Ultra-high Risk For Psychosis Research Articles

M22. IGG ANTIBODIES TO TOXOPLASMA GONDII ARE ASSOCIATED WITH INCREASED LONG-TERM RISK FOR PSYCHOSIS IN INDIVIDUALS AT ULTRA-HIGH RISK FOR PSYCHOSIS

BackgroundThe prevalence of antibodies to Toxoplasma gondii, a ubiquitous parasitic protozoan causing the infectious disease toxoplasmosis, is increased in patients with psychotic disorders compared to the general population. We have previously shown that antibody titers for T.gondii correlate with the severity of positive symptoms in young people at ultra-high risk (UHR) for psychosis, suggesting that infection with T. gondii may be relevant to the manifestation of psychosis. However, it is unclear if T. gondii antibodies represent a risk factor for psychosis onset or non-psychotic outcome in UHR individuals. The aim of the present study was to examine whether seropositivity for T.gondii is associated with transition to psychosis and other outcomes in young people at UHR for psychosis.MethodsThe study sample consisted of 96 individuals at UHR for psychosis who were referred to the Personal Assistance and Crisis Evaluation (PACE) clinic in Melbourne, Australia, between 2001 and 2004, consented to optional blood tests for infectious agents and were followed up for up to 10 years after baseline (median (interquartile range) duration of follow-up: 7.15 (3.14 – 7.72) years). Serum IgG antibodies to six viral and parasitic pathogens (Toxoplasma gondii, Herpes Simplex Virus Type 1 and 2, Cytomegalovirus, Epstein Barr Virus, Varicella-Zoster Virus) were measured at baseline. Outcome measures included transition to psychosis, general psychiatric symptomatology and positive psychotic symptoms (BPRS), negative symptoms (SANS), depressive symptoms (HAM-D), anxiety symptoms (HAM-A) and functioning (SOFAS and GAF). Cox proportional hazards regression and linear regression models were used to examine the associations of seropositivity and antibody titers at baseline and transition to psychosis and other outcomes at follow-up.ResultsA total of 17 individuals (17.7%) were seropositive for Toxoplasma gondii at baseline. The rate of transition to psychosis was higher among seropositive (35.7%) compared to seronegative participants (14.6%), although this was not statistically significant (p=0.101). Antibody titers (IgG) for Toxoplasma gondii were significantly higher at baseline in participants who later transitioned to psychosis (1.34 ± 1.36 vs. 0.79 ± 0.73, p=0.027). Seropositivity for T.gondii IgG at baseline significantly predicted transition to psychosis within the follow-up duration (hazard ratio [HR]=3.61, 95%CI 1.08 – 12.00, p=0.036). Toxoplasma IgG at baseline were significantly associated with higher BPRS scores at follow-up in participants who were seropositive at baseline (Beta=6.38, 95%CI 0.43 – 12.34, p=0.038). No significant associations were found between antibodies to other pathogens and outcome, or between antibodies to Toxoplasma gondii and any other outcomes.DiscussionOur findings suggest that the presence of IgG class antibodies for Toxoplasma gondii is associated with a higher risk for psychosis transition in individuals at UHR for psychosis, but not with risk for other long-term outcomes. These observations provide support for the hypothesis that infection with Toxoplasma gondii may be an environmental risk factor for psychosis and suggest that IgG antibodies for Toxoplasma gondii in individuals at UHR for psychosis have prognostic relevance.

T34. THE IMPACT OF ANTIDEPRESSANT USE ON THE TRANSITION TO PSYCHOSIS RATE IN THE NEURAPRO TRIAL

BackgroundOver the last two decades, several randomised controlled trials (RCTs) have indicated that preventive psychosocial, pharmacologic (Van der Gaag et al. 2013), and nutritional interventions (Amminger et al. 2010) are likely to be beneficial in people at ultra-high risk (UHR) of psychosis, in terms of delaying or preventing a transition to psychosis. Antidepressant medication is commonly prescribed in young people at UHR for psychosis; however, the evidence regarding its efficacy for psychosis prevention is limited (Fusar-Poli et al. 2007; Cornblatt et al. 2007; Fusar-Poli et al. 2015). The main aim of the present study is to investigate the impact of concomitant AD medication on the transition to psychosis rate in young people at ultra-high risk of psychosis who participated in the NEURAPRO trial (McGorry et al. 2017).MethodsIn this secondary analysis, data from 304 participants of a multicenter, double-blind, placebo-controlled, randomized clinical trial (NEURAPRO) of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) were included. During the trial, concomitant antidepressant medication was permitted for treatment of moderate to severe major depressive disorder (a score of ≥ 21 on the Montgomery-Asberg Depression Rating Scale, MADRS) in all participants.ResultsOf 304 participants, 189 (62.2%) were treated with ADs. 98 (64.1%) of those were in the omega-3 group and 91 (60.3%) in the placebo group. The transition rate to psychosis was higher in individuals who received AD treatment (13.2%; 25 of 189) as in individuals without ADs (6.1%; 7 of 115). The Kaplan-Meier survival curve estimated a group difference of X2 = 3.237, P = .072 (log rank test).DiscussionAntidepressants are widely used in early psychosis. This analysis does not support the view that antidepressants may have reduced the transition to psychosis rate in this cohort. The findings are limited by the fact that antidepressants were prescribed based on clinical discretion. A randomised controlled trial is needed to determine whether antidepressants have a role in prevention of transition to psychosis.

T61. FEELINGS OF SHAME AND GUILT IN INDIVIDUALS AT ULTRA-HIGH RISK FOR PSYCHOSIS

BackgroundSelf-conscious emotions, such as shame and guilt, play a key role in one’s thoughts and behaviors. Our study investigated how shame and guilt were different concerning multiple aspects of social cognitive abilities, and we evaluated the self-conscious emotions in individuals at ultra-high risk (UHR) for psychosis.MethodsFirstly, one hundred and sixty-six healthy youths were assessed for shame and guilt using the test of self-conscious affect, for empathy using interpersonal reactivity index (IRI), and for Theory of Mind (ToM) ability using the ToM picture stories task. Multiple linear regression analysis was performed to predict shame and guilt from the social cognitive variables. Secondly, twenty-four UHR and 24 age- and sex-matched normal controls were compared for shame, guilt, empathy, and ToM ability.ResultsResults in healthy youths, regression analysis with shame revealed that fantasy (t=3.0, p=0.003, β=0.22) and personal distress (t=5.8, p<0.001, β=0.42) of IRI and affective ToM (t=2.0, p=0.044, β=0.14) were significant determinants. In the regression model of guilt, there were independent predictors including perspective taking (t=3.5, p=0.001, β=0.28) and empathic concern (t=2.1, p=0.040, β=0.17) of IRI and cognitive ToM (t=2.1, p=0.037, β=0.15). In UHR individuals, higher levels of shame (t=-2.4, p=0.021), fantasy (t=-2.3, p=0.028), and personal distress (t=-3.4, p=0.001) and lower levels of perspective taking (t=4.0, p<0.001) and cognitive ToM (t=4.2, p<0.001) were observed. Moreover, high levels of shame was correlated with increased personal distress (r=0.78, p<0.001) in UHR for psychosis.DiscussionThese findings suggest that empathy and ToM ability predict persons’ shame- or guilt-proneness in healthy youths, and heightened personal distress in UHR individuals may possibly influence the level of shame which could lead to socially maladjustment behaviors. Dealing with social cognitive function would be helpful for reparation to UHR individuals.

M21. THE STEP TRIAL: A SEQUENTIAL MULTIPLE ASSIGNMENT RANDOMISED TRIAL (SMART) OF INTERVENTIONS FOR PATIENTS AT ULTRA-HIGH RISK OF PSYCHOSIS - STUDY RATIONALE, DESIGN AND BASELINE DATA

BackgroundAlthough approximately twenty randomised controlled trials have now been conducted with young people identified as being at high clinical risk of psychotic disorder, it remains unclear what the optimal type and sequence of treatments are for this clinical population. There has also been increased focus on clinical outcomes other than transition to psychotic disorder, such as psychosocial functioning, persistent attenuated psychotic symptoms and non-psychotic disorders. At Orygen, we are currently conducting a trial of a sequence of interventions consisting of two psychosocial therapies (support and problem solving [SPS] and cognitive-behavioural case management [CBCM]) and antidepressant medication. The primary outcome of the study is functional outcome after 6 months. This presentation will outline the background, rationale, design, recruitment and retention data and preliminary baseline results.MethodsSTEP is a sequential multiple assignment randomised trial (SMART) of treatments for young people (12–25 year olds) who meet ultra high risk for psychosis (UHR) criteria. Participants were recruited from primary (headspace) and secondary/tertiary (Orygen Youth Health) mental health services in Melbourne, Australia. The trial consists of three steps: Step 1: SPS (1.5 months); Step 2: SPS vs Cognitive Behavioural Case Management (4.5 months); Step 3: Cognitive Behavioural Case Management + Antidepressant Medication vs Cognitive Behavioural Case Management + Placebo (6 months). Patients who do not respond by the end of each step graduate to the next step in treatment. Responders are randomised to SPS or monitoring. Treatment response is based a combination of reduced attenuated psychotic symptoms, rated using the Comprehensive Assessment of At-Risk Mental States (CAARMS), and functional improvement (Social and Occupational Functioning Assessment Scale [SOFAS]) at the end of the treatment step. A ‘fast fail’ option is built into Step 3, whereby patients who deteriorate or have not responded 3 months into Step 3 are offered a choice of continuing existing treatment or commencing omega-3 fatty acids or low-dose antipsychotic medication. The intervention is for 12 months, with follow up at 18 and 24 months. A pilot study using the same design is currently being conducted at The University of California Davis.ResultsRecruitment has recently completed, with 342 patients recruited over a 2.4 year period, representing the largest UHR treatment study conducted to date. Preliminary results indicate an 8% response rate to Step 1 and a 23% response rate to Step 2. Discontinuation rates are 15% (step 1), 43% (step 2), 32% (step 3), primarily due to participants being lost to follow up or not wanting to start medication. The current transition to psychosis rate is 10.2%. Baseline clinical data are currently being analysed and will be presented at the conference.DiscussionPreliminary results indicate high non-response rates following SPS and moderate non-response rates following extended SPS or CBCM, possibly partly due to the stringent definition of response, which required substantial and persistent improvement in both attenuated psychotic symptoms and functioning. Discontinuation rates are low to moderate, reflecting the complexity and severity of this clinical population. The recruitment and retention data show that it is possible to conduct large-scale and complex stepped care trials with this high risk population in a primary mental health care setting (headspace services). Outcomes will inform the most effective type and sequence of treatments for improving psychosocial functioning, symptoms and reducing risk of developing psychotic disorder in this group, as well as identify predictors of treatment response.

S150. EMOTIONAL BEHAVIOUR IN HIGH-RISK AND FIRST-EPISODE PSYCHOSIS

BackgroundStudies indicate that people with schizophrenia and first-episode psychosis experience deficits in their ability to accurately detect and display emotions through facial expressions, and that functioning and symptoms are associated with these deficits. This study aims to examine how emotion recognition and facial emotion expression are related to functioning and symptoms in a sample of individuals at ultra-high risk, first-episode psychosis and healthy controls.MethodsDuring fMRI, we combined the presentation of emotional faces with the instruction to react with facial movements predetermined and assigned. 18 patients with first-episode psychosis (FEP), 18 individuals at ultra high risk of psychosis (UHR) and 22 healthy controls (HCs) were examined while viewing happy, sad, or neutral faces and were instructed to simultaneously move the corners of their mouths either (a). upwards or (b). downwards, or (c). to refrain from movement. The subjects’ facial movements were recorded with an MR-compatible video camera.ResultsNeurofunctional and behavioral response to emotional faces were measured. Analyses have only recently commenced and are ongoing. Full results of the clinical and functional impact of behavioral and neuroimaging results will be presented at the meeting.DiscussionIncreased knowledge about abnormalities in emotion recognition and behaviour as well as their neural correlates and their impact on clinical measures and functional outcome can inform the development of novel treatment approaches to improve social skills early in the course of schizophrenia and psychotic disorders.

M14. BDNF IS CORRELATE TO LOW EMOTION RECOGNITION IN UHR WOMEN: RESULTS FROM THE SSAPP POPULATIONAL UHR COHORT

BackgroundSchizophrenia is a disorder with prevalence rates of 1% in the general population. Science turned its efforts towards researching prodromal states, named “Ultra-high Risk” (UHR), in the hopes of impeding conversion to psychosis. Cognitive impairments are recognized among core features of schizophrenia and it is noted that they are already present at early stages of psychosis, such as ultra-high risk for psychosis (UHR). Schizophrenia in women has a more favorable outcome than in men with the disease in part mediated by cognitive performance. Neurotrophins, such as brain-derived neurotrophic factor (BDNF), play crucial roles in the expression of synaptic plasticity underpinning cognitive function, particularly expression of learning and memory. Previous studies showed conflicting results regarding neurotrophin levels in patients with psychosis. We hypothesized that UHR individuals would also show altered BDNF and cognitive performance levels.MethodsA sample of over 2500 individuals aged between 18 and 30 years old, from the city of São Paulo, Brazil, was drawn and screened with the Prodromal Questionnaire (PQ). 236 subjects with high scores (18+ points in the positive PQ subscale) where selected for psychiatric assessment with the SIPS (Structured Interview for Psychosis-Risk Syndromes), and 98 individuals were classified as UHR. Whole blood sample was collected and BDNF levels were analyzed with ELISA kits (Thermo-Fisher). Cognitive performance was measured by the emotion recognition task available via the UPenn Computerized neuropsychological testing (). Data was available for 93 UHR individuals (95%) and for 62 (46%) controls. IBM SPSS Statistics v23 for Mac was used to analyze data.ResultsBDNF levels and performance on emotion recognition task did not differ between control and UHR individuals. Differences were also not found if sample was analyzed according to sex. However, in UHR women (63% of UHR sample), worse performance was significantly associated with a higher BDNF level (Pearson correlation coefficient=-0.288, p=0.031).DiscussionIn our study, we found a correlation of worse emotion recognition task and higher BDNF levels in UHR women. This might be due a compensatory mechanism in which patients more severely impaired at baseline show higher BDNF levels. Estrogen might play a role in this difference as it induces BDNF expression. Several studies with psychotic patients shows higher BDNF levels in affected individuals as well as one study with UHR individual show higher BDNF levels within this group, but none showed differences between sexes. One study showed that treatment with selective estrogen receptor raloxifene increased activation in the right hippocampus and left inferior frontal gyrus areas, which are involved in facial recognition.Overall, literature suggests that women outperform men regarding overall cognitive function, including emotion recognition. Our findings might be related to a before homeostasis state has been reached in which baseline measures for emotion recognition in UHR women could be worse than in men but along time ameliorated via estrogen-induced BDNF expression.

T57. IMPAIRED FACIAL EMOTION RECOGNITION IN INDIVIDUALS AT ULTRA-HIGH RISK FOR PSYCHOSIS: CORRELATIONS WITH SCHIZOTYPY AND PARANOID LEVEL

BackgroundSchizophrenia patients and individuals at ultra-high risk for psychosis(UHR) have shown impaired facial emotion recognition(FER). Previous studies have reported lower accuracy and negative bias of FER in schizophrenia and UHR. These impairments have been studied with various factors such as schizotypy and paranoid level, but the results were inconsistent. This study aimed to identify the impairments of FER in UHR individuals and further to examine how these impairments relate to schizotypy and paranoid level.Methodsorty-three UHR individuals and 57 normal controls (NC) were requested to perform the facial emotion recognition(FER) task that consist of 60 facial photographs selected from standardized photographs of Ekman and Friesen series. For exploratory correlation analysis, schizotypy (Revised physical anhedonia scale, Magical ideation scale) and paranoid level (Paranoia scale, Persecution/suspicious item of Positive and Negative Syndrome Scale) were also examined in UHR individuals.ResultsThe UHR individuals showed lower accuracy rate for total FER task (70.6% vs. 75.6%, p=0.010) and more “fear” responses for neutral faces (14.5% vs. 6.0%, p=0.003) than NC. In exploratory correlation analysis for UHR individuals, the total accuracy rate of FER task showed significant correlation with both scales for schizotypy, but not with both scales for paranoid level. Among threat-related emotion response rates for neutral face, only “Disgust” response rate for neutral face was correlated with all scales for paranoid level, but not with scales for schizotypys in UHR individuals.DiscussionIn this study, we could identify inaccuracy and negative bias of FER in UHR individuals, Furthermore, we found that inaccuracy and negative bias were associated with schizotypy and paranoid level, respectively. These findings imply that inaccuracy and negative bias of FER in UHR individuals are of different nature. Future studies on the clinical implications of these findings would be needed.

T18. EFFECTS OF COGNITIVE REMEDIATION ON WHITE MATTER IN INDIVIDUALS AT ULTRA-HIGH RISK FOR PSYCHOSIS – A RANDOMIZED, CONTROLLED CLINICAL TRIAL

BackgroundIndividuals at ultra-high risk for psychosis (UHR) present with subtle white matter alterations, which have been associated with clinical and functional outcome. The effect of cognitive remediation on white matter (WM) in UHR-individuals has not been investigated.MethodsIn a randomized, clinical intervention-trial (FOCUS), UHR-individuals aged 18–40 years were assigned to treatment as usual (TAU) or TAU plus cognitive remediation (CR) for 20 weeks. CR comprised 20 x 2-hour sessions of neurocognitive and social-cognitive training (SCIT). Primary outcome was whole brain fractional anisotropy (FA) derived from diffusion weighted imaging. Secondary outcomes pertained to regions of interest analyses. Planned post-hoc analyses explored dose-response effects of CR on WM. Main analyses of treatment effect of CR on primary and secondary outcomes were conducted using linear mixed models, assessing the interaction of timepoint by group (CR and TAU). Analyses were conducted according to the intention-to-treat principle.Results111 UHR-individuals and 59 healthy controls were included. Attrition-rate was 30% at 6 months post-treatment follow-up. The CR group completed a mean of 12 hours of neurocognitive training.We found no effect of CR on whole-brain or regional FA. Planned post-hoc analyses revealed significant time*group (high- and low-attendance to CR) interactions in left superior corona radiata (p<0.01), left cingulum cingulate gyrus (P=0.03), and right superior longitudinal fasciculus (P<0,01), corrected. Specifically, when compared to UHR-individuals with high attendance (UHR-high >12 hours), those with low attendance (UHR-low <12 hours) had more co-morbid diagnoses, larger recreational smoking (nicotine and cannabis), more depressive and negative symptoms, and had significantly lower global FA at baseline, and showed a significant increase in FA after treatment. Furthermore, UHR-low displayed large effect-size (ES) improvements on depressive and negative symptoms, and moderate to large ES improvements in several cognitive functions (verbal fluency, verbal working memory, and processing speed). In contrast, UHR-high displayed large ES improvements in UHR-symptoms, and moderate ES improvement on social and occupational functioning.DiscussionContradicting our main hypothesis, we found no effect of CR on whole-brain or regional FA after six months. This may be explained by both the low number of neurocognitive training sessions and the attrition rate. The average of 12 hours of neurocognitive training is considerably lower than the recommended dosage of 25–30 hours necessary for cognitive improvements. The continuous need to develop feasible interventions and enhance adherence is stressed.Nevertheless, non-specific treatment may improve WM-integrity in UHR-individuals with lower global baseline FA in those with more severe psychopathology. The UHR-low subgroup exhibited improvements with large ES in levels of depressive and negative symptoms, as well as cognitive functions. We speculate, whether our results reflect that UHR-individuals with higher baseline FA (approaching the healthy controls), present with a preserved structural capacity for increased demands and new learning, while UHR-individuals characterized by lower FA at baseline may be more amendable to neuroplastic treatment-effects. The results support the value of subgrouping in a clinically heterogenous UHR-population, which also applies to examining WM integrity.

Metacognitive beliefs in individuals at risk for psychosis: asystematic review and meta-analysis of sex differences.

SummaryBackgroundSex differences were found in several domains in individuals at ultra-high risk for psychosis, but no previous work has systematically reviewed and analysed possible sex differences in metacognition in this population. However, alterations in metacognitive beliefs have been shown in the at-risk mental state for psychosis population. Our aim was to qualitatively review and quantitatively analyse the existing literature for data on sex differences in metacognitive beliefs—mainly depicted by the Metacognitions Questionnaire (MCQ) and its short form (MCQ-30)—in individuals with at-risk mental states.MethodsWe performed a systematic review of the literature on metacognition in help-seeking adolescents and young adults at ultra-high risk for psychosis. We included peer-reviewed articles that included a high-risk for psychosis group assessed with operationalised criteria and instruments. For the quantitative meta-analysis, only studies comparing MCQ data in high-risk individuals were included. A fixed-effect meta-model was used and forest plots drawn for each subscale and overall score. The studies were weighted according to the inverse variance method in order to calculate pooled confidence intervals and p values.ResultsNo article on metacognitive beliefs in individuals at increased risk for psychosis explicitly reported possible sex differences. Our meta-analysis of 234 (57% male) individuals’ scores in the MCQ yielded no significant sex difference.ConclusionsCurrently, no sex differences in metacognition can be described in the at-risk population; however, data are insufficient and heterogeneous with regard to thoroughly answering the question whether sex differences in clinical high-risk populations are mirrored in the metacognitive domain.

Associations between facial affect recognition and neurocognition in subjects at ultra-high risk for psychosis: A case-control study

The nature of facial affect recognition (FAR) deficits in subjects at ultra-high risk (UHR) for psychosis remains unclear. In schizophrenia, associations between FAR impairment and poor neurocognition have been demonstrated meta-analytically, but this potential link is understudied in the UHR population. Our study investigated a cross-sectional sample of UHR subjects (n = 22) and healthy controls (n = 50), with the Degraded Facial Affect Recognition (DFAR) Task and a neurocognitive test battery. Our primary aims were 1. to examine associations between FAR and neurocognition in UHR subjects and 2. to examine if associations differed between cases and controls. The secondary aim was to examine group differences in FAR and neurocognitive performance. In UHR subjects, FAR was significantly associated with working memory, a neurocognitive composite score and intelligence, and at trend level with most other assessed neurocognitive domains, with moderate to large effect sizes. There were no significant associations in controls. Associations between FAR and working memory and the neurocognitive composite score differed significantly between cases and controls. UHR subjects did not differ from controls on DFAR Task performance but showed significant deficits in three of six neurocognitive domains. Results may suggest that FAR is associated with working memory in UHR subjects, possibly reflecting a neurocognitive compensatory mechanism.

Subjective experience of social cognition in adolescents at ultra-high risk of psychosis: findings from a 24-month follow-up study

Deficits in social cognition have been reported in people at ultra-high risk (UHR) of psychosis exclusively using socio-cognitive tasks and in adolescent and young adult mixed population. Aim of this study was (1) to assess subjective experience of social cognition in adolescent help-seekers identified through UHR criteria, (2) to explore its significant correlations with psychopathology and functioning in UHR individuals; and (3) to monitor longitudinally its stability after a 24-month follow-up period. Participants [51 UHR, 91 first-episode psychosis (FEP), and 48 non-UHR/FEP patients], aged 13-18years, completed the comprehensive assessment of at-risk mental states and the GEOPTE scale of social cognition for psychosis. In comparison with non-UHR/FEP patients, both UHR and FEP adolescents showed significantly higher GEOPTE total scores. After 12months of follow-up, UHR individuals had a significant decrease in severity on GEOPTE "Social Cognition" subscore. In the UHR group at baseline, GEOPTE scores had significant positive correlations with general psychopathology, positive and negative dimensions. Across the 2-year follow-up period, social cognition subscores specifically showed more stable associations with general psychopathology and negative symptoms. Social cognition deficits are prominent in UHR adolescents and similar in severity to those of FEP patients at baseline. However, these impairments decreased over time, presumably together with delivery of targeted, specialized models for early intervention in psychosis.

Reduced activation of the ventromedial prefrontal cortex during self-referential processing in individuals at ultra-high risk for psychosis.

Defects in self-referential processing and perspective-taking are core characteristics that may underlie psychotic symptoms and impaired social cognition in schizophrenia. Here, we investigated the neural correlates of self-referential processing regardless of the perspective taken and third-person perspective-taking regardless of the target person to judge relevance in individuals at ultra-high risk for psychosis. We also explored relationships between alterations in neural activity and neurocognitive function and basic self ('ipseity') disorder. Twenty-two ultra-high-risk individuals and 28 healthy controls completed a functional magnetic resonance imaging task. While being scanned, participants were asked to take a first-person perspective or to put themselves in their close relative's place thereby adopting a third-person perspective during judgments of the relevance of personality trait adjectives to one's self and a close relative. For self-referential (vs other-referential) processing, ultra-high-risk individuals showed less neural activity in the left ventromedial prefrontal cortex/medial orbitofrontal cortex, which was correlated with poor working memory performance. When taking a third-person perspective (vs first-person perspective), ultra-high-risk individuals showed more activity in the middle occipital gyrus. Taken together, our findings suggest that ultra-high-risk individuals already show aberrant neural activity during self-referential processing which may possibly be related to engagement of working memory resources.

Metacognitive Therapy for Individuals at High Risk of Developing Psychosis: A Pilot Study.

Developing effective interventions for preventing first episode psychosis have been an important research focus in the last decade. Cognitive behavioral therapy is a currently indicated treatment for people at ultra-high risk of psychosis, however, access and resource issues limit its delivery within the NHS. Treatments which partial out potential active ingredients and are aimed at a range of psychological difficulties seen within this population have the potential to be more efficacious and efficient. We conducted a single-arm exploratory pilot trial, designed to investigate the feasibility and acceptability of Metacognitive therapy for individuals at ultra-high risk (UHR) of developing psychosis. Trial uptake was good, with 11 out of 12 referred individuals meeting for an eligibility assessment (one individual was excluded prior to the assessment). Of these, 10 individuals were eligible and included in the trial. Retention to treatment was high with 80% treatment adherence gained and an overall average of 8 sessions completed. All participants were offered follow-up assessments immediately post-treatment and at 6 months, which comprised measures of psychotic like experiences, anxiety and depression, and metacognitive processes implicated in the model. Retention to the post-treatment (12-week) follow-up was good, with 80% completion; however retention to the 6-month follow-up was lower at 60%. Clinically significant results were observed in psychotic like experiences, anxiety, depression and functioning with medium to large effect sizes. Measures related to beliefs and processes targeted within MCT showed clinically significant change with medium to large effect sizes. Our results suggest that MCT based upon a specific metacognitive model for individuals meeting ARMS criteria may be an important treatment target and warrants further attention. Limitations and possible focuses for future research are discussed.Registration: ISRCTN53190465 http://www.isrctn.com/ISRCTN53190465.

Investigating Cognitive and Clinical Predictors of Real-Life Functioning, Functional Capacity, and Quality of Life in Individuals at Ultra-High Risk for Psychosis

Abstract A substantial proportion of individuals at ultra-high risk (UHR) for psychosis show long-term functional impairments, which may have profound consequences for the individual and society. Finding predictors of these functional impairments is critical to inform on the individual’s functional prognosis and potentially develop targeted interventions. This study used data from 91 UHR individuals participating in a randomized, clinical trial, that were followed up at 12 months, to elucidate on clinical, neuro- and social-cognitive predictors of UHR individuals’ functional outcome in the domains of social- and role functioning, quality of life, and functional capacity. The proportion of UHR individuals showing a poor social- and role outcome at 12-month follow-up was 50% and 63%, respectively. Worse social outcome was predicted by higher levels of negative symptoms, reduced processing speed, and impaired baseline social functioning explaining 52% of the variance. Worse role outcome was predicted by impaired role functioning at baseline, explaining 25% of the variance. Quality of life impairments were predicted by better theory of mind explaining 4% of the variance, and functional capacity social skills deficits were predicted by impaired baseline social skills explaining 20% of the variance. Our findings indicate that processing speed and negative symptoms may contribute to social- and role-functioning deficits, and while aspects of social cognition may also relate to social- and role functioning, baseline-functional impairments seem to be a strong contributor to persistent impairments in functioning and quality of life. If replicated, our findings suggest the need for future studies investigating the effect of pro-functional interventions targeting baseline functioning and targeted cognitive domains in UHR.

Development of Executive Functions as Reflected in Daily Life Behaviors in Young Adults at Ultra-High Risk for Psychosis: Associations With Symptoms and Functioning

Abstract There is a paucity of evidence on executive functions (EF) as reflected in daily life behaviors in individuals at ultra-high risk (UHR) for psychosis. This prospective follow-up study investigated the 1-year development in EF in UHR compared to healthy controls (HC) and how this change may relate to change in severity of clinical symptoms, social communication, and functioning. UHR (N = 132) and HC (N = 66) were assessed with the Behaviour Rating Inventory of Executive Function–Adult version (BRIEF-A) self and informant report at baseline and 12 months follow-up comprising the Behavioral Regulation Index (BRI) and the Metacognition Index (MI). Additionally, data on depressive-, negative-, and attenuated psychotic symptoms and everyday social functioning were collected. The study found UHR to display large baseline impairments in EF in real life on both self- and informant reports. UHR and HC showed a significantly different development of EF over time, with UHR displaying greater improvements in EF compared to HC. Change in clinical symptoms did not relate to improvements in EF, except for depressive symptoms negatively associating with the development of the MI. Improvements on the BRI and MI were significantly associated with improvements in social functioning. Findings suggest the potential of UHR individuals displaying a larger ongoing maturational development of daily life EF than HC that seems predominantly independent of development of clinical symptoms. If replicated, this supports a maturational trajectory of daily life EF in UHR that approaches, but do not reach, the level of HC and may indicate a window of opportunity for targeted remediation approaches.

Baseline measures of cerebral glutamate and GABA levels in individuals at ultrahigh risk for psychosis: Implications for clinical outcome after 12months.

Cerebral glutamate and gamma-aminobutyric acid (GABA) levels might predict clinical outcome in individuals at ultrahigh risk (UHR) for psychosis but have previously primarily been investigated in smaller cohorts. We aimed to study whether baseline levels of glutamate and GABA in anterior cingulate cortex (ACC) and glutamate in thalamus could predict remission status and whether baseline metabolites differed in the remission versus the nonremission group. We also investigated the relationship between baseline metabolite levels and severity of clinical symptoms, functional outcome, and cognitive deficits at follow-up. About 124 UHR individuals were recruited at baseline. In this, 74 UHR individuals were clinically and cognitively assessed after 12months, while remission status was available for 81 (25 remission/56 nonremission). Glutamate and GABA levels were assessed at baseline using 3T proton magnetic resonance spectroscopy. Psychopathology, symptom severity, and remission were assessed with the Comprehensive Assessment of At-Risk Mental States and Clinical Global Impression and functional outcome with the Social and Occupational Functioning Assessment Scale. Cognitive function was estimated with the Cambridge Neuropsychological Test Automated Battery. There were no differences between baseline glutamate and GABA levels in subjects in the nonremission group compared with the remission group, and baseline metabolites could not predict remission status. However, higher baseline levels of GABA in ACC were associated with clinical global improvement (r=-0.34, N=51, p=0.01) in an explorative analysis. The variety in findings across studies suggests a probable multifactorial influence on clinical outcome in UHR individuals. Future studies should combine multimodal approaches to attempt prediction of long-term outcome.

Frontal brain activity in individuals at risk for schizophrenic psychosis and bipolar disorder during the emotional Stroop task - an fNIRS study.

The emotional Stroop effect is defined as increased reaction times to emotional stimuli compared to neutral ones. It has been often reported in the literature, on both behavioral and neurophysiological level. The goal of this study was to investigate the frontal brain activation in individuals at risk for schizophrenic psychosis and bipolar disorder during an emotional Stroop task. We expected to observe decreased activation in the at-risk individuals compared to the healthy controls. Individuals at high risk for psychosis (HR), at ultra-high risk for psychosis (UHR), at risk for bipolar disorder (BIP) and healthy controls (HC) performed an emotional Stroop task, which included positively, negatively and neutrally valenced words. Functional near-infrared spectroscopy (fNIRS) was used to measure levels of oxygenated hemoglobin (O2Hb) representing brain activity in the dorsolateral prefrontal and frontotemporal cortex. Results showed significantly decreased levels of O2Hb in the right dorsolateral prefrontal cortex (DLPFC) in the HR and UHR groups compared to the HC, indicating lower activity. Even though the decrease was independent from the valence of the words, it was the most visible for the negative ones. Moreover, significantly lower O2Hb levels in the frontotemporal cortex (FTC) were observed in all at risk groups compared to the HC. Lower activity in the FTC in groups at risk for psychosis and bipolar disorder reflects unspecific dysfunctions. Decreased activity in the DLPFC in the HR and UHR groups indicates that hypofrontality can be found already in individuals at risk for schizophrenic psychosis.

Fonctions exécutives chez les adolescents tunisiens à ultra-haut risque de psychose : étude comparative

BackgroundCognitive deficits have been identified in schizophrenia and in individuals at Ultra-High risk of psychosis (UHR). However, previous findings in this field are heterogeneous regarding which cognitive changes are specific to the development of schizophrenia. Our aim was to evaluate executive functions of adolescents at UHR of psychosis as compared to Help-Seeking Controls. MethodsWe studied 33 adolescents consisting of 17 at UHR of psychosis and 16 help-seeking adolescents, meeting the inclusion criteria of a National Research protocol for Early Detection of Psychosis. For detection, we used Comprehensive Assessment of At Risk Mental States (CAARMS), in its Arabic version. Executive functions were evaluated using the Stroop Color and Word Test, Trail Making Test-B (TMT-B) and the Rey complex figure test. Analyses compared cognitive performance between the two groups. ResultsThe performances of the UHR adolescents were impaired compared to those of the control adolescents in all the tests (Stroop, TMT-B, Rey complex figure). These differences reached a threshold of significance only in the Rey Complex Figure (Precision score in memory: P=0.010). ConclusionOur findings suggest that executive functions could serve as specific markers in UHR adolescents. However, experimental tasks challenging these cognitive functions are needed to interpret the predictive value of these findings.

Cerebral Glutamate and Gamma-Aminobutyric Acid Levels in Individuals at Ultra-high Risk for Psychosis and the Association With Clinical Symptoms and Cognition

BackgroundStudies examining glutamate or gamma-aminobutyric acid (GABA) in ultra-high risk for psychosis (UHR) and the association with pathophysiology and cognition have shown conflicting results. We aimed to determine whether perturbed glutamate and GABA levels in the anterior cingulate cortex and glutamate levels in the left thalamus were present in UHR individuals and to investigate associations between metabolite levels and clinical symptoms and cognition. MethodsWe included 122 UHR individuals and 60 healthy control subjects. Participants underwent proton magnetic resonance spectroscopy to estimate glutamate and GABA levels and undertook clinical and cognitive assessments. ResultsWe found no differences in metabolite levels between UHR individuals and healthy control subjects. In UHR individuals, we found negative correlations in the anterior cingulate cortex between the composite of glutamate and glutamine (Glx) and the Comprehensive Assessment of At-Risk Mental States composite score (p = .04) and between GABA and alogia (p = .01); positive associations in the anterior cingulate cortex between glutamate (p = .01) and Glx (p = .01) and spatial working memory and between glutamate (p = .04), Glx (p = .04), and GABA (p = .02) and set-shifting; and a positive association in the thalamus between glutamate and attention (p = .04). No associations between metabolites and clinical or cognitive scores were found in the healthy control subjects. ConclusionsAn association between glutamate and GABA levels and clinical symptoms and cognition found only in UHR individuals suggests a loss of the normal relationship between metabolite levels and cognitive function. Longitudinal studies with investigation of clinical and cognitive outcome and the association with baseline levels of glutamate and GABA could illuminate whether glutamatergic and GABAergic dysfunction predicts clinical outcome.

Basic symptoms in young people at ultra-high risk of psychosis: Association with clinical characteristics and outcomes

There has been limited research into the predictive value of basic symptoms and their relationship with other psychopathology in patients identified using the ‘ultra high risk’ (UHR) for psychosis approach. The current study investigated whether basic symptoms, specifically cognitive disturbances (COGDIS), were associated with a greater risk of transition to psychotic disorder and persistent attenuated psychotic symptoms (APS) at medium term follow-up (mean = 3.4 years) in UHR patients, as well as with general psychopathology at baseline. The sample included 304 UHR participants (mean age = 19.12 years) involved in an international multicenter trial of omega-3 fatty acids. UHR individuals who also met the COGDIS criteria (basic symptoms risk criteria) did not have a greater risk of transition than those who met the UHR criteria alone. However, meeting COGDIS risk criteria was associated with a greater likelihood of meeting the UHR attenuated psychotic symptoms risk group (i.e., having persistent attenuated psychotic symptoms) at 12-month follow-up (odds ratio = 1.85; 95% CI = 1.03, 3.32). Greater severity of cognitive basic symptoms was also independently associated with more severe general psychopathology at study entry. The findings do not support the notion that combined risk identification approaches (UHR and basic symptoms) aid in the identification of individuals at greatest risk of psychosis, although this interpretation is limited by the modest transition to psychosis rate (13%) and the time of follow up. However, the findings indicate that basic symptoms may be a clinically useful marker of more severe general psychopathology in UHR groups and risk for persistent attenuated psychotic symptoms.