's experience of life being meaningful.

[The Personality Inventory for ICD-11 (PiCD): Reliability and Validity of the German Version in a Clinical and Non-Clinical Sample]. / Das Persönlichkeitsinventar für ICD-11 (PiCD): Reliabilität und Validität der Deutschen Version in einer klinischen und nicht-klinischen Stichprobe.

The 11th version of the International Statistical Classification of Diseases and Related Health Problems (ICD-11) marks a paradigm shift in the diagnosis of personality disorders: In the near future, their classification will no longer be categorical, but dimensional along the severity of personality impairments and optionally regarding the presence of maladaptive personality traits. This study examines the reliability and validity of the German version of the Personality Inventory for ICD-11 (PiCD), a questionnaire designed to assess ICD-11 maladaptive personality domains, in a clinical and nonclinical sample (N=939). The factor structure of the PiCD was examined using Exploratory Factor Analysis (EFA) and showed a tendency for a four-factor model (Negative Affectivity, Dissociality, Detachment, and a bipolar factor Disinhibition-Anankastia). The subscales of the PiCD demonstrated acceptable to excellent reliability coefficients with Cronbach's α (0.79 - 0.89) and McDonald's ω (0.76 - 0.90). Convergent and discriminant validity were examined in conjunction with other questionnaires and were found to be satisfactory. The results suggest that the German version of the PiCD is a reliable and largely valid measurement instrument for assessing ICD-11 maladaptive personality traits. However, further research on factor structure, appropriate cut-off as well as norm values is needed.

Intensity of Treatment as Usual and Its Impact on the Effects of Face-to-Face and Internet-Based Psychotherapy for Depression: A Preregistered Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Treatment as usual (TAU) is the most frequently used control group in randomized trials of psychotherapy for depression. Concerns have been raised that the heterogeneity of treatments in TAU leads to biased estimates of psychotherapy efficacy and to an unclear difference between TAU and control groups like waiting list (WL). OBJECTIVE: We investigated the impact of control group intensity (i.e., amount and degree to which elements of common depression treatments are provided) on the effects of face-to-face and internet-based psychotherapy for depression. METHODS: We conducted a preregistered meta-analysis (www.osf.io/4mzyd). We included trials comparing psychotherapy with TAU or WL in patients with symptoms of unipolar depression. Six indicators were used to assess control group intensity. PRIMARY OUTCOME: Standardized mean difference (SMD) of psychotherapy and control in depressive symptoms at treatment termination. RESULTS: We included 89 trials randomizing 14,474 patients to 113 psychotherapy conditions and 89 control groups (TAU in 42 trials, WL in 47 trials). Control group intensity predicted trial results in preregistered (one-sided ps < 0.042) and exploratory analyses. Psychotherapy effects were significantly smaller (one-sided p = 0.002) in trials with higher intensity TAU (SMD = 0.324, CI 0.209 to 0.439) than in trials with lower intensity TAU (SMD = 0.628, CI 0.455 to 0.801). Psychotherapy effects against lower intensity TAU did not differ from effects against WL (two-sided p = 0.663). CONCLUSIONS: Our results suggest that variation in TAU intensity impacts the outcome of trials. More scrutiny in the design of control groups for clinical trials is recommended.

Future Challenges in Psychotherapy Research for Personality Disorders.

PURPOSE OF REVIEW: Individuals with personality disorders are frequently seen in mental health settings. Their symptoms typically reflect a high level of suffering and burden of disease, with potentially harmful societal consequences, including costs related to absenteeism at work, high use of health services, ineffective or harmful parenting, substance use, suicidal and non-suicidal self-harming behavior, and aggressiveness with legal consequences. Psychotherapy is currently the first-line treatment for patients with personality disorders, but the study of psychotherapy in the domain of personality disorders faces specific challenges. RECENT FINDINGS: Challenges include knowing what works for whom, identifying which putative mechanisms of change explain therapeutic effects, and including the social interaction context of patients with a personality disorder. By following a dimensional approach, psychotherapy research on personality disorders may serve as a model for the development and study of innovative psychotherapeutic interventions. We recommend developing the following: (a) an evidence base to make treatment decisions based on individual features; (b) a data-driven approach to predictors, moderators, and mechanisms of change in psychotherapy; (c) methods for studying the interaction between social context and psychotherapy.

Assessing Personality Change: Introduction to the Special Section.

Both clinical and personality psychologists are interested in assessing personality change, although they have tended to approach the issue in different ways. In this paper we argue that both sub-fields should focus more on basic issues in the assessment of personality change, and that they would make more progress on this issue together than alone. This Special Section on the Assessment of Personality Change includes four papers by researchers working primarily in basic personality science. Each paper addresses specific ways to advance the assessment of personality change that have both basic and applied clinical relevance, but collectively they show how far the field still has to go.

Assessing Maladaptive Personality in the Forensic Context: Development and Validation of the Personality Inventory for DSM-5 Forensic Faceted Brief Form (PID-5-FFBF).

The current study proposes an adaptation of the PID-5 to assesses maladaptive personal traits in forensic settings. Specifically, we adapted the item set of the PID-5 Faceted Brief Form (PID-5-FBF) to the forensic context and validated the resulting PID-5 Forensic Faceted Brief Form (PID-5-FFBF) using self- and informant-reports of 199 male prisoners. Exploratory factor analyses suggested a four-factor solution comprising Antagonism, Detachment, Disinhibited Aggression, and Insecurity. Antagonism and Detachment were very similar to the domains with the same name from the five-factor solution of the PID-5. Insecurity conceptually resembled Negative Affectivity. Disinhibited Aggression represented a forensically highly relevant composition of Antagonism, Disinhibition, and Negative Affectivity. We report results for this four- and the canonical five-factor solution throughout the manuscript. The PID-5-FFBF domains showed convergent associations with the corresponding Big Five personality traits. Furthermore, the PID-5-FFBF domains were differentially correlated with indicators of psychological adjustment and forensically relevant outcomes such as institutional misbehavior and risk for reoffending. In particular, Insecurity was associated with lower levels of psychological adjustment, while Antagonism and Disinhibited Aggression were associated with higher levels of institutional misbehavior and risk for reoffending. These findings provide initial evidence for the validity and utility of the PID-5-FFBF in forensic settings.

A Critical Evaluation of the Reflective Functioning Questionnaire (RFQ).

The Reflective Functioning Questionnaire (RFQ) is an 8-item self-report measure of reflective functioning that is presumed to capture individual differences in hypo- and hypermentalizing. Despite its broad acceptance by the field, we argue that the validity of the measure is not well-established. The current research elaborates on problems of the RFQ related to its item content, scoring procedure, dimensionality, and associations with psychopathology. We tested these considerations across three large clinical and non-clinical samples from Germany and the US (total N = 2289). In a first study, we found that the RFQ may assess a single latent dimension related to hypomentalizing but is rather unlikely to capture maladaptive forms of hypermentalizing. Moreover, the RFQ exhibited very strong associations with measures of personality pathology, while associations with measures of symptom distress were less strong. In a second preregistered study focused on convergent and discriminant validity, however, a commonality analysis indicated that associations with indicators of personality pathology are inflated because some of the RFQ items tap into emotional lability and impulsivity rather than mentalizing. Our findings demonstrate limitations of the RFQ. We discuss key challenges in assessing mentalizing via self-report.

Failure to resolve loss and compromised mentalizing in female inpatients with major depressive disorder.

Attachment and mentalizing are central concepts in research on the etiology, course, and treatment of depression. The goal of this cross-sectional study was to clarify the unique value of these constructs in characterizing the presence, severity, and chronicity of depression. We examined 50 female inpatients suffering from Major Depressive Disorder (MDD) in comparison to 47 matched healthy controls regarding their attachment states of mind, mentalizing capacities, and clinical variables indicating depression severity and chronicity (e.g. illness duration, number of hospitalizations). In the group of depressed patients, unresolved attachment with regard to loss was significantly overrepresented. Dimensionally, patients were more disorganized and more insecure, whereas there was no difference on the dismissing-preoccupied dimension between the two groups. Mentalizing was significantly lower in patients than in healthy controls. Logistic regression analysis revealed attachment insecurity, mentalizing deficits, and unresolved loss to be incrementally relevant to predict MDD. Correlations with clinical parameters in the group of depressed patients showed positive associations between mentalizing deficits, attachment insecurity, and variables indicating illness chronicity. Our findings highlight the relevance of the inability to resolve or reappraise loss experiences in depressive states.

Insight and Outcome in Long-Term Psychotherapies of Depression.

Objectives: In different therapeutic approaches, insight is acknowledged as an important part of patient's therapeutic change process. We examined whether the level of insight (1) differs between psychoanalytic (PA), psychodynamic (PD) and cognitive-behavioral therapy (CBT), and (2) predicts long-term symptomatic outcome. Methods: A completer sample of 67 depressed patients from the Munich Psychotherapy Study was analyzed. Symptoms were assessed with Beck Depression Inventory (BDI) and Symptom Checklist-Revised (SCL-90-R) at pre-treatment and three-year follow-up. Insight was assessed from 242 sessions of mid-therapy phase with the Experiencing Scale. Results: The general level of insight was higher in PA as compared to CBT, and associated with lower depressive symptoms (BDI) across all three therapeutic modalities at three-year follow-up. Insight was unrelated to general distress (SCL-90-R). Exploratory analyses suggested that patients treated with PA showed higher levels of insight especially in high quality sessions (assessed by therapist). Patients for whom the extent of insight was positively linked to session quality, suffered from more depressive symptoms at three-year follow-up than patients gaining insight when session quality was low. Conclusion: Insight differs between PA and CBT and may be a common change mechanism in long-term psychotherapies.

Efficacy and Moderators of Internet-Based Interventions in Adults with Subthreshold Depression: An Individual Participant Data Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Evidence on effects of Internet-based interventions to treat subthreshold depression (sD) and prevent the onset of major depression (MDD) is inconsistent. OBJECTIVE: We conducted an individual participant data meta-analysis to determine differences between intervention and control groups (IG, CG) in depressive symptom severity (DSS), treatment response, close to symptom-free status, symptom deterioration and MDD onset as well as moderators of intervention outcomes. METHODS: Randomized controlled trials were identified through systematic searches via PubMed, PsycINFO, Embase and Cochrane Library. Multilevel regression analyses were used to examine efficacy and moderators. RESULTS: Seven trials (2,186 participants) were included. The IG was superior in DSS at all measurement points (posttreatment: 6-12 weeks; Hedges' g = 0.39 [95% CI: 0.25-0.53]; follow-up 1: 3-6 months; g = 0.30 [95% CI: 0.15-0.45]; follow-up 2: 12 months, g = 0.27 [95% CI: 0.07-0.47], compared with the CG. Significantly more participants in the IG than in the CG reached response and close to symptom-free status at all measurement points. A significant difference in symptom deterioration between the groups was found at the posttreatment assessment and follow-up 2. Incidence rates for MDD onset within 12 months were lower in the IG (19%) than in the CG (26%). Higher initial DSS and older age were identified as moderators of intervention effect on DSS. CONCLUSIONS: Our findings provide evidence for Internet-based interventions to be a suitable low-threshold intervention to treat individuals with sD and to reduce the incidence of MDD. This might be particularly true for older people with a substantial symptom burden.

Maternal early life maltreatment and psychopathology affect the next generation: Alterations in post-awakening cortisol levels of primary school-aged children.

Early life maltreatment (ELM) has severe and lasting effects on the individual, which might also impact the next generation. On an endocrine level, the hypothalamus-pituitary-adrenal axis has been suggested to play an important role in the interplay between ELM and the development of mental disorders. Several studies have revealed that maternal post-awakening cortisol concentration, maternal sensitivity, maternal ELM and psychopathology are associated with children's cortisol levels. We investigated the post-awakening cortisol concentrations in 6- to 11-year-old children (N = 53) whose mothers either had experienced ELM and had developed a lifetime mental disorder (N = 15 ELM and disorder group), had experienced ELM without developing a mental disorder (N = 12 ELM-only group), or had neither experienced ELM nor developed a mental disorder (N = 26 HC-group). Furthermore, we assessed maternal post-awakening cortisol concentrations, maternal psychopathology, and sensitivity. Multilevel analysis revealed higher cortisol at awakening (S1) levels in children of mothers with ELM and disorder. Maternal cortisol at awakening (S1) also predicted the child's cortisol at awakening (S1), and no effect of maternal sensitivity could be found. The current results replicate an attunement of cortisol levels (S1) between mothers and children and suggest an association between the children's endocrine stress system and maternal factors such as ELM and psychopathology.