The temporal association between social isolation, distress, and psychotic experiences in individuals at clinical high-risk for psychosis.

BACKGROUND: Psychotic experiences (PEs) and social isolation (SI) seem related during early stages of psychosis, but the temporal dynamics between the two are not clear. Literature so far suggests a self-perpetuating cycle wherein momentary increases in PEs lead to social withdrawal, which, subsequently, triggers PEs at a next point in time, especially when SI is associated with increased distress. The current study investigated the daily-life temporal associations between SI and PEs, as well as the role of SI-related and general affective distress in individuals at clinical high risk (CHR) for psychosis. METHODS: We used experience sampling methodology in a sample of 137 CHR participants. We analyzed the association between SI, PEs, and distress using time-lagged linear mixed-effects models. RESULTS: SI did not predict next-moment fluctuations in PEs, or vice versa. Furthermore, although SI-related distress was not predictive of subsequent PEs, general affective distress during SI was a robust predictor of next-moment PEs. CONCLUSIONS: Our results suggest that SI and PEs are not directly related on a moment-to-moment level, but a negative emotional state when alone does contribute to the risk of PEs. These findings highlight the role of affective wellbeing during early-stage psychosis development.

Longitudinal clinical and functional outcome in distinct cognitive subgroups of first-episode psychosis: a cluster analysis.

BACKGROUND: Cognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes. METHODS: 204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up. RESULTS: Three distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition (n = 76), one moderately impaired cluster (n = 74) and one severely impaired cluster (n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present. CONCLUSIONS: Current results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes.

The bumpy road of trauma-focused treatment: Posttraumatic stress disorder symptom exacerbation in people with psychosis.

Concern for symptom exacerbation and treatment drop-out is an important barrier to the implementation of trauma-focused therapy (TFT), especially in people with a psychotic disorder. This study, which was part of a multicenter randomized controlled trial, investigated posttraumatic stress disorder (PTSD) symptom exacerbation during eye movement desensitization reprocessing (EMDR) therapy and prolonged exposure (PE) in a sample of 99 participants with PTSD and psychosis. Symptom exacerbations during the first four sessions (early exacerbation) and between-session exacerbations over the course of therapy were monitored using the PTSD Symptom Scale-Self Report. Analyses of covariance and chi-square tests were conducted to investigate exacerbation rates and their associations with treatment response and drop-out. Both early exacerbation and between-session exacerbation were relatively common (32.3% and 46.5%, respectively) but were unrelated to poor treatment response or an increased likelihood of treatment drop-out. Both clinicians and patients need to be aware that symptom exacerbation during TFT is common and not related to poor outcomes. Symptom exacerbation can be part of the therapeutic process, should be acknowledged and guided, and should not be a barrier to the implementation of TFT in people with psychosis.

Emotional and non-emotional mental imagery and auditory verbal hallucinations (hearing voices): A systematic review of imagery assessment tools.

It is unknown to what extent mental imagery and auditory verbal hallucinations (AVHs) are related. Trials evaluating this issue used both emotional and non-emotional mental imagery tools, thereby complicating outcomes comparisons. Therefore, the present study aimed to systematically review the literature on mental imagery in individuals with AVHs to (1) inventory imagery assessment tools used in this population, (2) to collect information on the relation between emotional and non-emotional mental imagery in all sensory domains and AVHs and (3) to integrate the outcomes of this systematic review in a model of different mental imagery domains and related assessment tools. We conducted a systematic literature search in the PubMed Database. After full-text screening, 17 papers were included. Findings showed that a variety of assessment methods have been used to assess various aspects of mental imagery in people with AVHs, suggesting that there is a lack of agreed theoretical conceptualization of mental imagery and AVHs. In addition, the studies confirmed as was expected that non-emotional mental imagery seemed unrelated to AVHs whereas emotional mental imagery was related to AVHs. Lastly, we proposed a model of mental imagery domains and corresponding assessment methods distinguishing between emotional and non-emotional mental imagery.

Efficacy of Acceptance and Commitment Therapy in Daily Life in Early Psychosis: Results from the Multi-Center INTERACT Randomized Controlled Trial.

INTRODUCTION/OBJECTIVE: This study aimed to investigate efficacy of Acceptance and Commitment Therapy in Daily Life (ACT-DL), combining face-to-face therapy with an Ecological Momentary Intervention (EMI), in addition to treatment as usual (TAU) for psychotic distress, in comparison to TAU. METHODS: Individuals aged 15-65 years with clinically established ultra-high risk or first episode of psychosis were randomly assigned to TAU or ACT-DL+TAU. ACT-DL+TAU consisted of 8 ACT-sessions augmented with an EMI-app. The primary outcome was psychotic distress assessed with the Comprehensive Assessment scale of At Risk Mental State (CAARMS) at post-intervention and 6- and 12-month follow-up. Secondary outcomes were functioning, symptom severity, and momentary psychotic distress. We performed multivariate mixed models according to intent-to-treat principles. RESULTS: Between June 1, 2015 and December 31, 2018, 668 participants were referred, of whom 148 were randomized to ACT-DL+TAU (n = 71) or TAU (n = 77). One hundred and fifteen (78%) provided primary outcome data at least at one follow-up assessment. There was no evidence of greater reduction in the primary outcome measure CAARMS distress in ACT-DL+TAU compared to TAU (χ2(3) = 2.36; p = 0.50). However, out of the tested secondary outcomes, global functioning (χ2(3) = 9.05; p = 0.033), and negative symptoms (χ2(3) = 19.91; p<0.001) improved in ACT-DL+TAU compared to TAU, as did momentary psychotic distress (χ2(3) = 21.56; p < 0.001). CONCLUSIONS: INTERACT did not support a significant effect of ACT-DL over TAU on the primary outcome measure of psychotic distress as assessed with the CAARMS. Although significant improvements were found for some secondary outcome measures, further replication studies are needed to confirm the strength and specificity of these effects.

Home alone: Social functioning as a transdiagnostic marker of mental health in youth, exploring retrospective and daily life measurements.

PURPOSE: Early detection and intervention of mental health problems in youth are topical given that mental disorders often start early in life. Young people with emerging mental disorders however, often present with non-specific, fluctuating symptoms. Recent reports indicate a decline in social functioning (SF) as an early sign of specific emerging mental disorders such as depression or anxiety, making SF a favorable transdiagnostic approach for earlier detection and intervention. Our aim was to investigate the value of SF in relation to transdiagnostic symptoms, and as a predictor of psychopathology over time, while exploring traditional retrospective versus innovative daily diary measurements of SF in youth. METHOD: Participants (N = 75) were 16-25 years of age and presented early stage psychiatric symptomatology. Psychiatric symptoms, including anxiety and depression, as well as SF -both in retrospect and in daily life- were assessed at two time points and analyzed cross-sectionally and longitudinally. RESULTS: A significant and negative association between SF and all psychiatric symptoms was found, and SF was a significant predictor of change in general psychiatric symptoms over time. Results were only significant when SF was measured traditionally retrospective. CONCLUSION: This study confirms a distinct relation between SF and transdiagnostic psychiatric symptoms in youth, even in a (sub)clinical population, and points towards SF as a predictor of transdiagnostic psychiatric symptoms. Further research is needed to learn more about the added value of daily life versus retrospective measurements.

Exploring the autism spectrum: Moderating effects of neuroticism on stress reactivity and on the association between social context and negative affect.

Neuroticism is associated with increased stress reactivity. In autism spectrum disorders (ASD), emotional stress reactivity is increased and there is some evidence for an increased negative affect (NA) when with less familiar people. The aim of this study was to compare adults with ASD and controls on levels of neuroticism and on interactions between neuroticism and appraised stress or social context in models of NA. This is a cross-sectional observational study comprising a group of 50 adults with ASD and 51 controls. Experience sampling method (ESM) reports were collected for 10 days to measure daily life stress, mood, and social context. Multilevel regression analyses revealed significantly higher neuroticism levels in ASD than in controls. Adults with ASD who scored high on neuroticism showed a significantly stronger association between activity/social stress and NA (i.e., higher stress reactivity) than those with low scores. Furthermore, the association between neuroticism and NA was stronger when adults with ASD were with less familiar people compared with being alone or with familiar people. No consistent corresponding significant interactions were found in the control group. In conclusion, in ASD, neuroticism moderates the association between appraised stress and NA as well as the association between social context and NA.

Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia-related genes.

Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case-control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case-control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia.

Integrating machining learning and multimodal neuroimaging to detect schizophrenia at the level of the individual.

Schizophrenia is a severe psychiatric disorder associated with both structural and functional brain abnormalities. In the past few years, there has been growing interest in the application of machine learning techniques to neuroimaging data for the diagnostic and prognostic assessment of this disorder. However, the vast majority of studies published so far have used either structural or functional neuroimaging data, without accounting for the multimodal nature of the disorder. Structural MRI and resting-state functional MRI data were acquired from a total of 295 patients with schizophrenia and 452 healthy controls at five research centers. We extracted features from the data including gray matter volume, white matter volume, amplitude of low-frequency fluctuation, regional homogeneity and two connectome-wide based metrics: structural covariance matrices and functional connectivity matrices. A support vector machine classifier was trained on each dataset separately to distinguish the subjects at individual level using each of the single feature as well as their combination, and 10-fold cross-validation was used to assess the performance of the model. Functional data allow higher accuracy of classification than structural data (mean 82.75% vs. 75.84%). Within each modality, the combination of images and matrices improves performance, resulting in mean accuracies of 81.63% for structural data and 87.59% for functional data. The use of all combined structural and functional measures allows the highest accuracy of classification (90.83%). We conclude that combining multimodal measures within a single model is a promising direction for developing biologically informed diagnostic tools in schizophrenia.

Detecting schizophrenia at the level of the individual: relative diagnostic value of whole-brain images, connectome-wide functional connectivity and graph-based metrics.

BACKGROUND: Previous studies using resting-state functional neuroimaging have revealed alterations in whole-brain images, connectome-wide functional connectivity and graph-based metrics in groups of patients with schizophrenia relative to groups of healthy controls. However, it is unclear which of these measures best captures the neural correlates of this disorder at the level of the individual patient. METHODS: Here we investigated the relative diagnostic value of these measures. A total of 295 patients with schizophrenia and 452 healthy controls were investigated using resting-state functional Magnetic Resonance Imaging at five research centres. Connectome-wide functional networks were constructed by thresholding correlation matrices of 90 brain regions, and their topological properties were analyzed using graph theory-based methods. Single-subject classification was performed using three machine learning (ML) approaches associated with varying degrees of complexity and abstraction, namely logistic regression, support vector machine and deep learning technology. RESULTS: Connectome-wide functional connectivity allowed single-subject classification of patients and controls with higher accuracy (average: 81%) than both whole-brain images (average: 53%) and graph-based metrics (average: 69%). Classification based on connectome-wide functional connectivity was driven by a distributed bilateral network including the thalamus and temporal regions. CONCLUSION: These results were replicated across the three employed ML approaches. Connectome-wide functional connectivity permits differentiation of patients with schizophrenia from healthy controls at single-subject level with greater accuracy; this pattern of results is consistent with the 'dysconnectivity hypothesis' of schizophrenia, which states that the neural basis of the disorder is best understood in terms of system-level functional connectivity alterations.

Childhood trauma- and cannabis-associated microstructural white matter changes in patients with psychotic disorder: a longitudinal family-based diffusion imaging study.

BACKGROUND: Decreased white matter (WM) integrity in patients with psychotic disorder has been a consistent finding in diffusion tensor imaging (DTI) studies. However, the contribution of environmental risk factors to these WM alterations is rarely investigated. The current study examines whether individuals with (increased risk for) psychotic disorder will show increased WM integrity change over time with increasing levels of childhood trauma and cannabis exposure. METHODS: DTI scans were obtained from 85 patients with a psychotic disorder, 93 non-psychotic siblings and 80 healthy controls, of which 60% were rescanned 3 years later. In a whole-brain voxel-based analysis, associations between change in fractional anisotropy (ΔFA) and environmental exposures as well as interactions between group and environmental exposure in the model of FA and ΔFA were investigated. Analyses were adjusted for a priori hypothesized confounding variables: age, sex, and level of education. RESULTS: At baseline, no significant associations were found between FA and both environmental risk factors. At follow-up as well as over a 3-year interval, significant interactions between group and, respectively, cannabis exposure and childhood trauma exposure in the model of FA and ΔFA were found. Patients showed more FA decrease over time compared with both controls and siblings when exposed to higher levels of cannabis or childhood trauma. CONCLUSIONS: Higher levels of cannabis or childhood trauma may compromise connectivity over the course of the illness in patients, but not in individuals at low or higher than average genetic risk for psychotic disorder, suggesting interactions between the environment and illness-related factors.

From laboratory to life: associating brain reward processing with real-life motivated behaviour and symptoms of depression in non-help-seeking young adults.

BACKGROUND: Depression has been associated with abnormalities in neural underpinnings of Reward Learning (RL). However, inconsistencies have emerged, possibly owing to medication effects. Additionally, it remains unclear how neural RL signals relate to real-life behaviour. The current study, therefore, examined neural RL signals in young, mildly to moderately depressed - but non-help-seeking and unmedicated - individuals and how these signals are associated with depressive symptoms and real-life motivated behaviour. METHODS: Individuals with symptoms along the depression continuum (n = 87) were recruited from the community. They performed an RL task during functional Magnetic Resonance Imaging and were assessed with the Experience Sampling Method (ESM), completing short questionnaires on emotions and behaviours up to 10 times/day for 15 days. Q-learning model-derived Reward Prediction Errors (RPEs) were examined in striatal areas, and subsequently associated with depressive symptoms and an ESM measure capturing (non-linearly) how anticipation of reward experience corresponds to actual reward experience later on. RESULTS: Significant RPE signals were found in the striatum, insula, amygdala, hippocampus, frontal and occipital cortices. Region-of-interest analyses revealed a significant association between RPE signals and (a) self-reported depressive symptoms in the right nucleus accumbens (b = -0.017, p = 0.006) and putamen (b = -0.013, p = .012); and (b) the quadratic ESM variable in the left (b = 0.010, p = .010) and right (b = 0.026, p = 0.011) nucleus accumbens and right putamen (b = 0.047, p < 0.001). CONCLUSIONS: Striatal RPE signals are disrupted along the depression continuum. Moreover, they are associated with reward-related behaviour in real-life, suggesting that real-life coupling of reward anticipation and engagement in rewarding activities might be a relevant target of psychological therapies for depression.

Neurobehavioural mechanisms of threat generalization moderate the link between childhood maltreatment and psychopathology in emerging adulthood

Background: Childhood maltreatment is a transdiagnostic risk factor for later psychopathology and has been associated with altered brain circuitry involved in the processing of threat and safety. Examining threat generalization mechanisms in young adults with childhood maltreatment and psychiatric symptoms may elucidate a pathway linking early-life adversities to the presence of subclinical psychopathology. Methods: We recruited youth aged 16­25 years with subclinical psychiatric symptomatology and healthy controls. They were dichotomized into 2 groups: 1 with a high level of childhood maltreatment (n = 58) and 1 with no or a low level of childhood maltreatment (n = 55). Participants underwent a functional MRI threat generalization paradigm, measuring self-reported fear, expectancy of an unconditioned stimulus (US) and neural responses. Results: We observed interactions between childhood maltreatment and threat generalization indices on subclinical symptom load. In individuals reporting high levels of childhood maltreatment, enhanced generalization in self-reported fear and US expectancy was related to higher levels of psychopathology. Imaging results revealed that in the group with high levels of childhood maltreatment, lower activation in the left hippocampus during threat generalization was associated with a higher symptom load. Associations between threat generalization and psychopathology were nonsignificant overall in the group with no or low levels of childhood maltreatment. Limitations: The data were acquired in a cross-sectional manner, precluding definitive insight into the causality of childhood maltreatment, threat generalization and psychopathology. Conclusion: Our results suggest that threat generalization mechanisms may moderate the link between childhood maltreatment and subclinical psychopathology during emerging adulthood. Threat generalization could represent a vulnerability factor for developing later psychopathology in individuals being exposed to childhood maltreatment.

The experience sampling method as an mHealth tool to support self-monitoring, self-insight, and personalized health care in clinical practice.

BACKGROUND: The experience sampling method (ESM) builds an intensive time series of experiences and contexts in the flow of daily life, typically consisting of around 70 reports, collected at 8-10 random time points per day over a period of up to 10 days. METHODS: With the advent of widespread smartphone use, ESM can be used in routine clinical practice. Multiple examples of ESM data collections across different patient groups and settings are shown and discussed, varying from an ESM evaluation of a 6-week randomized trial of mindfulness, to a twin study on emotion dynamics in daily life. RESULTS: Research shows that ESM-based self-monitoring and feedback can enhance resilience by strengthening the capacity to use natural rewards. Personalized trajectories of starting or stopping medication can be more easily initiated and predicted if sensitive feedback data are available in real time. In addition, personalized trajectories of symptoms, cognitive abilities, symptoms impacting on other symptoms, the capacity of the dynamic system of mental health to "bounce back" from disturbance, and patterns of environmental reactivity yield uniquely personal data to support shared decision making and prediction in clinical practice. Finally, ESM makes it possible to develop insight into previous implicit patterns of thought, experience, and behavior, particularly if rapid personalized feedback is available. CONCLUSIONS: ESM enhances clinical practice and research. It is empowering, providing co-ownership of the process of diagnosis, treatment evaluation, and routine outcome measurement. Blended care, based on a mix of face-to-face and ESM-based outside-the-office treatment, may reduce costs and improve outcomes.

Psychotic disorder and educational achievement: a family-based analysis.

BACKGROUND: Early social and cognitive alterations in psychotic disorder, associated with familial liability and environmental exposures, may contribute to lower than expected educational achievement. The aims of the present study were to investigate (1) how differences in educational level between parents and their children vary across patients, their healthy siblings, and healthy controls (effect familial liability), and across two environmental risk factors for psychotic disorder: childhood trauma and childhood urban exposure (effect environment) and (2) to what degree the association between familial liability and educational differential was moderated by the environmental exposures. METHODS: Patients with a diagnosis of non-affective psychotic disorder (n = 629), 552 non-psychotic siblings and 326 healthy controls from the Netherlands and Belgium were studied. Participants reported their highest level of education and that of their parents. Childhood trauma was assessed with the Dutch version of the Childhood Trauma Questionnaire-Short Form. Urban exposure, expressed as population density, was rated across five levels. RESULTS: Overall, participants had a higher level of education than their parents. This difference was significantly reduced in the patient group, and the healthy siblings displayed intergenerational differences that were in between those of controls and patients. Higher levels of childhood urban exposure were also associated with a smaller intergenerational educational differential. There was no evidence for differential sensitivity to childhood trauma and childhood urbanicity across the three groups. CONCLUSION: Intergenerational difference in educational achievements is decreased in patients with psychotic disorder and to a lesser extent in siblings of patients with psychotic disorder, and across higher levels of childhood urban exposure. More research is required to better understand the dynamics between early social and cognitive alterations in those at risk in relation to progress through the educational system and to understand the interaction between urban environment and educational outcomes.

The association between alterations in motor and cognitive dimensions of schizophrenia-spectrum disorders: A systematic review.

Motor and cognitive alterations in schizophrenia-spectrum disorders (SSD) share common neural underpinnings, highlighting the necessity for a thorough exploration of the connections between these areas. This relationship is crucial, as it holds potential significance in unraveling the underlying mechanisms of SSD pathophysiology, ultimately leading to advancements in clinical staging and treatment strategies. The purpose of this review was to characterize the relationship between different hyper and hypokinetic domains of motor alterations and cognition in SSD. We systematically searched the literature (PROSPERO protocol CRD42019145964) and selected 66 original scientific contributions for review, published between 1987 and 2022. A narrative synthesis of the results was conducted. Hyper and hypokinetic motor alterations showed weak to moderate negative correlations with cognitive function across different SSD stages, including before antipsychotic treatment. The literature to date shows a diverse set of methodologies and composite cognitive scores hampering a strong conclusion about which specific cognitive domains were more linked to each group of motor alterations. However, executive functions seemed the domain more consistently associated with parkinsonism with the results regarding dyskinesia being less clear. Akathisia and catatonia were scarcely discussed in the reviewed literature. The present review reinforces the intimate relationship between specific motor alterations and cognition. Identified gaps in the literature challenge the formulation of definitive conclusions. Nevertheless, a discussion of putative underlying mechanisms is included, prompting guidance for future research endeavors.

FKBP5 as a possible moderator of the psychosis-inducing effects of childhood trauma.

BACKGROUND: FK506 binding protein 5 (FKBP5) has repeatedly been shown to be a critical determinant of post-traumatic stress disorder (PTSD) and depression following childhood trauma. AIMS: To examine the role of FKBP5-trauma interactions in the partly stress-related psychosis phenotype. METHOD: In 401 general population twins, four functional polymorphisms were examined in models of psychosis and cortisol, and followed up in models of psychosis in three samples at different familial liability (175 controls, 200 unaffected siblings and 195 patients with a psychotic disorder). RESULTS: The most consistent finding was an interaction between childhood trauma and rs9296158/rs4713916 on psychotic symptoms and cortisol in the twin sample, combined with a directionally similar interaction in siblings (rs4713916) and patients (rs9296158), A-allele carriers at both polymorphisms being most vulnerable to trauma. CONCLUSIONS: Trauma may increase the risk of psychosis through enduring changes in the cortisol feedback loop, similar to that for PTSD, suggesting comparable biological mechanisms for psychosis across diagnostic boundaries.

The Direct and Long-Term Effects of Raloxifene as Adjunctive Treatment for Schizophrenia-Spectrum Disorders: A Double-Blind, Randomized Clinical Trial.

BACKGROUND AND HYPOTHESIS: Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum Disorders (SSD). We aimed to assess the effects of adjunctive raloxifene in women and men with SSD. STUDY DESIGN: This parallel, randomized, double-blind, placebo-controlled trial included adult SSD patients across the Netherlands and Belgium. Participants were stratified by age, sex, and global functioning and randomly assigned 1:1 to 12-week add-on raloxifene or placebo. Primary outcomes were symptom severity at 6, 12, and 38 weeks and cognition at 12 and 38 weeks, as measured with the Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia, respectively. Intention-to-treat analyses were performed using linear mixed-effect models. STUDY RESULTS: We assessed 261 patients for eligibility, of which 102 (28% female) were assigned to raloxifene (n = 52) or placebo (n = 48). Although we found no main effect of raloxifene, secondary sex-specific analysis showed that in women, raloxifene had beneficial effects on negative symptoms at week 6 (LSM -2.92; adjusted P = 0.020) and week 12 (LSM -3.12; adjusted P = 0.030), and on working memory at week 38 (LSM 0.73; adjusted P = 0.040), while having negative effects on working memory at week 38 in men (LSM -0.53; adjusted P = 0.026). The number of adverse events was similar between groups. CONCLUSIONS: Our results do not support the use of raloxifene in patients with SSD in general, but suggest female-specific beneficial effects of raloxifene on negative symptoms and working memory. Our findings encourage further research on sex-specific pharmacotherapeutic treatment.

Feedback based on experience sampling data: Examples of current approaches and considerations for future research.

Methodologies such as the Experience Sampling Method (ESM) or Ecological Momentary Assessment allow the gathering of fine-graded, dynamic, personal data within a patient's daily life. Currently, it is studied whether feedback based on experience sampling data (ESM-based feedback) can be used as a clinical tool to inform shared decision-making in clinical practice. Although the potential of feedback is recognized, little is known on how to generate, use, and implement it. This article (i) presents n = 15 ongoing ESM projects within the Belgian-Dutch network for ESM research wherein ESM-based feedback is provided to various patient populations, and (ii) summarizes qualitative data on experiences with ESM-based feedback of researchers (n = 8) with extensive expertise with ESM (average of 10 years) involved in these ongoing studies. The following aspects appear to be of relevance when providing ESM-based feedback: training for healthcare professionals and researchers, the use of online interfaces and graphical visualizations to present data, and interacting with patients in a face-to-face setting when discussing the contextual relevance and potential implications. Prospectively, research may build on these aspects and create coherent consensus-based guidelines for the use of ESM-based feedback.