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Pattern classification aims to establish a new approach in personalized treatment. The scope is to tailor treatment on individual characteristics during all phases of care including prevention, diagnosis, treatment, and clinical outcome. In psychotic disorders, this need results from the fact that a third of patients with psychotic symptoms do not respond to antipsychotic treatment and are described as having treatment-resistant disorders. This, in addition to the high variability of treatment responses among patients, enhances the need of applying advanced classification algorithms to identify antipsychotic treatment patterns. This review comprehensively summarizes advancements and challenges of pattern classification in antipsychotic treatment response to date and aims to introduce clinicians and researchers to the challenges of including pattern classification into antipsychotic treatment decision algorithms.

Objectives Reward system dysfunctions are considered to be a pathophysiological mechanism in schizophrenia. Electrophysiological studies of reward system functions have identified frequency-specific brain networks for the processing of positive (high-beta frequency) and negative (theta frequency) events. Remarkably, midbrain dopaminergic signalling also includes theta and high-beta frequency modes, which have been assumed to reflect tonic and phasic dopamine responses, respectively. The aim of the present study was to identify alterations of oscillatory responses to reward feedback in patients with schizophrenia. Methods Seventeen patients with schizophrenia and 18 healthy controls performed a gambling task during recording of 64-channel electroencephalography. The theta and high-beta band total power were investigated in response to feedback events depending on feedback valence (loss or gain) and magnitude (5 vs. 25 points). Results Both the increase of theta oscillatory activity in response to loss feedback (compared to gain feedback) and the increase of high-beta oscillatory activity in response to gain feedback (compared to loss feedback) were reduced in patients. The difference in high-beta responses to gain versus loss feedback in patients was associated with the severity of negative symptoms. Conclusions Our findings are consistent with current models of reward system dysfunction in schizophrenia, and indicate deficits in both cortical tonic and subcortical phasic dopamine activity, consistent with the complex dopaminergic abnormalities in schizophrenia.

Background Bullying as a specific subtype of adverse life events is a major risk factor for poor mental health. Although many questionnaires on bullying are available, so far none covers bullying retrospectively throughout school and working life. To close this gap, the Bullying Scale for Adults (BSA) was designed. Methods Based on data of 622 participants from five European countries collected in the prospective multicenter Personalized Prognostic Tools for Early Psychosis Management (PRONIA) study, we investigated whether the BSA is a reliable and valid measurement for bullying and whether there is a difference across different diagnostic groups of early mental disorders (recent onset depressive/ psychotic patients, patients at clinical high-risk of psychosis) and healthy controls. Results Bullying experiences were significantly less frequent in healthy controls than in patient groups, with no significant differences between the three clinical groups. The BSA exhibited a high item scale discrimination (r > .3) and very good internal consistency (Cronbach's α = .93). Four factors were identified: 1. Sexual harassment, 2. Emotional Abuse, 3. Physical Abuse, 4. Problems at school. The highly significant correlation between bullying, and childhood adversities and trauma (r = .645, p Discussion The BSA is the first validated questionnaire that, in retrospective, reliably records various aspects of bullying (incl. its consequences) not only throughout childhood but also working life. It can be used to assess bullying as a transdiagnostic risk factor of mental disorders in different mental disorders, esp. psychosis and depression.

Accepted manuscript version, licensed CC BY-NC-ND 4.0. 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).

Resting-state EEG microstates are brief (50–100 ms) periods, in which the spatial configuration of scalp global field power remains quasi-stable before rapidly shifting to another configuration. Changes in microstate parameters have been described in patients with psychotic disorders. These changes have also been observed in individuals with a clinical or genetic high risk, suggesting potential usefulness of EEG microstates as a biomarker for psychotic disorders. The present study aimed to investigate the potential of EEG microstates as biomarkers for psychotic disorders and future transition to psychosis in patients at ultra-high-risk (UHR). We used 19-channel clinical EEG recordings and orthogonal contrasts to compare temporal parameters of four normative microstate classes (A–D) between patients with first-episode psychosis (FEP; n = 29), UHR patients with (UHR-T; n = 20) and without (UHR-NT; n = 34) later transition to psychosis, and healthy controls (HC; n = 25). Microstate A was increased in patients (FEP & UHR-T & UHR-NT) compared to HC, suggesting an unspecific state biomarker of general psychopathology. Microstate B displayed a decrease in FEP compared to both UHR patient groups, and thus may represent a state biomarker specific to psychotic illness progression. Microstate D was significantly decreased in UHR-T compared to UHR-NT, suggesting its potential as a selective biomarker of future transition in UHR patients.

Background Reasoning biases such as the jumping-to-conclusions bias (JTC) are thought to contribute to delusions. Interventions targeting these biases such as metacognitive training (MCT) may improve delusions. So far, it is not clear whether JTC depends on dopaminergic reward areas that constitute the main action locus of antipsychotic drugs, or on additional cortical areas. The present study aimed to investigate fMRI activation and functional connectivity patterns underlying JTC, and their changes following MCT, in patients with delusions. Methods Participants were 25 healthy individuals and 26 patients with current delusions who were either medication-free or on stable medication without sufficient response. We assessed (1) BOLD activity in the task-positive (TPN), task-negative (TNN), and subcortical reward network (RN); (2) Psychophysiological interactions (PPI) of peak activation areas. Results Presence of JTC (irrespective of group) was associated with lower RN activity during conclusion events, and with increased effective connectivity between TPN and TNN during draw events. Following MCT, changes were observed in TPN activity and in effective connectivity of inferior parietal cortex (part of the TPN) with all three target networks. Conclusion JTC is associated not only with reward system areas that constitute the main target of antipsychotic drugs, but also with cortical areas, particularly of the TPN., Highlights • Faulty evidence gathering (jumping to conclusions, JTC) is associated with delusions. • We assessed data gathering with fMRI in patients with delusions vs healthy controls. • JTC was associated with abnormal activity and connectivity patterns. • Changes in the task-positive network were observed following metacognitive training.

Reports linking a 'jumping-to-conclusions' bias to delusions have led to growing interest in the neurobiological correlates of probabilistic reasoning. Several brain areas have been implicated in probabilistic reasoning; however, findings are difficult to integrate into a coherent account. The present study aimed to provide additional evidence by investigating, for the first time, effective connectivity among brain areas involved in different stages of evidence gathering. We investigated evidence gathering in 25 healthy individuals using fMRI and a new paradigm (Box Task) designed such as to minimize the effects of cognitive effort and reward processing. Decisions to collect more evidence ('draws') were contrasted to decisions to reach a final choice ('conclusions') with respect to BOLD activity. Psychophysiological interaction analysis was used to investigate effective connectivity. Conclusion events were associated with extensive brain activations in widely distributed brain areas associated with the task-positive network. In contrast, draw events were characterized by higher activation in areas assumed to be part of the task-negative network. Effective connectivity between the two networks decreased during draws and increased during conclusion events. Our findings indicate that probabilistic reasoning may depend on the balance between the task-positive and task-negative network, and that shifts in connectivity between the two may be crucial for evidence gathering. Thus, abnormal connectivity between the two systems may significantly contribute to the jumping-to-conclusions bias.

Patients diagnosed with schizophrenia display deficits in Theory of Mind (ToM) and Emotion Perception (EP) even before the appearance of full-blown symptomatology.We evaluated ToM and EP in a male cohort consisting of 25 First Episode Psychosis (FEP) and 16 relapsed schizophrenic patients (CHRON) compared to 12 subjects in Ultra-high Risk (UHR) and 23 healthy controls (CTR). Furthermore, we measured the levels of Cortisol, Insulin like Growth Factor (IGF-1), TNF-a, TNF-b and several interleukins as potential biomarkers.Deficits in EP and ToM were found in FEP, CHRON patients and UHR subjects compared to CTR. The impairments in these two domains seem to follow different patterns in the course of psychosis. EP was more impaired in subjects with a longer history of symptomatology whereas there was no statistically significant difference regarding ToM. On the other hand IL-4 was the only biomarker correlated to ToM and EP scores in two different samples of our study.Social Cognition (SC) domains are impaired in patients with psychosis as well as in UHR subjects compared to healthy controls. There are differences in the progress of ToM and EP deficits in the course of psychosis. Interleukins as IL-4 could correlate to SC.

AIM Gender differences in the current symptomatology of patients with psychotic disorders have previously been described in the literature. However, it has not yet been investigated whether gender differences exist in the very first self-perceived signs or symptoms of illness onset. The aim of this study was to investigate this aspect in at-risk mental state (ARMS) and first-episode psychosis (FEP) patients. METHODS ARMS and FEP were recruited via the early detection of psychosis (FePsy) clinic Basel, Switzerland. The Basel Interview for Psychosis (BIP) was used to retrospectively assess the first 3 self-perceived signs and symptoms at illness onset. Differences between gender and patient groups on single item and symptom cluster levels were analysed using logistic regression models. RESULTS One-hundred-thirty six ARMS (91 men, 45 women) and 89 FEP patients (63 men, 26 women) could be recruited for this study. On a single item level, women more frequently reported "unusual anxiety, fears" and men (at a trend level) "social withdrawal" as being among their 3 first self-perceived symptoms, independent of diagnostic group. On the symptom cluster level, women more frequently reported "increased worrying/anxiety" and (sub-threshold) "hallucinations", independent of diagnostic group. Problems with "thinking, concentration" were reported more frequently by men in the ARMS group only. CONCLUSION Our results suggest that only few and relatively small gender differences exist in the first self-perceived signs and symptoms. While men initially mainly notice negative/cognitive symptoms, women first notice (sub-threshold) positive and affective symptoms.

Schizophrenia is a complex psychiatric disorder with unknown and presumably heterogeneous etiology. While the disorder can have various outcomes, research is predominantly “deficit-oriented” emphasizing the hardship that the disorder inflicts on sufferers as well as their families and society. Beyond symptom reduction, imparting patients with hope and meaning in life is increasingly considered an important treatment target, which may raise self-esteem, and reduce self-stigma and suicidal ideation. The present study compared a psychotherapeutic treatment aimed at improving cognitive insight, individualized metacognitive intervention (MCT+), with an active control in order to elucidate if personal meaning-making and hope can be improved in patients with psychosis across time. A total of 92 patients were randomized to either individualized metacognitive therapy (MCT+) or CogPack (neuropsychological training) and followed up for up to 6 months. The “Subjective Sense in Psychosis Questionnaire” (SUSE) was administered which covers different salutogenetic vs pathogenetic views of the disorder, valence of symptom experiences and the consequences of psychosis. Patients in the MCT+ group showed a significant positive shift in attitudes towards the consequences of their illness over time relative to patients in the active control condition. There was some evidence that MCT+ also enhanced meaning-making. The perceived negative consequences of psychosis were highly correlated with depression and low self-esteem, as well as suicidality. The study shows that a cognitive insight training can improve meaning-making in patients and help them come to terms with their diagnosis.

Background: Targeting the N-methyl-d-aspartate receptor (NMDAR) is a major translational approach for treating negative symptoms of schizophrenia. Ketamine comprehensively produces schizophrenia-like symptoms, such as positive, cognitive and negative symptoms in healthy volunteers. The amplitude of the mismatch negativity (MMN) is known to be significantly reduced not only in patients with schizophrenia, but also in healthy controls receiving ketamine. Accordingly, it was the aim of the present study to investigate whether changes of MMN amplitudes during ketamine administration are associated with the emergence of schizophrenia-like negative symptoms in healthy volunteers. Methods: We examined the impact of ketamine during an MMN paradigm with 64-channel electroencephalography (EEG) and assessed the psychopathological status using the Positive and Negative Syndrome Scale (PANSS) in healthy male volunteers using a single-blind, randomized, placebo-controlled crossover design. Low-resolution brain electromagnetic tomography was used for source localization. Results: Twenty-four men were included in our analysis. Significant reductions of MMN amplitudes and an increase in all PANSS scores were identified under the ketamine condition. Smaller MMN amplitudes were specifically associated with more pronounced negative symptoms. Source analysis of MMN generators indicated a significantly reduced current source density (CSD) under the ketamine condition in the primary auditory cortex, the posterior cingulate and the middle frontal gyrus. Limitations: The sample included only men within a tight age range of 20–32 years. Conclusion: The MMN might represent a biomarker for negative symptoms in schizophrenia related to an insufficient NMDAR system and could be used to identify patients with schizophrenia with negative symptoms due to NMDAR dysfunction.

Background Precise prognosis of clinical outcomes in individuals at clinical high-risk (CHR) of developing psychosis is imperative to guide treatment selection. While much effort has been put into the prediction of transition to psychosis in CHR individuals, prognostic models focusing on negative symptom progression in this population are widely missing. This is a major oversight bearing in mind that 82% of CHR individuals exhibit at least one negative symptom in the moderate to severe range at first clinical presentation, whereas 54% still meet this criteria after 12 months. Negative symptoms are strong predictors of poor functional outcome irrespective of other symptoms such as depression or anxiety. Prognostic tools are therefore urgently required to track negative symptom progression in CHR individuals in order to guide early personalized interventions. Here, we applied machine-learning to multi-site data from five European countries with the aim of predicting negative symptoms of at least moderate severity 9-month after study inclusion. Methods We analyzed data from the ‘Personalized Prognostic Tools for Early Psychosis Management’ (PRONIA; www.pronia.eu) study, which consisted of 94 individuals at clinical high-risk of developing psychosis (CHR). Predictive models either included baseline level of negative symptoms, measured with the Structured Interview for Prodromal Syndromes, whole-brain gyrification pattern, or both to forecast negative symptoms of moderate severity or above in CHR individuals. Using data from the clinical and gyrification model, further sequential testing simulations were conducted to stratify CHR individuals into different risk groups. Lastly, we assessed the models’ ability to predict functional outcomes in CHR individuals. Results Baseline negative symptom severity alone predicted moderate to severe negative symptoms with a balanced accuracy (BAC) of 68%, whereas predictive models trained on gyrification measures achieved a BAC of 64%. Stacking the two modalities allowed for an increased BAC of 72%. Additional sequential testing simulations suggested, that CHR patients could be stratified into a high risk group with 83% probability of experiencing at least moderate negative symptoms at follow-up and a medium/low risk group with a risk ranging from 25 to 38%, when using the two models sequentially. Furthermore, the models trained to predict negative symptom severity from baseline symptoms were less predictive of role (60% BAC) and social (62% BAC) functioning at follow-up. However, the model trained on gyrification data also predicted role (74% BAC) and social (73% BAC) functioning later on. The stacking model predicted role, and social functioning with 64% BAC and 66% BAC respectively. Discussion To the best of our knowledge this is the first study using state-of-the-art predictive modelling to prospectively identify CHR subjects with negative symptoms in the moderate to above moderate severity range who potentially require further therapeutic consideration. While the predictive performance will need to be validated in other samples and may be improved by expanding the models with additional predictors, we believe that this pragmatic approach will help to stratify individual risk profiles and optimize personal interventions in the future.

Background and objectives Individualized Metacognitive Training (MCT+) is a manualized intervention designed to improve delusional severity by reducing delusion-associated cognitive biases such as jumping-to-conclusions. Increased interest in personalized medicine stipulates the identification of patients who are more likely to benefit from specialized interventions. The present study aimed to explore baseline moderators of MCT+ efficacy on delusions and overall positive symptoms in psychosis. Methods We analyzed data from a randomized rater-blind controlled trial, in which 92 patients with psychotic disorders and current or past delusions were randomly assigned to either MCT+ or CogPack®, a cognitive remediation software. Baseline moderator variables consisted of jumping-to-conclusions, cognitive insight, quality of life, self-esteem, selective attention, and patients’ attitudes towards their symptoms. Linear mixed-effects models were applied to investigate specific moderators of MCT+ efficacy. Results In MCT+ relative to CogPack, presence of a jumping-to-conclusions bias, a lowered decision threshold, and low self-esteem were associated with larger improvements in delusional severity and/or overall positive symptoms over time. Subjective reasoning style and insight, as well as subjective attitudes towards psychosis, did not moderate the treatment efficacy of MCT+ relative to CogPack. Limitations Participation of both treatment groups in group MCT as a part of standard care, possibly leading to additional effects on delusional severity. Conclusions Patients with low self-esteem and those who are prone to jumping-to-conclusions seem to particularly benefit from MCT+. Our results can help inform clinical practice as they provide specific criteria for selecting patients for whom MCT+ is most appropriate.

Study drop-out during follow-up and service disengagement frequently occur in patients at clinical high risk for psychosis (CHR-P). However, little is known about their predictors. Therefore, we aimed to analyze the rate and reasons for drop-out and service disengagement in CHR-P patients and investigate their sociodemographic and clinical predictors. Data from 200 patients of the prospective Fruherkennung von Psychosen (FePsy) study were analyzed with competing risks survival models, considering drop-out and transition to psychosis as competing events. To investigate whether symptoms changed immediately before drop-out, t tests were applied. Thirty-six percent of patients dropped out within 5 years. Almost all drop-outs also disengaged from our service. Hence, study drop-out was used as a proxy for service disengagement. Patients with more severe baseline disorganized symptoms and a late inclusion into the study were significantly more likely to disengage. Immediately before disengagement, there was significant improvement in negative symptoms only. A considerable proportion of CHR-P patients disengaged from our clinical study and service. Patients who were included during a later study period with more assessments disengaged more often, which might have been due to more frequent invitations to follow-up assessments and thereby increasing participation burden. Hence, our study provides a cautionary note on high-frequency follow-up assessments. Larger-scale studies evaluating predictors on multiple domains would help to further elucidate drop-out and disengagement.

Depressive symptoms in subjects at Clinical High Risk for Psychosis (CHR-P) or at first-episode psychosis (FEP) are often treated with antidepressants. Our cross-sectional study investigated whether brain morphology is altered by antidepressant medication. High-resolution T1-weighted structural MRI scans of 33 CHR-P and FEP subjects treated with antidepressants, 102 CHR-P and FEP individuals without antidepressant treatment and 55 controls, were automatically segmented using Freesurfer 6.0. Linear mixed-effects modelling was applied to assess the differences in subcortical volume, surface area and cortical thickness in treated, non-treated and healthy subjects, taking into account converted dosages of antidepressants. Increasing antidepressant dose was associated with larger volume of the pallidum and the putamen, and larger surface of the left inferior temporal gyrus. In a pilot subsample of separately studied subjects of known genomic risk loci, we found that in the right postcentral gyrus, the left paracentral lobule and the precentral gyrus antidepressant dose-associated surface increase depended on polygenic schizophrenia-related-risk score. As the reported regions are linked to the symptoms of psychosis, our findings reflect the possible beneficial effects of antidepressant treatment on an emerging psychosis.

Background:Few studies have followed up patients with a clinical high risk (CHR) for psychosis for more than 2–3 years. We aimed to investigate the rates and baseline predictors for remission from CHR and transition to psychosis over a follow-up period of up to 16 years. Additionally, we examined the clinical and functional long-term outcome of CHR patients who did not transition.Methods:We analyzed the long-term course of CHR patients that had been included in the longitudinal studies “Früherkennung von Psychosen” (FePsy) or “Bruderholz” (BHS). Those patients who had not transitioned to psychosis during the initial follow-up periods (2/5 years), were invited for additional follow-ups.Results:Originally, 255 CHR patients had been included. Of these, 47 had transitioned to psychosis during the initial follow-ups. Thus, 208 were contacted for the long-term follow-up, of which 72 (34.6%) participated. From the original sample of 255, 26%, 31%, 35%, and 38% were estimated to have transitioned after 3, 5, 10, and 16 years, respectively, and 51% had remitted from their high risk status at the latest follow-up. Better psychosocial functioning at baseline was associated with a higher rate of remission. Of the 72 CHR patients re-assessed at long-term follow-up, 60 had not transitioned, but only 28% of those were fully recovered clinically and functionally.Conclusions:Our study shows the need for follow-ups and clinical attention longer than the usual 2–3 years as there are several CHR patients with later transitions and only a minority of CHR those without transition fully recovers.

Dieser Artikel zeigt auf, wie Fachpersonen, die im Erstkontakt mit psychosegefahrdeten Menschen zu tun haben, den klinischen Verlauf und die Prognose konkret verbessern konnen.

Cet article montre comment les professionnels qui ont le premier contact avec les personnes a risque de psychose peuvent ameliorer concretement l’evolution clinique et le pronostic.

AIM Ultrahigh risk (UHR) criteria, consisting of brief limited intermittent psychotic symptoms (BLIPS), attenuated psychotic symptoms (APS) and genetic risk and deterioration (GRD) syndrome are the most widely used criteria for assessing the clinical high-risk state for psychosis (CHR-P). The Basel Screening Instrument for Psychosis (BSIP) includes a further risk category, the unspecific risk category (URC). However, little is known about the predictive power of this risk category compared to other risk categories. METHODS Two hundred CHR-P patients were detected as part of the Fruherkennung von Psychosen (FePsy) study using the BSIP. Transition to psychosis was assessed in regular intervals for up to 7 years. RESULTS Patients meeting only the URC criterion (n = 40) had a significantly lower risk of transition to psychosis than the UHR group (including BLIPS, APS and GRD) (HR 0.19 [0.05; 0.80] (P = 0.024). Furthermore, the URC only risk group had a lower transition risk than the APS without BLIPS group (P = 0.015) and a trendwise lower risk than the BLIPS group (P = 0.066). However, despite the lower transition risk in the URC only group, there were still two patients (5%) in this group with a later transition to psychosis. CONCLUSIONS The URC includes patients who have a lower risk of transition than those included by the UHR categories and thereby increases the sensitivity of the BSIP. This offers the possibility of a stratified intervention, with these subjects receiving low intensity follow-up and treatment.

Background:Gender differences in symptomatology in chronic schizophrenia and first episode psychosis patients have often been reported. However, little is known about gender differences in those at risk of psychotic disorders. This study investigated gender differences in symptomatology, drug use, comorbidity (i.e. substance use, affective and anxiety disorders) and global functioning in patients with an at-risk mental state (ARMS) for psychosis.Methods:The sample consisted of 336 ARMS patients (159 women) from the prodromal work package of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI; 11 centers). Clinical symptoms, drug use, comorbidity and functioning were assessed at first presentation to an early detection center using structured interviews.Results:In unadjusted analyses, men were found to have significantly higher rates of negative symptoms and current cannabis use while women showed higher rates of general psychopathology and more often displayed comorbid affective and anxiety disorders. No gender differences were found for global functioning. The results generally did not change when corrected for possible cofounders (e.g. cannabis use). However, most differences did not withstand correction for multiple testing.Conclusions:Findings indicate that gender differences in symptomatology and comorbidity in ARMS are similar to those seen in overt psychosis and in healthy controls. However, observed differences are small and would only be reliably detected in studies with high statistical power. Moreover, such small effects would likely not be clinically meaningful.

Objectives: Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive processes. Since cognitive deficits are a core feature of psychotic disorders, the investigation of BDNF levels in psychosis and their correlation with cognition has received increased attention. However, there are no studies investigating BDNF levels in individuals with an at-risk mental state (ARMS) for psychosis. Hence, the aims of the present study were: (1) assessing peripheral BDNF levels across different (potential) stages of psychosis; (2) investigating their association with cognition. Methods: Plasma and serum BDNF levels and neuropsychological performance were assessed in 16 ARMS, six first-episode psychosis (FEP), and 11 chronic schizophrenia (CS) patients. Neuropsychological assessment covered intelligence, verbal memory, working memory, attention and executive functioning. Results: Both plasma and serum BDNF levels were highest in CS, intermediate in FEP and lowest in ARMS. Multiple regression analysis revealed a significant positive association of plasma BDNF levels with planning ability across all groups. Conclusions: The lower peripheral BDNF levels in ARMS compared to FEP and CS might point towards an important drop of this neurotrophin prior to the onset of frank psychosis. The associations of peripheral BDNF with planning-abilities match previous findings.

Association Splitting, a novel cognitive intervention, was tested in patients with alcohol dependence as an add-on intervention in an initial randomized controlled trial. Preliminary support for Association Splitting has been found in patients with obsessive-compulsive disorder, as well as in an online pilot study of patients with alcohol use disorders. The present variant sought to reduce craving by strengthening neutral associations with alcohol-related stimuli, thus, altering cognitive networks. Eighty-four inpatients with verified diagnoses of alcohol dependence, who were currently undergoing inpatient treatment, were randomly assigned to Association Splitting or Exercise Therapy. Craving was measured at baseline, 4-week follow-up, and six months later with the Obsessive-Compulsive Drinking Scale (primary outcome) and the Alcohol Craving Questionnaire. There was no advantage for Association Splitting after three treatment sessions relative to Exercise Therapy. Among Association Splitting participants, 51.9% endorsed a subjective decline in craving and 88.9% indicated that they would use Association Splitting in the future. Despite high acceptance, an additional benefit of Association Splitting beyond standard inpatient treatment was not found. Given that participants were concurrently undergoing inpatient treatment and Association Splitting has previously shown moderate effects, modification of the study design may improve the potential to detect significant effects in future trials.

Childhood trauma (CT) is a comprehensive concept encompassing experiences of sexual, physical, and emotional abuse, and neglect during childhood and adolescence. Patients with schizophrenia-spectrum psychosis (SSP) display higher rates of CT than healthy controls. Among the potential mediators of this association, insecure attachment has gained attention and empirical validation. The present study aimed to extend existing knowledge on this field by exploring the role of the two attachment dimensions, attachment anxiety and attachment avoidance, in the CT-SSP association. A clinical sample of 63 SSP inpatients was compared to a healthy control group on CT and attachment style measures. Correlations between CT, attachment dimensions and psychopathology were sought. Mediation analyses were also performed to examine whether attachment anxiety and/or attachment avoidance mediated the CT-SSP association. Patients displayed higher rates of CT and insecure attachment than controls. Attachment anxiety and severity of Mother Antipathy were linked to severity of hallucinations. Attachment anxiety was recognized as the sole mediator of the CT-SSP association. Our findings suggest that individuals with severe CT and increased attachment anxiety represent a risk population warranting early clinical attention, regular monitoring and tailored therapeutic interventions aimed at reducing the psychological impact of trauma.

Several studies using electroencephalography (EEG) demonstrate that the processing of feedback in patients suffering from borderline personality disorder (BPD) is altered in comparison to healthy controls. Differences occur in the theta (ca. 5 Hz) and high-beta frequency-ranges (ca. 20 Hz) of oscillations in response to negative and positive feedback, respectively. However, alpha (ca. 10 Hz) and low-beta (ca. 15 Hz) oscillations have also been shown to be involved in feedback processing. We hypothesized that additional alterations might occur in these frequency ranges in BPD. Eighteen patients with BPD and twenty-two healthy controls performed a gambling task while 64-channel-EEG was recorded. Induced oscillatory responses to positive (i.e. gain) and negative (i.e. loss) feedback in the alpha and low-beta frequency range were investigated. No significant differences were found in the alpha frequency range. Regarding the low-beta frequency range a significant Group (i.e. BPD vs. healthy controls) × Valence (i.e. gain vs. loss) interaction in the time frame between 600 and 700 milliseconds after feedback was found. This effect showed a significant correlation with symptom severity (assessed with the BSL-23). The results indicate that feedback processing in BPD could be more heavily altered than previously expected, with more severe symptomatology being linked to stronger alterations in oscillatory responses to feedback in the low-beta range.

In the past few decades, sex differences have been identified in a number of clinical, cognitive and functional outcomes in patients with schizophrenia spectrum disorders. However, to date, sex differences in higher-order cognitive biases have not been systematically studied. The present study aimed to examine sex differences in jumping-to-conclusions and evidence integration impairment based on data collected in two previous studies in patients with schizophrenia spectrum disorders and healthy controls. For this purpose, data from n = 58 patients and n = 60 healthy controls on the Fish Task (as a measure of jumping to conclusions) and bias against disconfirmatory evidence (BADE; as a measure of evidence integration) task were analyzed. Results indicated a lack of sex differences in jumping-to-conclusions and evidence integration impairment both in patients with schizophrenia spectrum disorders and healthy controls. Although the present study was adequately powered to detect sex differences of a low medium effect size, larger studies are warranted to exclude differences of a smaller magnitude between men and women regarding delusion-associated cognitive biases.

Grey matter (GM) volume alterations have been repeatedly demonstrated in patients with first episode psychosis (FEP). Some of these neuroanatomical abnormalities are already evident in the at-risk mental state (ARMS) for psychosis. Not only GM alterations but also neurocognitive impairments predate the onset of frank psychosis with verbal learning and memory (VLM) being among the most impaired domains. Yet, their interconnection with alterations in GM volumes remains ambiguous. Thus, we evaluated associations of different subcortical GM volumes in the medial temporal lobe with VLM performance in antipsychotic-naive ARMS and FEP patients. Data from 59 ARMS and 31 FEP patients, collected within the prospective Fruherkennung von Psychosen study, were analysed. Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging scanner. VLM was assessed using the California Verbal Learning Test and its factors Attention Span, Learning Efficiency, Delayed Memory and Inaccurate Memory. FEP patients showed significantly enlarged volumes of hippocampus, pallidum, putamen and thalamus compared to ARMS patients. A significant negative association between amygdala and pallidum volume and Attention Span was found in ARMS and FEP patients combined, which however did not withstand correction for multiple testing. Although we found significant between-group differences in subcortical volumes and VLM is among the most impaired cognitive domains in emerging psychosis, we could not demonstrate an association between low performance and subcortical GM volumes alterations in antipsychotic-naive patients. Hence, deficits in this domain do not appear to stem from alterations in subcortical structures.

Ongoing research is shifting towards a dimensional understanding of borderline personality disorder (BPD). Aim of this study was to identify personality profiles in BPD that are predictive of self-destructive behaviors. Personality traits were assessed (n = 130) according to the five-factor model of personality (i.e., Neuroticism, Extraversion, Openness to Experience, Agreeableness, Conscientiousness) and an additional factor called Risk Preference. Self-destructive behavior parameters such as non-suicidal self-injury (NSSI) and other borderline typical dyscontrolled behaviors (e.g., drug abuse) were assessed by self-report measures. Canonical correlation analyses demonstrated that Neuroticism, Extraversion, and Conscientiousness are predictors of NSSI. Further, Neuroticism, Agreeableness, and Risk Preference were associated with dyscontrolled behaviors. Our results add further support on personality-relevant self-destructive behaviors in BPD. A combined diagnostic assessment could offer clinically meaningful insights about the causes of self-destruction in BPD to expand current therapeutic repertoires.

Auditory verbal hallucinations (AVH) are a common positive symptom of schizophrenia. Excitatory-to-inhibitory (E/I) imbalance related to disturbed N-methyl-D-aspartate receptor (NMDAR) functioning has been suggested as a possible mechanism underlying altered connectivity and AVH in schizophrenia. The current study examined the effects of ketamine, a NMDAR antagonist, on glutamate-related mechanisms underlying interhemispheric gamma-band connectivity, conscious auditory perception during dichotic listening (DL), and the emergence of auditory verbal distortions and hallucinations (AVD/AVH) in healthy volunteers. In a single-blind, pseudo-randomized, placebo-controlled crossover design, nineteen male, right-handed volunteers were measured using 64 channel electroencephalography (EEG). Psychopathology was assessed with the PANSS interview and the 5D-ASC questionnaire, including a subscale to detect auditory alterations with regard to AVD/AVH (AUA-AVD/AVH). Interhemispheric connectivity analysis was performed using eLORETA source estimation and lagged phase synchronization (LPS) in the gamma-band range (30-100 Hz). Ketamine induced positive symptoms such as hallucinations in a subgroup of healthy subjects. In addition, interhemispheric gamma-band connectivity was found to be altered under ketamine compared to placebo, and subjects with AUA-AVD/AVH under ketamine showed significantly higher interhemispheric gamma-band connectivity than subjects without AUA-AVD/AVH. These findings demonstrate a relationship between NMDAR functioning, interhemispheric connectivity in the gamma-band frequency range between bilateral auditory cortices and the emergence of AVD/AVH in healthy subjects. The result is in accordance with the interhemispheric miscommunication hypothesis of AVH and argues for a possible role of glutamate in AVH in schizophrenia.

Negative symptoms and neurocognitive performance have been reported to be negatively associated in patients with emerging psychosis. However, most previous studies focused on patients with frank psychosis and did not differentiate between subdomains of negative symptoms. Hence, we aimed to elucidate the specific relationship between negative symptoms and cognitive functioning in patients at clinical high risk (CHR) for psychosis. Data from 154 CHR patients collected within the prospective Fruherkennung von Psychosen (FePsy) study were analyzed. Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and cognitive functioning with an extensive neuropsychological test battery. Regression analyses revealed significant negative associations between negative symptoms and cognitive functioning, particularly in the domains of nonverbal intelligence and verbal fluency. When analyzing each negative symptom domain separately, alogia and asociality/anhedonia were significantly negatively associated with nonverbal intelligence and alogia additionally with verbal fluency. Overall, our results in CHR patients are similar to those reported in patients with frank psychosis. The strong negative association between verbal fluency and negative symptoms may be indicative of an overlap between these constructs. Verbal fluency might have a strong influence on the clinical impression of negative symptoms (particularly alogia) and vice versa.

Background Verbal learning and memory are impaired not only in patients with a first episode of psychosis (FEP) but also–to a lower extent–in those with an at-risk mental state for psychosis (ARMS). However, little is known about the specific nature of these impairments. Hence, we aimed to study learning and memory processes in ARMS and FEP patients by making use of structural equation modelling. Methods Verbal learning was assessed with the California Verbal Learning Test (CVLT) in 98 FEP patients, 126 ARMS patients and 68 healthy controls (HC) as part of the Basel early detection of psychosis (FePsy) study. The four-factorial CFA model of Donders was used to estimate test performance on latent variables of the CVLT and growth curve analysis was used to model the learning curve. The latter allows disentangling initial recall, which is strongly determined by attentional processes, from the learning rate. Results The CFA model revealed that ARMS and FEP patients were impaired in Attention Span, Learning Efficiency and Delayed Memory and that FEP patients were additionally impaired in Inaccurate Memory. Additionally, ARMS-NT, but not ARMS-T, performed significantly worse than HC on Learning Efficiency. The growth curve model indicated that FEP patients were impaired in both initial recall and learning rate and that ARMS patients were only impaired in the learning rate. Conclusions Since impairments were more pronounced in the learning rate than the initial recall, our results suggest that the lower scores in the CVLT reported in previous studies are more strongly driven by impairments in the rate of learning than by attentional processes.

We propose a new method for the localization of nonlinear cross-frequency coupling in EEG and MEG data analysis, based on the estimation of bicoherences at the source level. While for the analysis of rhythmic brain activity, source directions are commonly chosen to maximize power, we suggest to maximize bicoherence instead. The resulting nonlinear cost function can be minimized effectively using a gradient approach. We argue, that bicoherence is also a generally useful tool to analyze phase-amplitude coupling (PAC), by deriving formal relations between PAC and bispectra. This is illustrated in simulated and empirical LFP data. The localization method is applied to EEG resting state data, where the most prominent bicoherence signatures originate from the occipital alpha rhythm and the mu rhythm. While the latter is hardly visible using power analysis, we observe clear bicoherence peaks in the high alpha range of sensorymotor areas. We additionally apply our method to resting-state data of subjects with schizophrenia and healthy controls and observe significant bicoherence differences in motor areas which could not be found from analyzing power differences.

Disturbances in evidence gathering and disconfirmatory evidence integration have been associated with the presence of or propensity for delusions. Previous evidence suggests that these 2 types of reasoning bias might be differentially affected by antipsychotic medication. We aimed to investigate the effects of a dopaminergic agonist (L-dopa) and a dopaminergic antagonist (haloperidol) on evidence gathering and disconfirmatory evidence integration after single-dose administration in healthy individuals.The study used a randomized, double-blind, placebo-controlled, 3-way crossover design. Participants were healthy individuals aged 18-40 years. We administered a new data-gathering task designed to increase sensitivity to change compared with traditional tasks. The Bias Against Disconfirmatory Evidence (BADE) task was used as a measure of disconfirmatory evidence integration.We included 30 individuals in our study. In the data-gathering task, dopaminergic modulation had no significant effect on the amount of evidence gathered before reaching a decision. In contrast, the ability of participants to integrate disconfirmatory evidence showed a significant linear dopaminergic modulation pattern (highest with haloperidol, intermediate with placebo, lowest with L-dopa), with the difference between haloperidol and L-dopa marginally reaching significance.Although the doses used for haloperidol and L-dopa were similar to those used in previous studies, drug plasma level measurements would have added to the validity of findings.Evidence gathering and disconfirmatory evidence integration might be differentially influenced by dopaminergic agents. Our findings are in support of a dual-disturbance account of delusions and provide a plausible neurobiological basis for the use of interventions targeted at improving reasoning biases as an adjunctive treatment in patients with psychotic disorders.

The aim of the present study was to investigate the effects of comorbid obsessive-compulsive symptoms (OCS) on the perception of insincere speech (e.g., sarcasm and white lies) in patients with first-episode psychosis.Participants were 65 patients with nonaffective first-episode psychosis (FEP) and 47 healthy controls. The patient group was divided into two subgroups, those with (FEP+; n= 38) and those without OCS (FEP-; n = 27). The ability to process sarcasm and lie was assessed with the Perception of Social Inference Test (PESIT). Severity of psychotic symptoms and OCS was assessed with the Positive and Negative Syndrome Scale (PANSS) and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), respectively.Deficits in the perception of sarcasm and lie were confirmed in patients with nonaffective first-episode psychosis compared to healthy controls. In patients, comorbidity with OCS was associated with worse performance on certain aspects of insincere speech (i.e., lie) compared to FEP- patients. Y-BOCS scores correlated significantly with the perception of lying. The cognitive factor of the PANSS predicted accuracy on the perception of sincere speech, paradoxical sarcasm, and white lies, while the presence of OCS predicted accuracy on the perception of sincere speech and white lies.Our finding of impaired counterfactual information processing in patients with first-episode psychosis suggests that these deficits are already present at illness onset. Presence of OCS appears to have additional deleterious effects on the successful interpretation of intentional lying, further supporting that these patients are characterized by more extensive cognitive impairment.

Many patients with schizophrenia display neuropsychological deficits in concert with cognitive biases, particularly the tendency to jump to conclusions (JTC). The present study examined the effects of a generic psychoeducational cognitive bias correction (CBC) program. We hypothesized that demonstrating the fallibility of human cognition to patients would diminish their susceptibility to the JTC bias. A total of 70 participants with schizophrenia were recruited online. At baseline, patients were asked to fill out a JTC task (primary outcome) and the Paranoia Checklist before being randomized to either the CBC or a waitlist control condition. The CBC group received six successive pdf-converted PowerPoint presentations teaching them about cognitive biases; we neither placed any emphasis on psychosis-related cognitive distortions nor addressed psychosis. Six weeks after inclusion, subjects were re-administered the JTC task and the Paranoia Checklist. At a medium-to-large effect size the JTC bias was significantly improved under the CBC condition in comparison to controls for both the per protocol and the intention to treat analysis. The Paranoia Checklist remained essentially unchanged over time. No effects were observed for depression. Psychoeducational and cognitive programs are urgently needed as many patients are still deprived of any psychological treatment despite recommendations of most guidelines. Self-help may bridge the large treatment gap in schizophrenia and motivate patients to seek help. The study asserts both the feasibility and effectiveness of self-help programs in schizophrenia.

Patients with delusions exhibit an increased tendency to arrive at decisions based on very limited evidence (jumping-to-conclusions; JTC), making this reasoning bias relevant for the treatment of delusions. Neurocognitive deficits contribute to JTC, but it is not known whether this has any bearing on the clinical syndrome of delusions. We addressed this question by reanalyzing data from an efficacy study of non-pharmacological interventions as adjunctive treatments in schizophrenia. We investigated the longitudinal associations of cognitive functioning, JTC and delusions in patients with psychotic disorders receiving either a metacognitive intervention addressing reasoning biases (n=59), or cognitive remediation (n=58). Both interventions improved JTC; in the cognitive remediation group, tentative evidence suggested that better neurocognitive performance contributed to this improvement. However, JTC gains were associated with delusion improvement only in the metacognitive intervention group, suggesting a content-specific mechanism of action.

Background Patients with schizophrenia show overconfidence in memory and social cognition errors. The present investigation examined whether this cognitive distortion also manifests in perceptual tasks. Methods A total of 55 individuals with schizophrenia, 58 with obsessive–compulsive disorder (OCD) as well as 45 non-clinical controls were presented 24 blurry black and white pictures, half of which contained a hidden object; the other half contained (“snowy”) visual noise. Participants had to judge whether the pictures depicted an object or not and how confident they were in this judgment. Results Participants with schizophrenia showed overconfidence in errors and an enhanced knowledge corruption index (i.e. rate of high-confident errors on all high-confident responses) relative to both control groups. In contrast, accuracy scores did not differ between clinical groups. Metacognitive parameters were correlated with self-rated levels of current paranoia. Discussion To the best of our knowledge, this is the first study to demonstrate overconfidence in errors among individuals with psychosis using a visual perception task. Speaking to the specificity of this abnormality for schizophrenia and its pathogenetic relevance, overconfidence in errors and knowledge corruption were elevated in patients with schizophrenia relative to both control groups and were correlated with paranoia.

Antipsychotics represent the first-choice treatment for schizophrenia. However, the cognitive and emotional pathways through which symptom reduction is achieved have remained unclear. We recently proposed that the induction of doubt is a core mechanism of action of antipsychotics. In the framework of a randomized, double-blind, placebo-controlled, crossover design, 39 nonclinical participants filled out a questionnaire tapping into cognitive and emotional changes (Effect of Antipsychotic Medication on Emotion and Cognition-revised (EAMEC-r)) each time they had received one of three substances (haloperidol, placebo, L-dopa). Participants reported more doubt under haloperidol than under L-dopa lending support to the theory that antipsychotics decrease delusional conviction via the reduction of confidence. Key points from this study are: (a) antipsychotics induce doubt, and (b) doubt may represent a core mechanism of action for the reduction of delusional ideas

Our understanding of the neural correlates of auditory-verbal-hallucinations (AVH) has substantially increased during the last few years, but is far from sufficient. One current hypothesis, the interhemispheric miscommunication theory, is based on findings from fMRI, DTI and EEG, but there is only limited evidence so far concerning underlying functional coupling mechanisms. Here we report a 64-channel EEG study using lagged phase synchronization analysis and eLORETA source estimation to examine the functional connectivity between bilateral auditory cortices in the gamma-band in 26 schizophrenia patients (13 with and 13 without AVH) and 26 matched healthy controls (HC) while performing a dichotic listening task. We found a significantly reduced right-ear-advantage (REA) in AVH but not in non-AVH patients compared to HC. The major finding was significantly stronger gamma-band connectivity between bilateral auditory cortices during conscious perception of left (versus right) ear syllables in patients with AVH compared to HC and patients without AVH. A significant positive correlation was found between this connectivity alteration and the AVH symptom score in schizophrenia patients. These findings provide further support for the interhemispheric miscommunication hypothesis of AVH pathophysiology by indicating that aberrant gamma-band coupling between auditory cortices is related to the emergence of AVH in schizophrenia.

This is the peer-reviewed but unedited manuscript version of the following article: Moritz, S., Ludtke, T., Pfuhl, G., Balzan, R. P. & Andreou, C. (2017). Liberale akzeptanz als kognitiver mechanismus bei psychose: Eine 2-stufen-theorie der pathogenese schizophrener positivsymptome. Verhaltenstherapie (Basel), 27(2), 108-118. http://doi.org/10.1159/000464256. The final, published version is available at http://www.karger.com/?doi=10.1159/000464256. Positivsymptome wie Wahn und Halluzinationen stellen definierende Symptome einer (schizophrenen) Psychose dar. In dieser Übersichtsarbeit wird ein 2-stufiges heuristisches Modell für die Entstehung und Aufrechterhaltung psychotischer Positivsymptome vorgelegt. Im Kern der Theorie steht die Hypothese, dass von Psychose betroffene Menschen eine erniedrigte Entscheidungsschwelle aufweisen, die zu einer frühzeitigen Annahme von Hypothesen führt (liberale Akzeptanz). Im Unterschied zu nichtpsychotischen Personen ist die Konfidenz in falsche Urteile bei Betroffenen, als Folge dieser liberalen Akzeptanz, erhöht. Postuliert werden 2 Stufen der Wahnentwicklung. Auf Stufe 1 (Wahnentstehung) ist die subjektive Wahrscheinlichkeit für akzeptierte Hypothesen bei Menschen mit Psychose zunächst vergleichsweise gering. Wahnhafte Ideen sind in diesem Stadium häufig nicht voll entfaltet bzw. fragil und können zwischen 2 sich gegenseitig ausschließenden Ansichten oszillieren («doppelte Buchführung»). Im Zuge der 2. Stufe (Überzeugung, Aufrechterhaltung) verfestigen sich die flüchtigen wahnhaften Ideen zu falschen Überzeugungen aufgrund eines 2-gliedrigen Konsolidierungsprozesses – indem einerseits Gegenbeweise ignoriert und andererseits Belege zugunsten der Leithypothese einen Verarbeitungsvorteil erhalten (Bestätigungstendenz). Alternative Hypothesen rü- cken in den Hintergrund. Aufrechterhaltend für eine Wahnidee sind vielfältige psychologische Faktoren und Motive, wie die Kongruenz des Wahns mit dem emotionalen Befinden, persönliche Bedeutsamkeit und die temporäre Steigerung des Selbstwertgefühls sowie das Spannen eines Erklärungsrahmens für ein breites Spektrum von Beschwerden zur Reduktion kognitiver Dissonanz. Aus unserer Sicht können viele Formen von Halluzinationen und Erstrangsymptomen (z.B. Gedankeneingebung) ebenfalls durch liberale Akzeptanz erklärt werden. Diese Symptome basieren unseres Erachtens nicht zwingend auf fehlerhaften oder abnormalen Wahrnehmungen, sondern repräsentieren eine Fehlinterpretation von (teilweise) normalen sensorischen Phänomenen, die sich von einem (normalen) «Als-ob»-Gefühl bis hin zu einer wahnhaften Überzeugung steigern. Im Einklang mit dem erläuterten Modell werden Positivsymptome durch Interventionen wie das metakognitive Training (MKT) verringert, die Betroffene dazu anhalten, mehr Informationen zu sammeln und ihre Urteilssicherheit zu reduzieren (Säen von Zweifel). Die antipsychotische Wirkung von Antipsychotika/Neuroleptika wird im Rahmen der Theorie zum Teil durch ihre Eigenschaft erklärt, Zweifel zu induzieren. Die Bedeutung der Emotionsregulation bei der Reduktion von Positivsymptomen wird ebenfalls aufgezeigt, und zukünftige Forschungsrichtungen sowie offene Fragen diskutiert. Liberal Acceptance as a Cognitive Mechanism in Psychosis: A 2-Step-Therory on the Pathogenesis of Positive Symptoms in Schizophrenia Positive symptoms, such as delusions and hallucinations, are defining features of psychosis and schizophrenia, respectively. In this review article, we present a 2-stage heuristic model for the formation and maintenance of psychotic positive symptoms. At the heart of our theory is the assumption that individuals with psychosis have a lowered decision threshold resulting in the liberal acceptance of hypotheses. In contrast to non-psychotic persons, confidence in errors is enhanced as a result of liberal acceptance. Two stages are put forward here. At stage 1 (delusion formation), the subjective probability of an accepted hypothesis is relatively low. Delusional ideas at this stage are often fragile and may oscillate between mutually exclusive views (‘double book keeping’). During the 2. stage (conviction, maintenance), flighty delusional ideas crystallize due to a 2-fold consolidation process: a) counter-evidence is ignored and b) cues in favor of the dominant hypothesis have a processing advantage (confirmation bias). Alternative hypotheses are degraded in the course of this process. A number of psychological factors and motifs act as maintenance factors, for example the congruence between the delusion and present emotional states, personal importance and the temporary elevation of self-esteem, as well as a superstructure that may explain a broad range of impairments to reduce cognitive dissonance. From our point of view, some forms of hallucinations and first-rank symptoms (e.g., thought broadcasting) can be explained by liberal acceptance as well. These symptoms are not necessarily based on erroneous or abnormal perception but on the misinterpretation of (partially) normal sensory phenomena which evolve from an ‘as if’ feeling to delusional conviction. In accordance with the model, positive symptoms are decreased by interventions such as metacognitive training (MCT) which encourage individuals with psychosis to search for more information and to reduce their level of certainty (i.e., ‘sowing the seeds of doubt’). The antipsychotic properties of antipsychotics/neuroleptics are explained by their potential to induce doubt. The role of emotion regulation for the amelioration of positive symptoms is demonstrated, and further research directions and open questions are outlined.

Background Hyperprolactinemia is a known side effect of antipsychotics. In recent reports it has also been shown in antipsychotic-naive at-risk mental state (ARMS) and first-episode psychosis (FEP) patients. Prolactin is not only involved in reproduction and lactation, but is also synthesized in response to stress. As stress is thought to play an important role in the onset and relapse of schizophrenia, the aim of this study was to further elucidate the influence of prolactin in emerging psychosis. Methods The data analysed in this study were collected within the prospective Fruherkennung von Psychosen (FePsy) study. Blood sample collection took place under standardized conditions between 8 and 10 am after an overnight fast and 30 minutes of rest. All patients were antipsychotic-naive and did not take any prolactin influencing medication. Results Our sample consisted of 116 antipsychotic-naive ARMS and 49 FEP patients. Hyperprolactinemia was shown in 32% of ARMS and 35% of FEP patients. After correction for the normal biological variation between the sexes, we still found higher average prolactin levels in female than in male patients (β = 0.42; t = 2.47; p = 0.01) but no difference in prolactin levels between ARMS and FEP patients (β = − 0.05; t = − 0.30; p = 0.76). The survival analysis revealed no significant predictive value for prolactin levels to predict transition to psychosis. Conclusion Our findings support a possible role of prolactin in emerging psychosis and it could be speculated that stress, which can induce hyperprolactinemia, has a stronger effect on women than on men in emerging psychosis.

Background and objectives Previous research involving the probabilistic reasoning ‘beads task’ has consistently demonstrated a jumping-to-conclusions (JTC) bias, where individuals with delusions make decisions based on limited evidence. However, recent studies have suggested that miscomprehension may be confounding the beads task. The current study aimed to test the conventional beads task against a conceptually simpler probabilistic reasoning “box task” Methods One hundred non-clinical participants completed both the beads task and the box task, and the Peters et al. Delusions Inventory (PDI) to assess for delusion-proneness. The number of ‘draws to decision’ was assessed for both tasks. Additionally, the total amount of on-screen evidence was manipulated for the box task, and two new box task measures were assessed (i.e., ‘proportion of evidence requested’ and ‘deviation from optimal solution’). Results Despite being conceptually similar, the two tasks did not correlate, and participants requested significantly less information on the beads task relative to the box task. High-delusion-prone participants did not demonstrate hastier decisions on either task; in fact, for box task, this group was observed to be significantly more conservative than low-delusion-prone group. Limitations Neither task was incentivized; results need replication with a clinical sample. Conclusion Participants, and particularly those identified as high-delusion-prone, displayed a more conservative style of responding on the novel box task, relative to the beads task. The two tasks, whilst conceptually similar, appear to be tapping different cognitive processes. The implications of these results are discussed in relation to the JTC bias and the theoretical mechanisms thought to underlie it.

Background Theory-driven interventions targeting specific factors that contribute to delusions are receiving increased interest. The present study aimed to assess the efficacy of individualized metacognitive therapy (MCT+), a short manualized intervention that addresses delusion-associated cognitive biases. Methods 92 patients with current or past delusions were randomized to receive 12 twice-weekly sessions of either MCT+ or a control intervention within a randomized controlled rater-blind design. Psychopathology and cognitive biases were assessed at baseline, 6 weeks and 6 months. ANCOVAs adjusted for baseline scores were used to assess differences between groups regarding outcome variables. Both per-protocol and intention-to-treat analyses were conducted. Results At 6 weeks, there was a significant difference in favor of MCT+ regarding decrease in delusion severity and improvement of self-reflectiveness (medium effect size), and a trend-wise difference regarding probability thresholds to decision. These effects increased, when only patients attending a minimum of 4 therapy sessions were considered. Control group patients subsequently showed further improvement while patients in the MCT+ group remained stable, such that there were no differences between groups at the 6-month follow-up. Limitations Lower attendance rates in the control group possibly leading to unequal therapeutic effort; lower baseline delusion severity in the MCT+ group. Conclusions The result pattern suggests that MCT+ led to earlier improvement in delusions and cognitive biases compared to the control intervention. The absence of a long-term effect might reflect floor effects in the MCT+ group, but may also indicate the need for further measures to promote sustainability of MCT+ effects.

Background: Schizophrenia has long been suggested to represent a disorder with prominent neural dysconnectivity. Gamma-band oscillations are highly relevant in this context, due both to their proposed involvement in neuronal synchronization and to their association with neurotransmitter systems relevant for schizophrenia. Several task-related studies have confirmed reduced power and synchronization of gamma-band oscillations in schizophrenia, but it has been suggested that these findings might not apply to the resting state. The present study aimed to investigate resting-state gamma-band connectivity in patients with schizophrenia. Methods: Sixty-four channel resting-state electroencephalography (eyes closed) was recorded in 22 patients with first-episode schizophrenia and 22 healthy controls matched for age and gender. Orthogonalized power envelope correlation was used as a measure of connectivity across 80 cortical regions at 40 Hz. Mean connectivity at each region was compared across groups using the nonparametric randomization approach. Additionally, the network-based statistic was applied to identify affected networks in patients. Results: Patients displayed increased mean functional gamma-band connectivity compared to controls in the left rolandic operculum. Network-based analyses indicated increased connectivity in patients within a strongly lateralized network consisting mainly of left inferior frontal/orbitofrontal, lateral and medial temporal, and inferior parietal areas. Within this network, gamma-band connectivity was higher in patients with low positive and disorganization symptom levels. Conclusions: The present study provides a link between resting-state gamma-band connectivity and the core symptoms of schizophrenia. The observed findings are different than those reported by task-related studies, suggesting that resting-state studies might reveal new aspects in the pathophysiology of schizophrenia.

Studies revealed that patients with paranoid schizophrenia display overconfidence in errors for memory and social cognition tasks. The present investigation examined whether this pattern holds true for visual perception tasks. Nonclinical participants were recruited via an online panel. Individuals were asked to complete a questionnaire that included the Paranoia Checklist and were then presented with 24 blurry pictures; half contained a hidden object while the other half showed snowy (visual) noise. Participants were asked to state whether the visual items contained an object and how confident they were in their judgment. Data from 1966 individuals were included following a conservative selection process. Participants high on core paranoid symptoms showed a poor calibration of confidence for correct versus incorrect responses. In particular, participants high on paranoia displayed overconfidence in incorrect responses and demonstrated a 20% error rate for responses made with high confidence compared to a 12% error rate in participants with low paranoia scores. Interestingly, paranoia scores declined after performance of the task. For the first time, overconfidence in errors was demonstrated among individuals with high levels of paranoia using a visual perception task, tentatively suggesting it is a ubiquitous phenomenon. In view of the significant decline in paranoia across time, bias modification programs may incorporate items such as the one employed here to teach patients with clinical paranoia the fallibility of human cognition, which may foster subsequent symptom improvement.

Introduction Positive symptoms in schizophrenia often deal with themes of control. For the first time, the “illusion of control” bias was examined in patients with schizophrenia. Methods A total of 32 patients with schizophrenia and 31 nonclinical controls were administered two versions of an illusion of control paradigm. Participants were presented two sequences of green and red stimuli and could choose to press or not press a computer key to get the (desired) green stimulus (participants should press the key to test their level of control). Later, they were asked to rate their level of control over the appearance of the green sequence. The chain of events followed a fixed pseudo-random sequence (experiment A: 75% desired events; B: 25%). Results Both groups displayed an illusion of control bias. The subgroup with high positive symptom scores showed excessive illusion of control in experiment A relative to individuals scoring low on positive symptoms. Hallucinators scored significantly higher on illusion of control compared to both healthy individuals and non-hallucinators. Discussion Illusion of control was elevated in high-positive-symptom patients, particularly those with hallucinations. Future studies should elucidate whether the magnitude of the illusion of control effect is moderated by the specific contents of positive symptoms, as delusions of control can manifest as active or passive control beliefs.

Converging evidence suggests that frontostriatal abnormalities underlie OCD symptoms. The event-related potential P300 is generated along a widely distributed network involving several of the areas implicated in OCD. P300 abnormalities reported in patients with OCD suggest increased activity in these areas. The aim of the present study was to investigate this assumption in unmedicated patients with OCD, and to assess the effects of OCD treatment on P300 brain activity patterns. Seventy-one unmedicated patients with a DSM-IV diagnosis of OCD and 71 age- and gender-matched healthy control subjects participated in the study. The P300 was obtained through 32-channel EEG during an auditory oddball paradigm. Forty-three patients underwent a second EEG assessment after treatment with sertraline and behavioural therapy. Low-resolution electromagnetic tomography (LORETA) was used to localize the sources of brain electrical activity. Results: Increased P300-related activity was observed predominantly in the left orbitofrontal cortex, but also in left prefrontal, parietal and temporal areas, in patients compared to controls at baseline. After treatment, reduction of left middle frontal cortex hyperactivity was observed in patients. Conclusions: Findings of increased activity in frontoparietal areas in patients are consistent with several previous studies. Importantly, OCD treatment led to reduction of hyperactivity in the left middle frontal cortex, an area associated with context processing and uncertainty that might be important for the emergence of OCD symptoms. Thus, the present study is the first to show an association between P300 abnormalities and activity in brain regions postulated to be involved in the pathophysiology of OCD.