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Objective Widespread neurocognitive impairment is well‐established in individuals at ultra‐high risk (UHR) for developing psychoses, but it is unknown whether slowed processing speed may underlie impairment in other neurocognitive domains, as found in schizophrenia. The study delineated domain functioning in a UHR sample and examined if neurocognitive slowing might account for deficits across domains. Methods The cross‐sectional study included 50 UHR individuals with no (n = 38) or minimal antipsychotic exposure (n = 12; mean lifetime dose of haloperidol equivalent = 17.56 mg; SD = 13.04) and 50 matched healthy controls. Primary analyses compared group performance across neurocognitive domains before and after covarying for processing speed. To examine the specificity of processing speed effects, post hoc analyses examined the impact of the other neurocognitive domains and intelligence as covariates. Results UHR individuals exhibited significant impairment across all neurocognitive domains (all ps ≤ .010), with medium to large effect sizes (Cohen's ds = −0.53 to −1.12). Only processing speed used as covariate eliminated significant between‐group differences in all other domains, reducing unadjusted Cohen's d values with 68% on average, whereas the other domains used as covariates averagely reduced unadjusted Cohen's d values with 20% to 48%. When covarying each of the other domains after their shared variance with speed of processing was removed, all significant between‐group domain differences remained (all ps ≤ .024). Conclusion Slowed processing speed may underlie generalized neurocognitive impairment in UHR individuals and represent a potential intervention target., The study delineated neurocognitive domain functioning in 50 ultra‐high risk individuals and 50 healthy controls, examining if slowed processing speed might contribute significantly to impairment in other neurocognitive domains in the ultra‐high risk group. The results showed that the ultra‐high risk individuals exhibited significant impairment across all neurocognitive domains, and processing speed was able to account for the significant between‐group differences in all other domains.

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BackgroundThe effect of antipsychotics medication on cognitive functioning in patients diagnosed with schizophrenia is poorly understood. Some studies of second generation antipsychotics indicated that they improved cognitive functioning while other studies have found that they decrease the level of cognitive functioning.MethodWe included patients with schizophrenia who were in treatment with antipsychotics 1.5 years (baseline) after initiation of treatment and followed them up 3.5 years later (n= 189). At follow-up 60 (32%) had discontinued their antipsychotic treatment and 129 (68%) were still taking antipsychotics. Using the Brief Assessment of Cognition in Schizophrenia (BACS) we assessed cognition at baseline and follow-up.ResultsThe patients who discontinued their medication had a higher level of cognitive functioning in all domains at baseline, as well as Global cognitive function [meanz-score −1.50 (s.d. 1.24)v.−2.27 (s.d. 1.30),p= 0.00015]. After controlling for relevant confounders those who discontinued antipsychotic medication improved significantly more than those who remained on antipsychotic medication during the course of the follow-up on the Token Motor task [estimated mean change difference −0.46 (95% CI −0.89 to −0.04)], the Speed of Processing Domain [estimated mean change difference −0.38 (95% CI −0.68 to −0.08)] and global cognition [estimated mean change difference −0.36 (95% CI −0.66 to −0.07)].ConclusionDue to the naturalistic design, we cannot conclude on the direction of the relationship between antipsychotics and cognition. There is no evidence that discontinuation of medication had a negative effect on cognitive functioning. Rather, we found that that discontinuation of medication was associated with better cognitive functioning.

IntroductionAbnormalities within hypothalamus-pituitary-adrenal (HPA) axis might interact with other neurobiological systems to enhance the risk of psychosis. Most of the neurodevelopmental and HPA axis changes occur in adolescence; this is also the period when prodromal and psychotic symptoms occur for the first time. More knowledge about how various stress components interact can advance understanding of the link between psychosis and the HPA axis.MethodWe examined 41 ultra high-risk (UHR) patients and 40 antipsychotic-naïve first-episode schizophrenia (FES) patients and compared them with 47 matched controls. The Perceived Stress Scale and the Recent Life Events Questionnaire were used to assess the stress levels. Day-time saliva samples were taken to measure cortisol. The pituitary gland volume was measured manually on the structural MRI using stereology.ResultsOnly the UHR patients, had a higher cortisol increase just after awakening (p = 0.009) compared to healthy controls. In UHR patients, we found a negative correlation between cortisol increase after awakening and symptom severity (p = 0.008). Pituitary gland volume and diurnal cortisol were not significantly different among the three groups. There was no correlation between pituitary gland volume, perceived stress/recent life events and any of the cortisol measures or symptoms.ConclusionSymptom severity during the very early phase of illness (UHR) seems to be associated with altered cortisol increase. Longitudinal studies in UHR patients would be useful to examine how stress levels affect the course of the illness.

BackgroundIndividuals at ultra-high-risk (UHR) for psychosis present with emerging symptoms and decline in functioning. Previous univariate analyses have indicated widespread white matter (WM) aberrations in multiple brain regions in UHR individuals and patients with schizophrenia. Using multivariate statistics, we investigated whole brain WM microstructure and associations between WM, clinical symptoms, and level of functioning in UHR individuals.MethodsForty-five UHR individuals and 45 matched healthy controls (HCs) underwent magnetic resonance diffusion tensor imaging (DTI) at 3 Tesla. UHR individuals were assessed with the Comprehensive Assessment of At-Risk Mental States, Scale for the Assessment of Negative Symptoms, and Social and Occupational Functioning Assessment Scale. Partial least-squares correlation analysis (PLSC) was used as statistical method.ResultsPLSC group comparisons revealed one significant latent variable (LV) accounting for 52% of the cross-block covariance. This LV indicated a pattern of lower fractional anisotropy (FA), axial diffusivity (AD), and mode of anisotropy (MO) concomitant with higher radial diffusivity (RD) in widespread brain regions in UHR individuals compared with HCs. Within UHR individuals, PLSC revealed five significant LVs associated with symptoms and level of functioning. The first LV accounted for 31% of the cross-block covariance and indicated a pattern where higher symptom score and lower level of functioning correlated to lower FA, AD, MO, and higher RD.ConclusionsUHR individuals demonstrate complex brain patterns of WM abnormalities. Despite the subtle psychopathology of UHR individuals, aberrations in WM appear associated with positive and negative symptoms as well as level of functioning.

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.

Impaired cognitive test performance is well-documented in subjects at ultra-high risk (UHR) for psychosis. However, assessment of cognitive deficits as manifested in real life is a neglected area of UHR research that may add to the understanding of cognitive impairment and its relationship with psychosocial functioning and positive symptomatology. This study applied the interview-based Schizophrenia Cognition Rating Scale (SCoRS) and the questionnaire-based Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) in a cross-sectional sample of 39 UHR subjects and 50 healthy controls. Cognitive test performance, psychosocial functioning, and positive symptoms were also assessed. The UHR subjects demonstrated significant cognitive impairment, with large effect sizes for the SCoRS and BRIEF-A composite outcome variables (rs = -0.67 to -0.80) and a neurocognitive composite score (d = -0.97). Within the UHR group, several significant associations between worse cognitive ratings and worse cognitive test performance (rs = -0.210 to -0.343), poorer psychosocial functioning (rs = -0.058 to -0.728), and worse positive symptoms (rs= 0.415 to 0.478) were found. Worse cognitive test performance showed significant associations with more pronounced positive symptoms (rs = -0.299 to -0.457). Interview and questionnaire assessment may hold promise for supplementing traditional performance-based cognitive assessment in identifying treatment targets in the UHR population.

AIM Deterioration in premorbid adjustment is related to ultra-high risk (UHR) individuals developing psychosis, but it has not been examined how UHR individuals' development differs compared to healthy controls. This study investigates differences in premorbid adjustment between UHR individuals and a healthy control group. METHOD A total of 48 UHR individuals and 50 healthy controls matched on group level for age, gender and parents' socio-economic status were included in the study. Both groups were assessed with the Premorbid Adjustment Scale (PAS). Based on the PAS scores, composite social and academic scales were computed. RESULTS Compared to the healthy controls the UHR individuals' social and academic premorbid adjustment declined across age periods. Social premorbid adjustment declined particularly between late adolescence and adulthood. Academic premorbid adjustment declined particularly between childhood and early adolescence. The UHR individuals had more premorbid adjustment difficulties on both the social and academic scale, and on the individual PAS scales. CONCLUSION From childhood UHR individuals have lower levels of social and academic premorbid adjustment compared to healthy controls, and the difficulties increase with age. As such, social and academic premorbid adjustment could be an important focus for early intervention.

It has been suggested that patients with schizophrenia develop higher levels of oxidative stress, which may contribute to deteriorating mental illness. In order to examine oxidative stress in the early stages of severe mental illness, we examined the levels of systemic Deoxyribonucleic Acid (DNA) and Ribonucleic Acid (RNA) oxidation, 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine, perceived stress and recent life events in patients at ultra high-risk (UHR) of developing psychosis, in antipsychotic naïve patients with first-episode schizophrenia (FES), and in healthy controls. We included 41 UHR patients, 35 FES patients, and 29 healthy controls. There was no difference in the level of DNA/RNA oxidative damage between UHR patients and FES patients compared with healthy controls. We found no association between levels of DNA/RNA oxidative damage and perceived stress/life events. Based on the results, we suggest that DNA and RNA oxidative markers are not increased during the early stages of illness, but further longitudinal studies in first-episode psychosis should be carried out to examine whether DNA and RNA oxidative damage are potential markers of severe illness.

Background Many psychological treatments have shown effect on reducing self-harm in adults with borderline personality disorder. There is a need of brief psychotherapeutical treatment alternative for suicide prevention in specialized outpatient clinics. Methods/Design The DiaS trial was designed as a pragmatic single-center, two-armed, parallel-group observer-blinded, randomized clinical superiority trial. The participants had at least two criteria from the borderline personality disorder diagnosis and a recent suicide attempt (within a month). The participants were offered 16 weeks of dialectical behavior therapy (DBT) versus up to 16 weeks of collaborative assessment and management of suicidality (CAMS) treatment. The primary composite outcome was the number of participants with a new self-harm (nonsuicidal self-injury [NSSI] or suicide attempt) at week 28 from baseline. Other exploratory outcomes were: severity of borderline symptoms, depressive symptoms, hopelessness, suicide ideation, and self-esteem. Results At 28 weeks, the number of participants with new self-harm in the DBT group was 21 of 57 (36.8%) versus 12 of 51 (23.5%) in the CAMS treatment (OR: 1.90; 95% CI: 0.80–4.40; P = .14). When assessing the effect of DBT versus CAMS treatment on the individual components of the primary outcome, we observed no significant differences in the number of NSSI (OR: 1.60; 95% CI: 0.70–3.90; P = .31) or number of attempted suicides (OR: 2.24; 95% CI: 0.80–7.50; P = .12). Conclusion In adults with borderline personality traits and disorder and a recent suicide attempt, DBT does not seem superior compared with CAMS for reduction of number of self-harm or suicide attempts. However, further randomized clinical trials may be needed.

Objective The neurodevelopmental hypothesis of psychosis suggests that disrupted white matter (WM) maturation underlies disease onset. In this longitudinal study, we investigated WM connectivity and compared WM changes between individuals at ultra-high-risk for psychosis (UHR) and healthy controls (HCs). Method Thirty UHR individuals and 23 HCs underwent MR diffusion tensor imaging before and after 12 months of non-manualized standard care. Positive and negative symptoms and level of functioning were assessed. Tract-based spatial statistics were employed. Results During 12 months, none of the UHR individuals transitioned to psychosis. Both UHR individuals and HCs increased significantly in fractional anisotropy (FA). UHR individuals showed significant FA increases predominantly in the left superior longitudinal fasciculus (SLF) (P = 0.01), and HCs showed significant FA increases in the left uncinate fasciculus (P = 0.03). Within UHR individuals, a significant positive correlation between FA change and age was observed predominantly in the left SLF (P = 0.02). Within HCs, no significant correlation between FA change and age was observed. No significant correlations between baseline FA and clinical outcomes were observed; however, FA changes were significantly positively correlated to changes in negative symptoms (P = 0.04). Conclusion As normal brain maturation occurs in a posterior to frontal direction, our findings could suggest disturbed WM maturation in UHR individuals.

Background The presence of cognitive defects in patients suffering from schizophrenia is well established. While the earlier “Kraepelinian” view was one of deteriorating cognitive functioning, more recent studies have found that cognitive deficits tend to be stable or improving over time. Cognitive impairments are associated with poorer functional outcomes and understanding the factors that influence cognitive functioning is critical for understanding how to improve cognitive and functional outcomes in patients. The effect of antipsychotics medication on cognitive functioning in patients diagnosed with schizophrenia is poorly understood. Some studies of second-generation antipsychotics indicated that they improved cognitive functioning while other studies have found that they decrease the level of cognitive functioning. Methods We included patients with schizophrenia who were in treatment with antipsychotics 1.5 years (baseline) after initiation of treatment and followed them up 3.5 years later (n=189). At follow-up 60 (32%) had discontinued their antipsychotic treatment and 129 (68%) were still taking antipsychotics. Using the Brief Assessment of Cognition in Schizophrenia (BACS) we assessed cognition at baseline and follow-up. Results The patients who had discontinued their medication had a higher level of cognitive functioning in all domains at baseline, as well as Global cognitive function (mean z-score -1.50 (SD 1.24) vs. -2.27 (SD 1.30), p

Aim To make a thorough characterization of the co-morbidity, psychopathology and demographics in the first Danish ultra high-risk (UHR) sample. Method Forty-two UHR subjects went through comprehensive interviews assessing their psychopathology, psychiatric disorders, substance use and family history of psychiatric disorders. Results All UHR subjects met the criteria of at least 1 axis I diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and met on average four diagnoses (both axis I and II), mostly within the areas of depression, anxiety and substance abuse. A total of 48% had schizotypal personality disorder and 19% had borderline personality disorder. Level of functioning was low with a mean score on the Social and Occupational Functioning Assessment Scale corresponding to “major impairment in several areas,” and mean scores in the Global Functioning: Social and Role scales between “moderate impairment in social functioning” and “very serious impairment independently.” Forty-seven percent were unemployed and 29% on sick leave. Fifty-five percent relied financially on public support. Conclusion As seen in previous UHR populations, Danish UHR subjects had low function socio-economically and met criteria of several psychiatric diagnoses, suggesting that they require pharmacological and non-pharmacological psychiatric treatment as well as vocational and educational guidance and support.

Deterioration in premorbid adjustment is related to ultra-high risk (UHR) individuals developing psychosis, but it has not been examined how UHR individuals' development differs compared to healthy controls. This study investigates differences in premorbid adjustment between UHR individuals and a healthy control group.A total of 48 UHR individuals and 50 healthy controls matched on group level for age, gender and parents' socio-economic status were included in the study. Both groups were assessed with the Premorbid Adjustment Scale (PAS). Based on the PAS scores, composite social and academic scales were computed.Compared to the healthy controls the UHR individuals' social and academic premorbid adjustment declined across age periods. Social premorbid adjustment declined particularly between late adolescence and adulthood. Academic premorbid adjustment declined particularly between childhood and early adolescence. The UHR individuals had more premorbid adjustment difficulties on both the social and academic scale, and on the individual PAS scales.From childhood UHR individuals have lower levels of social and academic premorbid adjustment compared to healthy controls, and the difficulties increase with age. As such, social and academic premorbid adjustment could be an important focus for early intervention.

Cognitive deficits are a distinct feature among people at ultra-high risk (UHR) for psychosis and pose a barrier to functional recovery. Insufficient evidence exists on how to ameliorate these cognitive deficits in patients at UHR for psychosis and hence improve daily living and quality of life. The aim of the trial is to investigate whether cognitive remediation can improve cognitive and psychosocial function in patients at UHR for psychosis. The FOCUS trial (Function and Overall Cognition in Ultra-high risk States) is a randomised, parallel group, observer-blinded clinical trial enrolling 126 patients meeting the standardised criteria of being at UHR for psychosis. Patients are recruited from psychiatric in- and outpatient facilities in the Copenhagen catchment area. Patients are randomised to one of the two treatment arms: cognitive remediation plus standard treatment versus standard treatment. The cognitive remediation consists of 24 weekly group-based and manualised sessions targeting neurocognition and social cognition. In addition to the group sessions, the patients will be offered 12 individual sessions aiming at maximising the transfer of the effects of the cognitive training to their everyday lives. Follow-up assessments will be conducted at 6 and 12 months after randomisation. The primary outcome is the composite score on the Brief Assessment of Cognition in Schizophrenia at cessation of treatment after 6 months. Secondary outcomes are social and daily functioning, psychosis-like symptoms, negative symptomatology, and depressive symptomatology as measured with the Personal and Social Performance Scale, Brief Psychiatric Rating Scale-Expanded Version, Scale for the Assessment of Negative Symptoms, and the Montgomery-Asberg Depression Rating Scale. This is the first trial to evaluate the effects of neurocognitive and social cognitive remediation in UHR patients. The FOCUS trial results will provide evidence on the effect of targeted and comprehensive cognitive rehabilitation on cognition, daily living, and symptomatology as well as long-term outcome in preventing transition to psychosis in UHR patients. ClinicalTrials.gov NCT 02098408 . Date of registration 18 March 2014.

BACKGROUND: Recovery, the optimal goal in treatment, is the attainment of both symptomatic and functional remission over a sustained period of time. Identification of factors that promote recovery can help develop interventions that facilitate good outcomes for people with first episode psychosis.AIM: To examine long-term outcomes within a cohort of people with first episode psychosis in relation to symptom remission, functioning and recovery, 10 years after diagnosis.METHOD: The study had a prospective design. Participants from the OPUS trial (1998-2000) (n=496) completed a series of interviews and questionnaires to measure current levels of psychopathology and social/vocational functioning, ten years after diagnosis. Predictors of recovery were identified using socio-demographic and clinical characteristics collected at baseline.RESULTS: A total of 304 participants were interviewed, giving a follow-up rate of 61%. A total of 42 people (14%) met the criteria for symptomatic and psychosocial recovery at 10 years. A multivariable binary logistic regression analysis indicated that baseline predictors accounted for 22% of the variance of full recovery. Lower severity of negative symptoms at baseline (Odds Ratio (OR) 0.53, 95% confidence interval CI 0.36-0.78, pCONCLUSION: Results of this study indicated that negative symptoms could play a central role in the process of recovery from schizophrenia. A challenge for clinicians and researchers is to understand the mechanisms behind negative symptoms and develop interventions that can prevent or ameliorate these symptoms in order to promote recovery.

Introduction Diagnoses of anxiety and/or depression are common in subjects at Ultra-High Risk for Psychosis (UHR) and associated with extensive functional impairment. Less is known about the impact of affective comorbidities on the prospective course of attenuated psychotic symptoms (APS). Method Latent class mixed modelling identified APS trajectories in 331 UHR subjects assessed at baseline, 6, 12, and 24 months follow-up. The prognostic value of past, baseline, and one-year DSM-IV depressive or anxiety disorders on trajectories was investigated using logistic regression, controlling for confounders. Cox proportional hazard analyses investigated associations with transition risk. Results 46.8% of participants fulfilled the criteria for a past depressive disorder, 33.2% at baseline, and 15.1% at one-year follow-up. Any past, baseline, or one-year anxiety disorder was diagnosed in 42.9%, 37.2%, and 27.0%, respectively. Participants were classified into one of three latent APS trajectory groups: (1) persistently low, (2) increasing, and (3) decreasing. Past depression was associated with a higher risk of belonging to the increasing trajectory group, compared to the persistently low (OR = 3.149, [95%CI: 1.298–7.642]) or decreasing group (OR = 3.137, [1.165–8.450]). In contrast, past (OR = .443, [.179–1.094]) or current (OR = .414, [.156–1.094]) anxiety disorders showed a trend-level association with a lower risk of belonging to the increasing group compared to the persistently low group. Past depression was significantly associated with a higher risk of transitioning to psychosis (HR = 2.123, [1.178–3.828]). Conclusion A past depressive episode might be a particularly relevant risk factor for an unfavorable course of APS in UHR individuals. Early affective disturbances may be used to advance detection, prognostic, and clinical strategies.

Background The high prevalence of obsessive-compulsive symptoms (OCS) among subjects at Ultra-High Risk (UHR) for psychosis is well documented. However, the network structure spanning the relations between OCS and symptoms of the at risk mental state for psychosis as assessed with the Comprehensive Assessment of At Risk Mental States (CAARMS) has not yet been investigated. This article aimed to use a network approach to investigate the associations between OCS and CAARMS symptoms in a large sample of individuals with different levels of risk for psychosis. Method Three hundred and forty-one UHR and 66 healthy participants were included, who participated in the EU-GEI study. Data analysis consisted of constructing a network of CAARMS symptoms, investigating central items in the network, and identifying the shortest pathways between OCS and positive symptoms. Results Strong associations between OCS and anxiety, social isolation and blunted affect were identified. Depression was the most central symptom in terms of the number of connections, and anxiety was a key item in bridging OCS to other symptoms. Shortest paths between OCS and positive symptoms revealed that unusual thought content and perceptual abnormalities were connected mainly via anxiety, while disorganized speech was connected via blunted affect and cognitive change. Conclusions Findings provide valuable insight into the central role of depression and the potential connective component of anxiety between OCS and other symptoms of the network. Interventions specifically aimed to reduce affective symptoms might be crucial for the development and prospective course of symptom co-occurrence.

International audience; Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case-control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58-3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.