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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.

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.

Prospective momentary psychological and biological measures of real-time daily life stress experiences have been examined in several psychiatric disorders, but not in adults with an autism spectrum disorder (ASD). The current electronic self-monitoring study examined associations between momentary daily life stressors and (i) negative affect (NA; emotional stress reactivity) and (ii) cortisol levels (biological stress reactivity) in males and females with ASD (N = 50) and without ASD (N = 51). The Experience Sampling Method, including saliva sampling, was used to measure three types of daily life stress (activity-related, event-related, and social stress), NA, and cortisol. Multilevel regression analyses demonstrated significant interactions between group and stress (i.e., activity-related and event-related stress) in the model of NA, indicating stronger emotional stress reactivity in the ASD than in the control group. In the model of cortisol, none of the group × stress interactions were significant. Male/female sex had no moderating effect on either emotional or biological stress reactivity. In conclusion, adults with ASD showed a stronger emotional stress (but not cortisol) reactivity in response to unpleasant daily life events and activities. The findings highlight the feasibility of electronic self-monitoring in individuals with ASD, which may contribute to the development of more personalized stress-management approaches.

FreeSurfer is a popular software package to measure cortical thickness and volume of neuroanatomical structures. However, little if any is known about measurement reliability across various data processing conditions. Using a set of 30 anatomical T1-weighted 3T MRI scans, we investigated the effects of data processing variables such as FreeSurfer version (v4.3.1, v4.5.0, and v5.0.0), workstation (Macintosh and Hewlett-Packard), and Macintosh operating system version (OSX 10.5 and OSX 10.6). Significant differences were revealed between FreeSurfer version v5.0.0 and the two earlier versions. These differences were on average 8.8 ± 6.6% (range 1.3-64.0%) (volume) and 2.8 ± 1.3% (1.1-7.7%) (cortical thickness). About a factor two smaller differences were detected between Macintosh and Hewlett-Packard workstations and between OSX 10.5 and OSX 10.6. The observed differences are similar in magnitude as effect sizes reported in accuracy evaluations and neurodegenerative studies.The main conclusion is that in the context of an ongoing study, users are discouraged to update to a new major release of either FreeSurfer or operating system or to switch to a different type of workstation without repeating the analysis; results thus give a quantitative support to successive recommendations stated by FreeSurfer developers over the years. Moreover, in view of the large and significant cross-version differences, it is concluded that formal assessment of the accuracy of FreeSurfer is desirable.

Extinction learning is assumed to represent a core mechanism underlying exposure therapy. Empirical evaluations of this assumption, however, are largely lacking. The current study investigated whether neural activations and self-report outcomes during extinction learning and extinction recall could specifically predict exposure therapy response in specific phobia. In this double-blind randomized controlled trial, individuals with spider phobia (N = 45; female/male = 41/4) were on group basis randomly allocated to exposure therapy (n = 25; female/male = 24/1) or progressive muscle relaxation (PMR; n = 20; female/male = 17/3). Intervention effects were measured with the Fears of Spiders questionnaire. Participants also underwent a three-day fear conditioning, extinction learning, and extinction recall paradigm during functional magnetic resonance imaging at baseline. Extinction outcomes were self-reported fear and threat expectancy, and neural responses during conditioned stimulus processing and during extinction-related prediction errors (US omissions) in regions of interest (ventromedial prefrontal cortex (vmPFC) and nucleus accumbens). Results showed that exposure therapy resulted in stronger symptom reductions than PMR (Cohen’s d = 0.90). Exposure therapy response was specifically predicted by prediction-error related vmPFC activation during early extinction. There were also indications vmPFC activations during conditioned safety stimulus processing at early extinction predicted therapy outcome. Neural activations during extinction recall and self-report data did however not predict therapy outcome. These findings indicate that exposure therapy may rely on neural extinction learning processes. Prediction errors are thought to drive the extinction learning process, and prediction error-related vmPFC activation specifically predicted therapy outcome. The extent to which vmPFC processes safety signals may additionally be predictive of exposure therapy response, but the specificity is less clear.

•We present Neuroharmony, a harmonization tool for images from unseen scanners.•We developed Neuroharmony using a total of 15,026 sMRI images.•The tool was able to reduce scanner-related bias from unseen scans.•Neuroharmony represents a significant step towards imaging-based clinical tools.•Neuroharmony is available at https://github.com/garciadias/Neuroharmony.

Abstract Background In psychosis spectrum disorders, maladaptive mental imagery is associated with auditory verbal hallucinations (AVHs). This study evaluates the feasibility, acceptability, and effectiveness of the following 4 imagery techniques in targeting mental imagery and AVHs severity: Imagery Rescripting (ImRs), Promoting positive Imagery de novo (Pos-Im), Metacognitive Imagery techniques (Meta-Im), and playing Tetris. Study Design Four replicated single-case series experimental designs were used. Participants were randomized to 1 of the 4 treatment conditions. Primary, we measured the severity of mental imagery and AVHs thrice daily on an 11-point VAS scale during a 2-week baseline, throughout 3 weeks of therapy, and during a 2-week follow-up phase. Randomization tests were used to examine whether daily severity levels of momentary mental imagery and AVHs decreased post-therapy. Secondary, questionnaires assessing the severity of AVHs, mental imagery characteristics, and levels of mood, anxiety, and functioning were administered at baseline, before, and posttreatment. Results Twenty-eight participants completed all treatment sessions. Mental imagery significantly decreased after ImRs (P < .001, d = 1.13) and Pos-Im (P = .039, d = 0.22), with no significant effects observed following Meta-Im or Tetris. AVHs significantly decreased with all treatment conditions, with largest effects for ImRs (P = .001, d = 1.39) and Pos-Im (P < .001, d = 1.99). Secondary results demonstrated reductions in the severity of AVHs, mood, anxiety, imagery frequency, and appraisals. Conclusions Imagery techniques appear feasible and acceptable for addressing mental imagery and AVHs in the psychosis continuum and may be valuable additions to current treatment for AVHs.

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. To examine the role of FKBP5-trauma interactions in the partly stress-related psychosis phenotype. 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). 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. 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.

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 We recruited youth aged 16–25 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. 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. The data were acquired in a cross-sectional manner, precluding definitive insight into the causality of childhood maltreatment, threat generalization and psychopathology. 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.

Research suggests that altered interregional connectivity in specific networks, such as the default mode network (DMN), is associated with cognitive and psychotic symptoms in schizophrenia. In addition, frontal and limbic connectivity alterations have been associated with trauma, drug use and urban upbringing, though these environmental exposures have never been examined in relation to DMN functional connectivity in psychotic disorder. Resting-state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 non-psychotic siblings of patients with psychotic disorder and 72 healthy controls. Posterior cingulate cortex (PCC) seed-based correlation analysis was used to estimate functional connectivity within the DMN. DMN functional connectivity was examined in relation to group (familial risk), group × environmental exposure (to cannabis, developmental trauma and urbanicity) and symptomatology. There was a significant association between group and PCC connectivity with the inferior parietal lobule (IPL), the precuneus (PCu) and the medial prefrontal cortex (MPFC). Compared to controls, patients and siblings had increased PCC connectivity with the IPL, PCu and MPFC. In the IPL and PCu, the functional connectivity of siblings was intermediate to that of controls and patients. No significant associations were found between DMN connectivity and (subclinical) psychotic/cognitive symptoms. In addition, there were no significant interactions between group and environmental exposures in the model of PCC functional connectivity. Increased functional connectivity in individuals with (increased risk for) psychotic disorder may reflect trait-related network alterations. The within-network \"connectivity at rest\" intermediate phenotype was not associated with (subclinical) psychotic or cognitive symptoms. The association between familial risk and DMN connectivity was not conditional on environmental exposure.