Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

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.

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study.

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6-52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen's d's ranging from -0.9 to -1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size.

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

White matter abnormalities in 22q11.2 deletion syndrome patients showing cognitive decline.

BACKGROUND: Decline in cognitive functioning precedes the first psychotic episode in the course of schizophrenia and is considered a hallmark symptom of the disorder. Given the low incidence of schizophrenia, it remains a challenge to investigate whether cognitive decline coincides with disease-related changes in brain structure, such as white matter abnormalities. The 22q11.2 deletion syndrome (22q11DS) is an appealing model in this context, as 25% of patients develop psychosis. Furthermore, we recently showed that cognitive decline also precedes the onset of psychosis in individuals with 22q11DS. Here, we investigate whether the early cognitive decline in patients with 22q11DS is associated with alterations in white matter microstructure. METHODS: We compared the fractional anisotropy (FA) of white matter in 22q11DS patients with cognitive decline [n = 16; -18.34 (15.8) VIQ percentile points over 6.80 (2.39) years] to 22q11DS patients without cognitive decline [n = 18; 17.71 (20.17) VIQ percentile points over 5.27 (2.03) years] by applying an atlas-based approach to diffusion-weighted imaging data. RESULTS: FA was significantly increased (p < 0.05, FDR) in 22q11DS patients with a cognitive decline in the bilateral superior longitudinal fasciculus, the bilateral cingulum bundle, all subcomponents of the left internal capsule and the left superior frontal-occipital fasciculus as compared with 22q11DS patients without cognitive decline. CONCLUSIONS: Within 22q11DS, the early cognitive decline is associated with microstructural differences in white matter. At the mean age of 17.8 years, these changes are reflected in increased FA in several tracts. We hypothesize that similar brain alterations associated with cognitive decline take place early in the trajectory of schizophrenia.

Personal recovery in first-episode psychosis: Beyond clinical and functional recovery.

BACKGROUND: The concept of personal recovery after psychotic illness focuses more on patients' social and existential needs compared to traditional outcome measures including clinical and functional recovery. This research aims to contribute to a broad framework on (personal) recovery and associated factors. METHODS: Data from 203 persons with symptomatic remission of their first-episode psychosis from the ongoing HAMLETT study were analyzed. To determine the relative importance of several biological, clinical, psychological, and social factors in explaining personal recovery as measured by the Recovery Assessment Scale (RAS), partial Spearman correlations (controlling for clinical recovery (PANSS) and functional recovery (WHODAS 2.0)) and a bootstrapped multiple regression were performed. Indirect effects on personal recovery within these factors, clinical recovery, and functional recovery were explored using a regularized partial correlation network. RESULTS: Of the factors that explained personal recovery beyond the effects of clinical and functional recovery, social support was the strongest predictor, followed by self-esteem, internalized stigma, and insecure attachment, collectively explaining 48.2 % of the variance. Anhedonia/apathy showed a trend towards a negative correlation. Age at onset, sex, early trauma/neglect, cognition, and being married/cohabiting did not significantly correlate with personal recovery. The network (n = 143) was consistent with these findings and indicated possible mediation pathways for early trauma/neglect, insecure attachment, cognition, and being married/cohabiting. CONCLUSIONS: Personal recovery is an important addition to traditional measures of outcome after psychosis. Various quality of life indicators, such as self-esteem and social support, explain variance in personal recovery over clinical and functional recovery.

Speech as a Biomarker for Depression.

BACKGROUND: Depression is a debilitating disorder that at present lacks a reliable biomarker to aid in diagnosis and early detection. Recent advances in computational analytic approaches have opened up new avenues in developing such a biomarker by taking advantage of the wealth of information that can be extracted from a person's speech. OBJECTIVE: The current review provides an overview of the latest findings in the rapidly evolving field of computational language analysis for the detection of depression. We cover a wide range of both acoustic and content-related linguistic features, data types (i.e., spoken and written language), and data sources (i.e., lab settings, social media, and smartphone-based). We put special focus on the current methodological advances with regard to feature extraction and computational modeling techniques. Furthermore, we pay attention to potential hurdles in the implementation of automatic speech analysis. CONCLUSION: Depressive speech is characterized by several anomalies, such as lower speech rate, less pitch variability and more self-referential speech. With current computational modeling techniques, such features can be used to detect depression with an accuracy of up to 91%. The performance of the models is optimized when machine learning techniques are implemented that suit the type and amount of data. Recent studies now work towards further optimization and generalizability of the computational language models to detect depression. Finally, privacy and ethical issues are of paramount importance to be addressed when automatic speech analysis techniques are further implemented in, for example, smartphones. Altogether, computational speech analysis is well underway towards becoming an effective diagnostic aid for depression.

Time varying dynamics of hallucinations in clinical and non-clinical voice-hearers.

Auditory verbal hallucinations (AVH) are frequently associated with psychotic disorders, yet also occur in non-clinical voice-hearers. AVH in this group are similar to those within clinical voice-hearers in terms of several phenomenological aspects, but non-clinical voice-hearers report to have more control over their AVH and attribute less emotional valence to them. These dissimilarities may stem from differences on the neurobiological level, as it is still under debate whether the mechanisms involved in AVH are the same in clinical and non-clinical voice-hearers. In this study, 21 clinical and 21 non-clinical voice-hearers indicated the onset and offsets of AVH during an fMRI scan. Using a method called leading eigenvector dynamics analysis (LEiDA), we examined time-varying dynamics of functional connectivity involved in AVH with a sub-second temporal resolution. We assessed differences between groups, and between hallucination and rest periods in dwell time, switching frequency, probability of occurrence, and transition probabilities of nine recurrent states of functional connectivity with a permutation ANOVA. Deviations in dwell times, switching frequencies, and switch probabilities in the hallucination period indicated more erratic dynamics during this condition regardless of their clinical status. Post-hoc analyses of the dwell times exhibited the most distinct differences between the rest and hallucination condition for the non-clinical sample, suggesting stronger differences between the two conditions in this group. Overall, these findings suggest that the neurobiological mechanisms involved in AVH are similar in clinical and non-clinical individuals.

Hallucinations in Hearing Impairment: How Informed Are Clinicians?

BACKGROUND AND HYPOTHESIS: Patients with hearing impairment (HI) may experience hearing sounds without external sources, ranging from random meaningless noises (tinnitus) to music and other auditory hallucinations (AHs) with meaningful qualities. To ensure appropriate assessment and management, clinicians need to be aware of these phenomena. However, sensory impairment studies have shown that such clinical awareness is low. STUDY DESIGN: An online survey was conducted investigating awareness of AHs among clinicians and their opinions about these hallucinations. STUDY RESULTS: In total, 125 clinicians (68.8% audiologists; 18.4% Ear-Nose-Throat [ENT] specialists) across 10 countries participated in the survey. The majority (96.8%) was at least slightly aware of AHs in HI. About 69.6% of participants reported encountering patients with AHs less than once every 6 months in their clinic. Awareness was significantly associated with clinicians' belief that patients feel anxious about their hallucinations (ß = .018, t(118) = 2.47, P < .01), their belief that clinicians should be more aware of these hallucinations (ß =.018, t(118) = 2.60, P < .01), and with confidence of clinicians in their skills to assess them (ß = .017, t(118) = 2.63, P < .01). Clinicians felt underequipped to treat AHs (Median = 31; U = 1838; PFDRadj < .01). CONCLUSIONS: Awareness of AHs among the surveyed clinicians was high. Yet, the low frequency of encounters with hallucinating patients and their belief in music as the most commonly perceived sound suggest unreported cases. Clinicians in this study expressed a lack of confidence regarding the assessment and treatment of AHs and welcome more information.

Natural Language Processing Markers for Psychosis and Other Psychiatric Disorders: Emerging Themes and Research Agenda From a Cross-Linguistic Workshop.

This workshop summary on natural language processing (NLP) markers for psychosis and other psychiatric disorders presents some of the clinical and research issues that NLP markers might address and some of the activities needed to move in that direction. We propose that the optimal development of NLP markers would occur in the context of research efforts to map out the underlying mechanisms of psychosis and other disorders. In this workshop, we identified some of the challenges to be addressed in developing and implementing NLP markers-based Clinical Decision Support Systems (CDSSs) in psychiatric practice, especially with respect to psychosis. Of note, a CDSS is meant to enhance decision-making by clinicians by providing additional relevant information primarily through software (although CDSSs are not without risks). In psychiatry, a field that relies on subjective clinical ratings that condense rich temporal behavioral information, the inclusion of computational quantitative NLP markers can plausibly lead to operationalized decision models in place of idiosyncratic ones, although ethical issues must always be paramount.

Modular-Level Functional Connectome Alterations in Individuals With Hallucinations Across the Psychosis Continuum.

Functional connectome alterations, including modular network organization, have been related to the experience of hallucinations. It remains to be determined whether individuals with hallucinations across the psychosis continuum exhibit similar alterations in modular brain network organization. This study assessed functional connectivity matrices of 465 individuals with and without hallucinations, including patients with schizophrenia and bipolar disorder, nonclinical individuals with hallucinations, and healthy controls. Modular brain network organization was examined at different scales of network resolution, including (1) global modularity measured as Qmax and Normalised Mutual Information (NMI) scores, and (2) within- and between-module connectivity. Global modular organization was not significantly altered across groups. However, alterations in within- and between-module connectivity were observed for higher-order cognitive (e.g., central-executive salience, memory, default mode), and sensory modules in patients with schizophrenia and nonclinical individuals with hallucinations relative to controls. Dissimilar patterns of altered within- and between-module connectivity were found bipolar disorder patients with hallucinations relative to controls, including the visual, default mode, and memory network, while connectivity patterns between visual, salience, and cognitive control modules were unaltered. Bipolar disorder patients without hallucinations did not show significant alterations relative to controls. This study provides evidence for alterations in the modular organization of the functional connectome in individuals prone to hallucinations, with schizophrenia patients and nonclinical individuals showing similar alterations in sensory and higher-order cognitive modules. Other higher-order cognitive modules were found to relate to hallucinations in bipolar disorder patients, suggesting differential neural mechanisms may underlie hallucinations across the psychosis continuum.

Occurrence and phenomenology of hallucinations in the general population: A large online survey.

Although epidemiological studies report that hallucinations occur in 6-15% of the general population, little is known about their phenomenology. To overcome this paucity, this study investigates the phenomenological characteristics of hallucinations in the general population, by using a nationally promoted online survey to assess hallucination phenomenology in four sensory modalities, through a self-report version of the Questionnaire for Psychotic Experiences (QPE), in 10,448 participants (aged 14-88 years). The phenomenology of hallucinations was assessed if hallucinations reportedly occurred in the past month. In the past month, auditory hallucinations were reported most frequently (29.5%), followed by visual (21.5%), tactile (19.9%), and olfactory hallucinations (17.3%); hallucinations in two or more modalities were reported by 47.6%. Substantial numbers of participants rated their hallucinations as severe, due to negative content (16.0-31.6%), previous bothersome experiences (14.8-20.2%), ensuing distress (10.5-16.8%), and/or ensuing disfunctioning (12.7-17.3%). Decreased insight was found in 10.2-11.4%. Hypnagogia was reported by 9.0-10.6%, and bereavement hallucinations by 2.8%. Despite a low prevalence of delusions (7.0%), these phenomena were significantly associated with recent hallucinations, observed in up to 13.4% of the participants with hallucinations during the past week (p < 0.001). Our results indicate a wide variety of the phenomenology of hallucinations in the general population and support the existence of a phenomenological continuum.

Efficacy of Transcranial Direct Current Stimulation to Improve Insight in Patients With Schizophrenia: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND AND HYPOTHESIS: Impaired insight into the illness and its consequences is associated with poor outcomes in schizophrenia. While transcranial direct current stimulation (tDCS) may represent a potentially effective treatment strategy to relieve various symptoms of schizophrenia, its impact on insight remains unclear. To investigate whether tDCS would modulate insight in patients with schizophrenia, we undertook a meta-analysis based on results from previous RCTs that investigated the clinical efficacy of tDCS. We hypothesize that repeated sessions of tDCS will be associated with insight improvement among patients. STUDY DESIGN: PubMed and ScienceDirect databases were systematically searched to identify RCTs that delivered at least 10 tDCS sessions in patients with schizophrenia. The primary outcome was the change in insight score, assessed by the Positive and Negative Syndrome Scale (PANSS) item G12 following active tDCS sessions as opposed to sham stimulation. Effect sizes were calculated for all studies and pooled using a random-effects model. Meta-regression and subgroup analyses were conducted. STUDY RESULTS: Thirteen studies (587 patients with schizophrenia) were included. A significant pooled effect size (g) of -0.46 (95% CI [-0.78; -0.14]) in favor of active tDCS was observed. Age and G12 score at baseline were identified as significant moderators, while change in total PANSS score was not significant. CONCLUSIONS: Ten sessions of active tDCS with either frontotemporoparietal or bifrontal montage may improve insight into the illness in patients with schizophrenia. The effect of this treatment could contribute to the beneficial outcomes observed in patients following stimulation.

Effect of disease related biases on the subjective assessment of social functioning in Alzheimer's disease and schizophrenia patients.

BACKGROUND: Questionnaires are the current hallmark for quantifying social functioning in human clinical research. In this study, we compared self- and proxy-rated (caregiver and researcher) assessments of social functioning in Schizophrenia (SZ) and Alzheimer's disease (AD) patients and evaluated if the discrepancy between the two assessments is mediated by disease-related factors such as symptom severity. METHODS: We selected five items from the WHO Disability Assessment Schedule 2.0 (WHODAS) to assess social functioning in 53 AD and 61 SZ patients. Caregiver- and researcher-rated assessments of social functioning were used to calculate the discrepancies between self-rated and proxy-rated assessments. Furthermore, we used the number of communication events via smartphones to compare the questionnaire outcomes with an objective measure of social behaviour. RESULTS: WHODAS results revealed that both AD (p < 0.001) and SZ (p < 0.004) patients significantly overestimate their social functioning relative to the assessment of their caregivers and/or researchers. This overestimation is mediated by the severity of cognitive impairments (MMSE; p = 0.019) in AD, and negative symptoms (PANSS; p = 0.028) in SZ. Subsequently, we showed that the proxy scores correlated more strongly with the smartphone communication events of the patient when compared to the patient-rated questionnaire scores (self; p = 0.076, caregiver; p < 0.001, researcher-rated; p = 0.046). CONCLUSION: Here we show that the observed overestimation of WHODAS social functioning scores in AD and SZ patients is partly driven by disease-related biases such as cognitive impairments and negative symptoms, respectively. Therefore, we postulate the development and implementation of objective measures of social functioning that may be less susceptible to such biases.

Social dysfunction is transdiagnostically associated with default mode network dysconnectivity in schizophrenia and Alzheimer's disease.

OBJECTIVES: Social dysfunction is one of the most common signs of major neuropsychiatric disorders. The Default Mode Network (DMN) is crucially implicated in both psychopathology and social dysfunction, although the transdiagnostic properties of social dysfunction remains unknown. As part of the pan-European PRISM (Psychiatric Ratings using Intermediate Stratified Markers) project, we explored cross-disorder impact of social dysfunction on DMN connectivity. METHODS: We studied DMN intrinsic functional connectivity in relation to social dysfunction by applying Independent Component Analysis and Dual Regression on resting-state fMRI data, among schizophrenia (SZ; N = 48), Alzheimer disease (AD; N = 47) patients and healthy controls (HC; N = 55). Social dysfunction was operationalised via the Social Functioning Scale (SFS) and De Jong-Gierveld Loneliness Scale (LON). RESULTS: Both SFS and LON were independently associated with diminished DMN connectional integrity within rostromedial prefrontal DMN subterritories (pcorrected range = 0.02-0.04). The combined effect of these indicators (Mean.SFS + LON) on diminished DMN connectivity was even more pronounced (both spatially and statistically), independent of diagnostic status, and not confounded by key clinical or sociodemographic effects, comprising large sections of rostromedial and dorsomedial prefrontal cortex (pcorrected=0.01). CONCLUSIONS: These findings pinpoint DMN connectional alterations as putative transdiagnostic endophenotypes for social dysfunction and could aid personalised care initiatives grounded in social behaviour.

Spontaneous brain activity underlying auditory hallucinations in the hearing-impaired.

Auditory hallucinations, the perception of a sound without a corresponding source, are common in people with hearing impairment. Two forms can be distinguished: simple (i.e., tinnitus) and complex hallucinations (speech and music). Little is known about the precise mechanisms underlying these types of hallucinations. Here we tested the assumption that spontaneous activity in the auditory pathways, following deafferentation, underlies these hallucinations and is related to their phenomenology. By extracting (fractional) Amplitude of Low Frequency Fluctuation [(f)ALFF] scores from resting state fMRI of 18 hearing impaired patients with complex hallucinations (voices or music), 18 hearing impaired patients with simple hallucinations (tinnitus or murmuring), and 20 controls with normal hearing, we investigated differences in spontaneous brain activity between these groups. Spontaneous activity in the anterior and posterior cingulate cortex of hearing-impaired groups was significantly higher than in the controls. The group with complex hallucinations showed elevated activity in the bilateral temporal cortex including Wernicke's area, while spontaneous activity of the group with simple hallucinations was mainly located in the cerebellum. These results suggest a decrease in error monitoring in both hearing-impaired groups. Spontaneous activity of language-related areas only in complex hallucinations suggests that the manifestation of the spontaneous activity represents the phenomenology of the hallucination. The link between cerebellar activity and simple hallucinations, such as tinnitus, is new and may have consequences for treatment.

Functional connectome differences in individuals with hallucinations across the psychosis continuum.

Hallucinations may arise from an imbalance between sensory and higher cognitive brain regions, reflected by alterations in functional connectivity. It is unknown whether hallucinations across the psychosis continuum exhibit similar alterations in functional connectivity, suggesting a common neural mechanism, or whether different mechanisms link to hallucinations across phenotypes. We acquired resting-state functional MRI scans of 483 participants, including 40 non-clinical individuals with hallucinations, 99 schizophrenia patients with hallucinations, 74 bipolar-I disorder patients with hallucinations, 42 bipolar-I disorder patients without hallucinations, and 228 healthy controls. The weighted connectivity matrices were compared using network-based statistics. Non-clinical individuals with hallucinations and schizophrenia patients with hallucinations exhibited increased connectivity, mainly among fronto-temporal and fronto-insula/cingulate areas compared to controls (P < 0.001 adjusted). Differential effects were observed for bipolar-I disorder patients with hallucinations versus controls, mainly characterized by decreased connectivity between fronto-temporal and fronto-striatal areas (P = 0.012 adjusted). No connectivity alterations were found between bipolar-I disorder patients without hallucinations and controls. Our results support the notion that hallucinations in non-clinical individuals and schizophrenia patients are related to altered interactions between sensory and higher-order cognitive brain regions. However, a different dysconnectivity pattern was observed for bipolar-I disorder patients with hallucinations, which implies a different neural mechanism across the psychosis continuum.

Repetitive transcranial magnetic stimulation (rTMS) for schizophrenia patients treated with clozapine.

OBJECTIVES: Biological strategies to improve treatment efficacy in clozapine-treated patients are urgently needed. Repetitive transcranial magnetic stimulation (rTMS) merits consideration as intervention for patients with persistent auditory hallucinations (AH) or negative symptoms (NS) not responding sufficiently to clozapine treatment. METHODS: Data from 10 international RCTs of rTMS for patients being treated with clozapine were pooled. Two levels of symptomatic response were defined: improvement of ≥20% and ≥50% on study-specific primary endpoint scales. Changes in the positive and negative syndrome scale (PANSS) from baseline to endpoint assessment were also analysed. RESULTS: Analyses of 131 patients did not reveal a significant difference for ≥20% and ≥50% response thresholds for improvement of AH, negative or total symptoms between active and sham rTMS groups. The number needed to treat (NNT) for an improvement in persistent AH was nine following active rTMS. PANSS scores did not improve significantly from baseline to endpoint between active and sham groups in studies investigating NS and AH. CONCLUSIONS: rTMS as a treatment for persistent symptoms in clozapine-treated patients did not show a beneficial effect of active compared to sham treatment. For AH, the size of the NNTs indicates a possible beneficial effect of rTMS.

Simvastatin Augmentation for Patients With Early-Phase Schizophrenia-Spectrum Disorders: A Double-Blind, Randomized Placebo-Controlled Trial.

Schizophrenia-spectrum disorders (SSD) are associated with increased inflammatory markers, both in brain and periphery. Augmentation with drugs that lower this pro-inflammatory status may improve clinical presentation. Simvastatin crosses the blood-brain barrier, has anti- inflammatory and neuroprotective effects and reduces metabolic syndrome. In this study, we investigated if 12 months of simvastatin augmentation can improve symptoms and cognition in patients with early SSD. This double-blind placebo-controlled trial included 127 SSD patients across the Netherlands, <3 years after their diagnosis. From these, 119 were randomly assigned 1:1 to simvastatin 40 mg (n = 61) or placebo (n = 58), stratified for sex and study site. Primary outcomes were symptom severity and cognition after 12 months of treatment. Depression, symptom subscores, general functioning, metabolic syndrome, movement disorders, and safety were secondary outcomes. Intention to treat analyses were performed using linear mixed models and ANCOVA. No main effect of simvastatin treatment was found on total symptom severity after 12 months of treatment as compared to placebo (X2(1) = 0.01, P = .90). Group differences varied over time (treatment*time X2(4) = 11.2; P = .025), with significantly lower symptom severity in the simvastatin group after 6 months (mean difference = -4.8; P = .021; 95% CI: -8.8 to -0.7) and at 24 months follow-up (mean difference = -4.7; P = .040; 95% CI: -9.3 to -0.2). No main treatment effect was found for cognition (F(1,0.1) = 0.37, P = .55) or secondary outcomes. SAEs occurred more frequently with placebo (19%) than with simvastatin (6.6%). This negative finding corroborates other large scale studies on aspirin, minocycline, and celecoxib that could not replicate positive findings of smaller studies, and suggests that anti-inflammatory augmentation does not improve the clinical presentation of SSD.