Microtubule end-on attachment maturation regulates Mps1 association with its kinetochore receptor.

Faithful chromosome segregation requires that sister chromatids establish bi-oriented kinetochore-microtubule attachments. The spindle assembly checkpoint (SAC) prevents premature anaphase onset with incomplete attachments. However, how microtubule attachment and checkpoint signaling are coordinated remains unclear. The conserved kinase Mps1 initiates SAC signaling by localizing transiently to kinetochores in prometaphase and is released upon bi-orientation. Using biochemistry, structure predictions, and cellular assays, we shed light on this dynamic behavior in Saccharomyces cerevisiae. A conserved N-terminal segment of Mps1 binds the neck region of Ndc80:Nuf2, the main microtubule receptor of kinetochores. Mutational disruption of this interface, located at the backside of the paired CH domains and opposite the microtubule-binding site, prevents Mps1 localization, eliminates SAC signaling, and impairs growth. The same interface of Ndc80:Nuf2 binds the microtubule-associated Dam1 complex. We demonstrate that the error correction kinase Ipl1/Aurora B controls the competition between Dam1 and Mps1 for the same binding site. Thus, binding of the Dam1 complex to Ndc80:Nuf2 may release Mps1 from the kinetochore to promote anaphase onset.

Multivalent Molecular Tweezers Disrupt the Essential NDC80 Interaction with Microtubules.

Binding of microtubule filaments by the conserved Ndc80 protein is required for kinetochore-microtubule attachments in cells and the successful distribution of the genetic material during cell division. The reversible inhibition of microtubule binding is an important aspect of the physiological error correction process. Small molecule inhibitors of protein-protein interactions involving Ndc80 are therefore highly desirable, both for mechanistic studies of chromosome segregation and also for their potential therapeutic value. Here, we report on a novel strategy to develop rationally designed inhibitors of the Ndc80 Calponin-homology domain using Supramolecular Chemistry. With a multiple-click approach, lysine-specific molecular tweezers were assembled to form covalently fused dimers to pentamers with a different overall size and preorganization/stiffness. We identified two dimers and a trimer as efficient Ndc80 CH-domain binders and have shown that they disrupt the interaction between Ndc80 and microtubules at low micromolar concentrations without affecting microtubule dynamics. NMR spectroscopy allowed us to identify the biologically important lysine residues 160 and 204 as preferred tweezer interaction sites. Enhanced sampling molecular dynamics simulations provided a rationale for the binding mode of multivalent tweezers and the role of pre-organization and secondary interactions in targeting multiple lysine residues across a protein surface.

Predictors of paranoia in the daily lives of people with non-affective psychosis and non-clinical controls: A systematic review of intensive longitudinal studies.

BACKGROUND AND OBJECTIVES: Worrying, self-esteem, sleep problems, anomalous internal experiences, reasoning biases, and interpersonal sensitivity are associated with paranoia. However, no review has examined whether these variables function as predictors of paranoia in everyday life. The present systematic review of intensive longitudinal studies (e.g., experience sampling) examined contemporaneous and time-lagged associations between paranoia and each candidate mechanism in individuals with non-affective psychosis and controls (pre-registration: https://osf.io/uwr9d). METHODS: We searched electronic databases, PsyArXiv, and reference lists for studies published since 1994. RESULTS: Of n = 5,918 results, n = 54 fulfilled inclusion criteria (n = 43 datasets). Most studies examined individuals with non-affective psychosis (n = 34). Strong evidence emerged for negative affect (subsumed under 'anomalous internal experiences') and sleep problems. For self-esteem, results suggest contemporaneous and lagged effects on paranoia but associations are likely driven by between-person variance. The low number of studies (n = 2 studies each) allowed no conclusions regarding worrying and reasoning biases. Findings on interpersonal sensitivity, which should be interpreted with caution because of the predictor's conceptual overlap with paranoia, indicate contemporaneous effects whereas time-lagged and within-person associations could not be judged due to insufficient data. LIMITATIONS: The present review used a narrative data-synthetization and it did not cover outcomes such as hallucinations. CONCLUSIONS: Despite convincing evidence for affect and sleep problems, it remains unclear whether affective states are precursors or also consequences of paranoia (vicious circle), and which of the actigraphy measures (sleep time, -efficiency, -fragmentation, etc.) best predicts paranoia.

Systematic analysis of microtubule plus-end networks defines EB-cargo complexes critical for mitosis in budding yeast.

Microtubules are ubiquitous cytoskeletal polymers with essential functions in chromosome segregation, intracellular transport, and cellular morphogenesis. End-binding proteins (EBs) form the nodes of intricate microtubule plus-end interaction networks. Which EB binding partners are most critical for cell division and how cells organize a microtubule cytoskeleton in the absence of an EB protein are open questions. Here, we perform a detailed analysis of deletion and point mutants of the budding yeast EB protein Bim1. We demonstrate that Bim1 executes its key mitotic functions as part of two cargo complexes-Bim1-Kar9 in the cytoplasm and Bim1-Bik1-Cik1-Kar3 in the nucleus. The latter complex acts during initial metaphase spindle assembly and supports tension establishment and sister chromatid biorientation. We demonstrate that engineered plus-end targeting of Cik1-Kar3 and overexpression of the microtubule crosslinker Ase1 restore distinct aspects of the bim1Δ spindle phenotype. In addition to defining key Bim1-cargo complexes our study also characterizes redundant mechanisms that allow cells to proliferate in the absence of Bim1.

Motive-Oriented, Personalized, Internet-Based Interventions for Depression: Nonclinical Experimental Study.

BACKGROUND: The low level of adherence in internet-based self-help interventions for depression suggests that in many existing programs, the motivational fit between the program and the user is unsatisfactory (eg, the user seeks autonomy, but the program provides directive guidance). Personalized, motive-oriented, self-help interventions could enable participants who interact with a program and its contents to have more engaging and less aversive experiences and thus increase adherence. OBJECTIVE: In an experimental study with a nonclinical analogue sample, we aimed to test the hypotheses that a better motivational person-program fit is linked with higher anticipated adherence, working alliance, and satisfaction with the program. METHODS: Motivational person-program fit was examined with respect to the 2 contrasting motives being autonomous and being supported. The hypotheses were tested by specifically varying the motivational person-program fit in a nonclinical sample (N=55), where participants were asked to work on, and subsequently evaluate, a limited set of individual pages of a self-help program with guidance (in the form of text messages) for depression. The sections of the self-help program were redesigned to either particularly address the autonomy motive or the support motive. For the quasi-experimental variation of the motivational person-program characteristics, we divided the 55 participants into 2 groups (autonomy group: n=27, 49%; support group: n=28, 51%) by screening method (using the Inventory of Approach and Avoidance Motivation), corresponding to the 2 motives. Both groups evaluated (in randomized order) 2 excerpts of the program-one that matched their motive (fit) and one that was contrary to it (no fit). Immediately after the evaluation of each excerpt, anticipated adherence, working alliance, and treatment satisfaction were assessed. RESULTS: Regarding being supported, the satisfaction with or violation of this motive had an impact on (optimal) anticipated adherence as well as working alliance and satisfaction with the intervention; a congruent person-program fit resulted in significantly higher anticipated adherence (t27=3.00; P=.006), working alliance (t27=3.20; P=.003), and satisfaction (t27=2.86; P=.008) than a noncongruent fit. However, a similar impact could not be found for the motive being autonomous. Several correlations were found that supported our hypotheses (eg, for the congruent person-program fit autonomy motive and autonomy group, support satisfaction negatively correlated with optimal anticipated adherence). CONCLUSIONS: This first experimental study gives reason to assume that motive orientation may have a positive influence on adherence, working alliance, and satisfaction in internet-based self-help interventions for depression and other mental disorders. Future studies should conduct randomized controlled trials with clinical samples and assess clinical outcomes.

Emergence and assessment of interpersonal experience and behavior in a nonverbal, generative, game-like paradigm.

Dominance, hostility and autonomy are interpersonal phenomena that emerge from the complex dyadic interplay of two individuals reciprocally influencing each other. Assessing the complexity of interpersonal interactions usually involves its reduction, for example with self-report and observer-rated measures informed by the structural analysis of social behavior (SASB). In contrast, letting individuals generate a complex stream of interpersonal experience and behavior from moment to moment is an empirical approach not yet usual in interpersonal theory. In the present study, we developed and evaluated an interpersonal, generative paradigm that allows participants to interact nonverbally and spontaneously with a computer-controlled other player in real-time without the need for introspection or the capacity to verbalize potentially implicit interpersonal processes. In the game-like paradigm, participants use the keyboard to take over objects such as a handcar to move autonomously around and encounter interfering or freedom granting artificial other players. We expected that participants (1) experience the nonverbal so-called game mechanics of the paradigm as interpersonal in nature, (2) behave towards the other players in an interpersonally complementary way, and (3) are influenced by their own trait interpersonal expectations. During the paradigm, 40 participants appraised the majority of the game mechanics and computer-controlled other players as intended. Also, interpersonal traits affected the spontaneous behavior towards artificial characters. These findings corroborate the feasibility and validity of a generative assessment of interpersonal dynamics beyond self-reports and observer ratings. The paradigm paves the way for the empirical testing of formal, computational models of dyadic interaction.

Insight and the number of completed modules predict a reduction of positive symptoms in an Internet-based intervention for people with psychosis.

Emerging evidence suggests that Internet-based interventions for people with psychosis (ICBTp) are feasible and efficacious. However, predictors of adherence and treatment outcomes are largely unknown. To narrow this research gap, we conducted secondary analyses on data from a randomized controlled trial, which evaluated an eight-week ICBTp intervention targeting topics, such as voice hearing, mindfulness, and others. In n = 100 participants with psychosis, we aimed at identifying sociodemographic, psychopathological, and treatment-related predictor variables of post-treatment symptoms and adherence (i.e., at least four completed modules). We followed a two-stage approach. First, we conducted regression analyses to examine the effect of single candidate predictors on post-treatment symptoms as well as adherence. Subsequently, we selected variables that met a significance threshold of p < .1 and entered them into linear and logistic multiple regression models. Whereas no variable was able to predict adherence, the number of completed modules was negatively associated with self-reported delusion severity at post-treatment. Additionally, higher pre-treatment insight predicted fewer hallucinations after treatment. Because this was one of the first studies to investigate predictors in ICBTp, more research is needed to customize future interventions to the needs of users.

Cdc4 phospho-degrons allow differential regulation of Ame1CENP-U protein stability across the cell cycle.

Kinetochores are multi-subunit protein assemblies that link chromosomes to microtubules of the mitotic and meiotic spindle. It is still poorly understood how efficient, centromere-dependent kinetochore assembly is accomplished from hundreds of individual protein building blocks in a cell cycle-dependent manner. Here, by combining comprehensive phosphorylation analysis of native Ctf19CCAN subunits with biochemical and functional assays in the model system budding yeast, we demonstrate that Cdk1 phosphorylation activates phospho-degrons on the essential subunit Ame1CENP-U, which are recognized by the E3 ubiquitin ligase complex SCF-Cdc4. Gradual phosphorylation of degron motifs culminates in M-phase and targets the protein for degradation. Binding of the Mtw1Mis12 complex shields the proximal phospho-degron, protecting kinetochore-bound Ame1 from the degradation machinery. Artificially increasing degron strength partially suppresses the temperature sensitivity of a cdc4 mutant, while overexpression of Ame1-Okp1 is toxic in SCF mutants, demonstrating the physiological importance of this mechanism. We propose that phospho-regulated clearance of excess CCAN subunits facilitates efficient centromere-dependent kinetochore assembly. Our results suggest a novel strategy for how phospho-degrons can be used to regulate the assembly of multi-subunit complexes.

Phospho-regulated Bim1/EB1 interactions trigger Dam1c ring assembly at the budding yeast outer kinetochore.

Kinetochores form the link between chromosomes and microtubules of the mitotic spindle. The heterodecameric Dam1 complex (Dam1c) is a major component of the Saccharomyces cerevisiae outer kinetochore, assembling into 3 MDa-sized microtubule-embracing rings, but how ring assembly is specifically initiated in vivo remains to be understood. Here, we describe a molecular pathway that provides local control of ring assembly during the establishment of sister kinetochore bi-orientation. We show that Dam1c and the general microtubule plus end-associated protein (+TIP) Bim1/EB1 form a stable complex depending on a conserved motif in the Duo1 subunit of Dam1c. EM analyses reveal that Bim1 crosslinks protrusion domains of adjacent Dam1c heterodecamers and promotes the formation of oligomers with defined curvature. Disruption of the Dam1c-Bim1 interaction impairs kinetochore localization of Dam1c in metaphase and delays mitosis. Phosphorylation promotes Dam1c-Bim1 binding by relieving an intramolecular inhibition of the Dam1 C-terminus. In addition, Bim1 recruits Bik1/CLIP-170 to Dam1c and induces formation of full rings even in the absence of microtubules. Our data help to explain how new kinetochore end-on attachments are formed during the process of attachment error correction.

A randomized controlled trial on a self-guided Internet-based intervention for gambling problems.

The majority of individuals with problematic and pathological gambling remain untreated, and treatment barriers are high. Internet-based interventions can help to address existing barriers, and first studies suggest their potential for this target group. Within a randomized controlled trial (N = 150) with two assessment times (baseline and post-intervention), we aimed to investigate the feasibility, acceptance, and effectiveness of a self-guided Internet-based intervention targeted at gambling problems. We expected a significant reduction in gambling symptoms (primary outcome) and depressive symptoms as well gambling-specific dysfunctional thoughts (secondary outcomes) in the intervention group (IG) compared to a wait-list control group with access to treatment-as-usual (control group, CG) after the intervention period of 8 weeks. Results of the complete cases, per protocol, intention-to-treat (ITT), and frequent user analyses showed significant improvements in both groups for primary and secondary outcomes but no significant between-group differences (ITT primary outcome, F(1,147) = .11, p = .739, ηp2 < .001). Moderation analyses indicated that individuals in the IG with higher gambling and depressive symptoms, older age, and comorbid anxiety symptoms showed significant improvement relative to the CG. The intervention was positively evaluated (e.g., 96.5% rated the program as useful). Possible reasons for the nonsignificant between-group differences are discussed. Future studies should include follow-up assessments and larger samples to address limitations of the present study. Trial Registration ClinicalTrials.gov (NCT03372226), http://clinicaltrials.gov/ct2/show/NCT03372226 , date of registration (13/12/2017).

Sleep problems and worrying precede psychotic symptoms during an online intervention for psychosis.

OBJECTIVE: Experience sampling assessments (multiple assessments per day for approximately one week) indicate that positive symptoms fluctuate over time in psychosis. Precursors, such as sleep problems or worrying, predict these fluctuations. To date, it remains unclear whether the same precursors predict symptom variability also during treatment in an online intervention for psychosis, using assessments lying temporally further apart. METHODS: Participants completed brief intermediate online self-report assessments on their computers (up to every 7 days during a 2-month waiting period and up to twice every 6 days during a 2-month intervention period) within a randomized controlled trial. We monitored the course of paranoia, auditory verbal hallucinations, and their theory-driven precursors worrying, negative affect, self-esteem, self-reported cognitive biases, and quality of sleep in n = 124 participants (M = 10.32 assessments per participant; SD = 6.07). We tested group differences regarding the course of the composite of precursors, group differences regarding the effect of the composite on subsequent momentary psychotic symptoms, and the effect of each individual precursor on subsequent psychotic symptoms, using (lagged) linear mixed models. RESULTS: The course composite precursors over time and their lagged effect on subsequent momentary psychotic symptoms did not differ between groups. During the intervention, increased worrying and decreased quality of sleep preceded heightened momentary psychotic symptoms. CONCLUSION: The regression-based design does not allow drawing causal conclusions. However, worrying and sleep problems likely represent underlying mechanisms of psychotic symptom variability during online psychosis treatment, indicating that experience sampling findings from everyday life generalize to interventions with assessments lying several days apart. PRACTITIONER POINTS: Worrying and sleep problems represent important mechanisms of symptom fluctuations during an online intervention for people with psychosis. Our findings further support the notion that worrying and sleep problems are important treatment targets in psychological interventions for people with psychosis. Momentary levels of worrying and quality of sleep can signal subsequent fluctuations of psychotic symptom severity so practitioners should monitor these variables during treatment. Worrying seems to predict subsequent paranoia specifically during treatment whereas quality of sleep predicts both paranoia and auditory verbal hallucinations.

Unguided Internet-based cognitive-behavioral therapy for obsessive-compulsive disorder: A randomized controlled trial.

BACKGROUND: Many individuals with obsessive-compulsive disorder (OCD) do not receive professional treatment due to various idiosyncratic barriers. Internet-based cognitive-behavioral therapy (iCBT) is increasingly used to narrow treatment gaps, but the efficacy of such interventions without guidance of therapists has not been well studied. This study evaluated the efficacy of an unguided iCBT that includes third-wave approaches for the treatment of OCD symptoms. METHODS: A total of 128 individuals with self-reported OCD symptoms were randomly allocated to either an intervention group (unguided iCBT) or to a care-as-usual (CAU) control group following an anonymous baseline assessment via an online survey. Eight weeks after inclusion, a reassessment was carried out online. The Yale-Brown Obsessive-Compulsive Scale served as the primary outcome parameter for detecting symptom changes in the per-protocol sample with at least 60 minutes utilization. RESULTS: The iCBT group showed a significantly stronger reduction of OCD symptoms with a medium effect size (η²p = 0.06) compared with the control condition. This effect was moderated by the general frequency of Internet usage (η²p = 0.08); the more time per day users spent online, the less they benefited from the intervention. Secondary outcomes revealed (1) a medium effect size on self-esteem (η²p = 0.06); (2) no statistically significant effects on quality of life, depression symptoms, impulsivity, or social insecurity; and (3) good acceptability of the intervention. CONCLUSIONS: The current study provides evidence that unguided iCBT for OCD may be a viable option for individuals who experience treatment barriers. As non-compliance remains a challenge, this topic needs further research.

The EB1-Kinesin-14 complex is required for efficient metaphase spindle assembly and kinetochore bi-orientation.

Kinesin-14s are conserved molecular motors required for high-fidelity chromosome segregation, but their specific contributions to spindle function have not been fully defined. Here, we show that key functions of budding yeast Kinesin-14 Cik1-Kar3 are accomplished in a complex with Bim1 (yeast EB1). Genetic complementation of mitotic phenotypes identifies a novel KLTF peptide motif in the Cik1 N-terminus. We show that this motif is one element of a tripartite binding interface required to form a high-affinity Bim1-Cik1-Kar3 complex. Lack of Bim1-binding by Cik1-Kar3 delays cells in mitosis and impairs microtubule bundle organization and dynamics. Conversely, constitutive targeting of Cik1-Kar3 to microtubule plus ends induces the formation of nuclear microtubule bundles. Cells lacking the Bim1-Cik1-Kar3 complex rely on the conserved microtubule bundler Ase1/PRC1 for metaphase spindle organization, and simultaneous loss of plus-end targeted Kar3 and Ase1 is lethal. Our results reveal the contributions of an EB1-Kinesin-14 complex for spindle formation as a prerequisite for efficient kinetochore clustering and bi-orientation.

Selective suppression of rapid eye movement sleep increases next-day negative affect and amygdala responses to social exclusion.

Healthy sleep, positive general affect, and the ability to regulate emotional experiences are fundamental for well-being. In contrast, various mental disorders are associated with altered rapid eye movement (REM) sleep, negative affect, and diminished emotion regulation abilities. However, the neural processes mediating the relationship between these different phenomena are still not fully understood. In the present study of 42 healthy volunteers, we investigated the effects of selective REM sleep suppression (REMS) on general affect, as well as on feelings of social exclusion, cognitive reappraisal (CRA) of emotions, and their neural underpinnings. Using functional magnetic resonance imaging we show that, on the morning following sleep suppression, REMS increases general negative affect, enhances amygdala responses and alters its functional connectivity with anterior cingulate cortex during passively experienced experimental social exclusion. However, we did not find effects of REMS on subjective emotional ratings in response to social exclusion, their regulation using CRA, nor on functional amygdala connectivity while participants employed CRA. Our study supports the notion that REM sleep is important for affective processes, but emphasizes the need for future research to systematically investigate how REMS impacts different domains of affective experience and their neural correlates, in both healthy and (sub-)clinical populations.

Internet-based self-help for psychosis: Findings from a randomized controlled trial.

OBJECTIVE: Cognitive-behavioral therapy (CBT) for psychosis is recommended in many national guidelines, but dissemination into routine health care remains poor. This study tests whether an 8-week, CBT-oriented, Internet-based intervention (IBI) for people with psychosis is feasible, effective, and safe compared to care as usual. METHOD: A sample of 101 people diagnosed with schizophrenia-spectrum disorders (age: M = 40.0, SD = 9.60; sex: 58% female) was randomly assigned to either an IBI for psychosis or a wait-list control condition. The primary outcome was a composite score of the positive factor of the Positive and Negative Syndrome Scale, the Launay Slade Hallucination Scale, and the paranoia checklist (clinicaltrials.gov, NCT02974400). RESULTS: The composite score of psychotic symptom severity decreased more in the IBI condition than in the wait-list condition, reflected in the significant interaction of Time × Condition, F(1, 87.28) = 4.04, p = .047, dbetween = 0.24, 95% CI [-0.15, 0.63]. In the combined sample of participants who received immediate or delayed access to the intervention, the outcome improved further during the 6-month follow up period with a significant main effect of time, F(1, 69.35) = 9.59, p = .003, d = -0.37, 95% CI [-0.66, -0.07]. Participants were satisfied with the intervention (89%), and many used the intervention as defined per protocol (52%; at least four completed modules). Adverse events were infrequent (4.9%). CONCLUSIONS: Internet-based, CBT-oriented interventions provide an add-on effect to care as usual and have the potential to narrow the psychological treatment gap in psychosis. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Prolonged rather than hasty decision-making in schizophrenia using the box task. Must we rethink the jumping to conclusions account of paranoia?

Jumping to conclusions (JTC) is the best established cognitive bias in schizophrenia and is increasingly targeted in interventions aimed to improve positive symptoms. To address shortcomings of the standard measure to capture JTC, the beads task, we developed a new variant-the box task-which was subsequently validated in people with elevated psychotic-like experiences. For the first time, the box task was administered in a sample of individuals with manifest schizophrenia. We hypothesized that patients with schizophrenia would display an elevated JTC bias relative to controls. METHOD: We recruited a large sample of 101 patients with schizophrenia and matched them to an online sample recruited from the general population. In the box task, participants must decide which of two kinds of colored balls are presented more often. Participants are told that the task may end prematurely, and that task performance will be counted as an error if no decision had been made before that point. The primary measure was the number of draws to decision (DTD), where fewer DTD corresponds to greater JTC. RESULTS: In contrast to expectations, participants with schizophrenia showed significantly higher DTD (i.e., reduced JTC). Consistent with our previous findings, patients also displayed a lowered decision threshold compared to controls. Response confidence for the final decision was lower in patients and correlated with self-esteem and positive symptoms. While there was evidence that previous knowledge of the box task lowered DTD, exclusion of participants with experience on the box task did not substantially change results. DISCUSSION: The study fits a growing body of experiments casting doubt on the generalizability of the JTC effect in schizophrenia across different tasks. While the study tentatively supports a liberal acceptance account of psychosis, caution is warranted and we recommend that research should explore and control for potentially important mediators (e.g., task difficulty, stress, test-taking attitudes).

Auto-inhibition of Mif2/CENP-C ensures centromere-dependent kinetochore assembly in budding yeast.

Kinetochores are chromatin-bound multi-protein complexes that allow high-fidelity chromosome segregation during mitosis and meiosis. Kinetochore assembly is exclusively initiated at chromatin containing Cse4/CENP-A nucleosomes. The molecular mechanisms ensuring that subcomplexes assemble efficiently into kinetochores only at centromeres, but not anywhere else, are incompletely understood. Here, we combine biochemical and genetic experiments to demonstrate that auto-inhibition of the conserved kinetochore subunit Mif2/CENP-C contributes to preventing unscheduled kinetochore assembly in budding yeast cells. We show that wild-type Mif2 is attenuated in its ability to bind a key downstream component in the assembly pathway, the Mtw1 complex, and that addition of Cse4 nucleosomes overcomes this inhibition. By exchanging the N-terminus of Mif2 with its functional counterpart from Ame1/CENP-U, we have created a Mif2 mutant which bypasses the Cse4 requirement for Mtw1 binding in vitro, thereby shortcutting kinetochore assembly. Expression of this Mif2 mutant in cells leads to mis-localization of the Mtw1 complex and causes pronounced chromosome segregation defects. We propose that auto-inhibition of Mif2/CENP-C constitutes a key concept underlying the molecular logic of kinetochore assembly.

Mindfulness Mediates the Effect of a Psychological Online Intervention for Psychosis on Self-Reported Hallucinations: A Secondary Analysis of Voice Hearers From the EviBaS Trial.

BACKGROUND: Psychological online interventions (POIs) could represent a promising approach to narrow the treatment gap in psychosis but it remains unclear whether improving mindfulness functions as a mechanism of change in POIs. For the present study, we examined if mindfulness mediates the effect of a comprehensive POI on distressing (auditory) hallucinations. METHODS: We conducted a secondary analysis on voice hearers (n = 55) from a randomized controlled trial evaluating a POI for psychosis (EviBaS; trial registration NCT02974400, clinicaltrials.gov). The POI includes a module on mindfulness and we only considered POI participants in our analyses who completed the mindfulness module (n = 16). RESULTS: Participants who completed the mindfulness module reported higher mindfulness (p = 0.015) and lower hallucinations (p = 0.001) at post assessment, compared to controls, but there was no effect on distress by voices (p = 0.598). Mindfulness mediated the POI's effect on hallucinations (b = -1.618, LLCI = -3.747, ULCI = -0.054) but not on distress by voices (b = -0.057, LLCI = -0.640, ULCI = 0.915). LIMITATIONS AND DISCUSSION: Completion of the mindfulness module was not randomized. Hence, we cannot draw causal inferences. Even if we assumed causality, it remains unclear which contents of the POI could have resulted in increased mindfulness and reduced hallucinations, as participants completed other modules as well. In addition, confounding variables could explain the mediation and the sample size was small. Nonetheless, the overall pattern of results indicates that the POI is likely to improve mindfulness, and that increased mindfulness could partially explain the POI's efficacy.

Brief Web-Based Intervention for Depression: Randomized Controlled Trial on Behavioral Activation.

BACKGROUND: Web-based interventions have been shown to be effective for the treatment of depression. However, interventions are often complex and include a variety of elements, making it difficult to identify the most effective component(s). OBJECTIVE: The aim of this pilot study was to shed light on mechanisms in the online treatment of depression by comparing a single-module, fully automated intervention for depression (internet-based behavioral activation [iBA]) to a nonoverlapping active control intervention and a nonactive control group. METHODS: We assessed 104 people with at least mild depressive symptoms (Patient Health Questionnaire-9, >4) via the internet at baseline (t0) and 2 weeks (t1) and 4 weeks (t2) later. After the t0 assessment, participants were randomly allocated to one of three groups: (1) iBA (n=37), (2) active control using a brief internet-based mindfulness intervention (iMBI, n=32), or (3) care as usual (CAU, n=35). The primary outcome was improvement in depressive symptoms, as measured using the Patient Health Questionnaire-9. Secondary parameters included changes in activity, dysfunctional attitudes, and quality of life. RESULTS: While groups did not differ regarding the change in depression from t0 to t1 (ηp2=.007, P=.746) or t0 to t2 (ηp2=.008, P=.735), iBA was associated with a larger decrease in dysfunctional attitudes from t0 to t2 in comparison to CAU (ηp2=.053, P=.04) and a larger increase in activity from t0 to t1 than the pooled control groups (ηp2=.060, P=.02). A change in depression from t0 to t2 was mediated by a change in activity from t0 to t1. At t1, 22% (6/27) of the participants in the iBA group and 12% (3/25) of the participants in the iMBI group indicated that they did not use the intervention. CONCLUSIONS: Although we did not find support for the short-term efficacy of the single-module iBA regarding depression, long-term effects are still conceivable, potentially initiated by changes in secondary outcomes. Future studies should use a longer intervention and follow-up interval. TRIAL REGISTRATION: DKRS (#DRKS00011562).