Brief rapport: Perceptual aberration in patients at ultra-high risk for psychosis.

BACKGROUND: Ultra-high risk (UHR) is considered a forerunner of psychosis, but most UHR individuals do not later convert, yet remain symptomatic, disabled and help-seeking. Thus, there is an increased recognition of the UHR phenotype as a syndrome in itself, rather than merely a risk syndrome. It is therefore essential to investigate outcomes other than transition to psychosis. For this purpose, perceptual aberration appears to be a distinct, as well as a stable and less state-specific vulnerability indicator. We aimed to investigate perceptual aberration and associations with functional, neuro and social cognitive risk factors in an UHR sample. METHOD: One hundred and twenty UHR and 64 healthy controls were compared on levels of perceptual aberration using the perceptual aberration scale. We further investigated cross-sectional associations between perceptual aberration and CAARMS (as a measure of subthreshold psychotic symptoms) and functional, neuro and social cognitive risk factors within the UHR using Spearmans ρ. RESULTS: Perceptual aberration was significantly higher in UHR than in healthy controls and was associated with social functioning, executive functioning, and emotion recognition. CONCLUSION: Our findings are consistent with a view of perceptual aberration as a stable vulnerability indicator that varies little with clinical state.

Premorbid functioning in adolescence associates with comorbid disorders in individuals at ultra-high risk for psychosis: A brief report.

AIM: This study examines associations between premorbid adjustment and comorbid disorders in individuals at ultra-high risk (UHR) for psychosis. METHODS: Premorbid social and academic adjustment data were collected from 146 UHR individuals using the Premorbid Adjustment Scale. Comorbid disorders were determined by the Structural Clinical Interview for DSM-IV. RESULTS: Logistic regressions showed lower premorbid social adjustment associated with personality disorders. Lower premorbid academic adjustment associated with affective disorders. More specifically, poor premorbid social adjustment in early and late adolescence associated with personality disorders. Lower premorbid social adjustment in late adolescence and lower premorbid academic adjustment in early adolescence associated with affective disorders. CONCLUSION: Partly corroborating evidence from schizophrenia samples, our findings suggest that poor premorbid adjustment relate to distinct comorbid disorders in UHR individuals. If replicated, it indicates that premorbid adjustment deficits may be a key area for targeted interventions improving the clinical prognosis of UHR individuals.

Sleep disturbances and the association with attenuated psychotic symptoms in individuals at ultra high-risk of psychosis.

Sleep disturbances are common in individuals at ultra high-risk (UHR) of psychosis and have proven to play a causal role in the occurrence of psychotic symptoms in healthy individuals. Only a few studies have systematically investigated sleep disturbances in UHR individuals. The help-seeking UHR individuals were 18-40 years old, and we included 72 UHR individuals according to the Comprehensive Assessment of At-Risk Mental State criteria (CAARMS) and 36 healthy controls. Sleep was measured with a modified version of the Karolinska Sleep Questionnaire and actigraphy for one night, and melatonin was measured at awakening and bedtime. We compared subjective rated sleep and actigraphy between healthy and UHR individuals (t-test and chi-square test) and examined the association between a CAARMS-composite score (linear regression). UHR individuals subjectively experienced poor sleep, categorised as disturbed sleep- and awakening index compared with healthy controls. We found no differences in actigraphy variables or morning/evening melatonin between UHR and healthy controls (t-test and chi-square). A high CAARMS-composite score was associated with high morning melatonin (B = 0.15, CI 0.02 to 0.27, p = 0.024) and high awakening index (B = 1.86, CI 0.58 to 3.14, p = 0.004) in UHR individuals. The results suggest that UHR individuals with high CAARMS scores have a delayed sleep phase; they have difficulties waking up and feel exhausted at awakening. It might be necessary to evaluate how UHR individuals sleep, and it would be of great interest to follow these patients over time according to the development of psychosis.

Associations between saliva alpha-amylase, heart rate variability, saliva cortisol and cognitive performance in individuals at ultra high-risk for psychosis.

BACKGROUND: Cognitive impairments are present in individuals at ultra-high risk (UHR) of psychosis and UHR individuals exhibit a hyperactive and dysfunctional HPA-axis. Increasing stress levels could potentially lead to cognitive impairments and no previous studies have examined the association between physiological stress biomarkers and cognition in UHR individuals. This study aims to examine the association between saliva alpha amylase (SAA), heart rate variability (HRV), saliva cortisol, and cognition in UHR individuals. METHOD: We included 72 UHR individuals, aged 18-40, fulfilling criteria of the comprehensive assessment of at-risk mental state (CAARMS). Cognitive tests indexed the 7 core domains as stated by Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). Physiological stress levels were observed for one day: saliva was collected at awakening, 30 min and 60 min after awakening and at bedtime. HRV was measured during sleep and before awakening. We used generalized linear model and controlled for multiple testing using false discovery rate (FDR). RESULTS: Higher levels of SAA were significantly associated with lower cognitive performance in the domains of verbal and visual learning and memory, sustained attention, working memory and global neurocognition looking at unadjusted data. Controlling for FDR visual memory, sustained attention and global neurocognition remained significant associated with SAA. We discovered no associations between cortisol and cognition. CONCLUSION: Visual learning and memory, sustained attention and global neurocognition remained significantly associated with SAA. This finding supports our hypothesis that an association between abnormal stress biomarkers and impaired cognition might be present in UHR individuals.

A longitudinal study on physiological stress in individuals at ultra high-risk of psychosis.

INTRODUCTION: Individuals at ultra high-risk (UHR) of psychosis exhibit significantly higher stress levels than healthy controls (HC). This study investigates how physiological stress measures differ between HC and UHR individuals and how physiological stress is associated with attenuated psychotic symptoms and changes over time in UHR individuals. Additionally, it examines how the use of medication affects physiological levels of stress. METHOD: The study included 72 UHR individuals and 36 HC. UHR were included according to the comprehensive assessment of at-risk mental state (CAARMS); a total-CAARMS score measured the attenuated psychotic symptoms and was calculated from the four psychosis subscales. HC and UHR were examined at baseline, and 47 UHR individuals were followed up after six months. Physiological stress measures were salivary cortisol, alpha-amylase (SAA) and heart-rate variability (HRV). Saliva was collected at four-time points during the day. RESULTS: There was no significant difference regarding cortisol (awakening response) or SAA measures between HC and UHR individuals. The use of antipsychotics and antidepressants was associated with low HRV in UHR individuals. In an exploratory analysis of 19 UHR individuals, we found an association between the change in total-CAARMS (six months total-CAARMS minus baseline total CAARMS) and the change in HRV during sleep (six months HRV minus baseline HRV). CONCLUSION: Our findings indicate that the use of antipsychotics and antidepressants could be associated with lower HRV in UHR individuals. There might be potential to investigate how HRV develops during the course of illness in UHR individuals.

Premorbid adjustment associates with cognitive and functional deficits in individuals at ultra-high risk of psychosis.

Premorbid social and academic adjustment are important predictors of cognitive and functional performance in schizophrenia. Whether this relationship is also present in individuals at ultra-high risk (UHR) for psychosis is the focus of the present study. Using baseline data from a randomised clinical trial (N = 146) this study investigated associations between premorbid adjustment and neuro- and social cognition and functioning in UHR individuals aged 18-40 years. Patients were evaluated with the Premorbid Adjustment Scale (PAS) comprising a social and an academic domain. Using validated measures neurocognition was assessed in the domains of processing speed, executive function, attention, verbal learning and memory, visual learning and memory, and working memory along with estimated IQ. Social cognitive domains assessed were theory of mind, emotion recognition, and attributional bias. Functional assessment comprised the domains of social- and role functioning, functional capacity, and quality of life. Linear regression analyses revealed poor premorbid academic adjustment to be associated with poorer performance in processing speed, working memory, attention, full scale IQ, and verbal IQ. Poor premorbid social adjustment was associated with theory of mind deficits. Additionally, both premorbid adjustment domains were associated with social- and role functioning and quality of life. Corroborating evidence from schizophrenia samples, our findings indicate poor premorbid adjustment to correlate with deficits in specific cognitive and functional domains in UHR states. Early premorbid adjustment difficulties may therefore indicate a poor cognitive and functional trajectory associated with significant impairments in early and established psychotic disorders suggesting targets for primary intervention.

Differential Effects of Aripiprazole and Amisulpride on Negative and Cognitive Symptoms in Patients With First-Episode Psychoses.

Introduction: Aripiprazole is hypothesized to have an effect on negative and cognitive symptoms in schizophrenia. Likewise, amisulpride is one of the only second-generation antipsychotics with which an effect on negative symptoms is reported. In the present study, we compare the effect of aripiprazole and amisulpride in initially antipsychotic-naïve patients with first-episode psychoses. Methods: Psychopathology and cognitive measures from two consecutive cohorts of antipsychotic-naïve first episode psychotic patients were obtained before and after 6 weeks of antipsychotic monotherapy with either aripiprazole or amisulpride. Matched healthy controls were included to account for retest effects on the cognitive measures. Analyses of variance (repeated-measures ANOVA) were performed to detect effect of time and possible cohort*time interactions. Results: Longitudinal data was obtained from 47 and 48 patients treated for 6 weeks with amisulpride or aripiprazole, respectively. For the Wallwork negative symptom dimension, there was a cohort*time interaction [F (1, 93) = 4.29, p = 0.041] and a significant effect of time [F (1, 93) = 6.03, p = 0.016], which was driven by an improvement in patients treated with aripiprazole [t (47) = 4.1, p < 0.001] and not observed in patients treated with amisulpride (p > 0.5). For the eight cognitive measures, no cohort*time interaction was found and neither was cognitive improvement in any of the cohorts when accounting for retest effect. Conclusion: Patients treated with aripiprazole improved on negative symptoms, which was not the case for patients treated with amisulpride. This may point to a general effect of a partial D2 receptor agonist on negative symptoms in patients with first-episode psychoses. There was, however, no improvement in cognitive functions.

Self-perceived cognitive impairments in psychosis ultra-high risk individuals: associations with objective cognitive deficits and functioning.

There is a scarcity of evidence on subjectively reported cognitive difficulties in individuals at ultra-high risk (UHR) for psychosis and whether these self-perceived cognitive difficulties may relate to objective cognitive deficits, psychopathology, functioning, and adherence to cognitive remediation (CR). Secondary, exploratory analyses to a randomized, clinical trial were conducted with 52 UHR individuals receiving a CR intervention. Participants completed the Measure of Insight into Cognition-Self Report (MIC-SR), a measure of daily life cognitive difficulties within the domains of attention, memory, and executive functions along with measures of neuropsychological test performance, psychopathology, functioning, and quality of life. Our study found participants with and without objectively defined cognitive deficits reported self-perceived cognitive deficits of the same magnitude. No significant relationship was revealed between self-perceived and objectively measured neurocognitive deficits. Self-perceived cognitive deficits associated with attenuated psychotic symptoms, overall functioning, and quality of life, but not with adherence to, or neurocognitive benefits from, a CR intervention. Our findings indicate that UHR individuals may overestimate their cognitive difficulties, and higher levels of self-perceived cognitive deficits may relate to poor functioning. If replicated, this warrants a need for both subjective and objective cognitive assessment in at-risk populations as this may guide psychoeducational approaches and pro-functional interventions. Self-perceived cognitive impairments do not seem to directly influence CR adherence and outcome in UHR states. Further studies are needed on potential mediator between self-perceived cognitive deficits and functioning and quality of life.

Experiential negative symptoms are more predictive of real-life functional outcome than expressive negative symptoms in clinical high-risk states.

BACKGROUND: Negative symptoms are key features of psychosis-spectrum disorders linked to psychosis development and functional impairments. This study investigated the predictive strength of negative symptoms domains on multiple aspects of real-life functional outcome in individuals at clinical high-risk (CHR) for psychosis. METHODS: A total of 146 UHR individuals were enrolled in a randomized, clinical trial (RCT), with this being analyses secondary to the RCT. The participants were assessed at baseline with the Scale for the Assessment of Negative Symptoms (SANS) encompassing the four domains of affect, alogia, avolition, and anhedonia. Functioning measures, encompassing overall-, social-, and role functioning, self-report social functioning, and quality of life, were obtained at 12-month follow-up. Regression analyses elucidated on the relationship between the four negative symptom domains and functional outcomes. RESULTS: Anhedonia and avolition were the aspects of negative symptoms most predictive of real-life functioning at 12-month follow-up explaining 7-20% of the variance on the outcome measures. Alogia was predictive of social functioning. These findings were maintained when controlling for the effect of neurocognition, antipsychotic medication, and depressive symptoms. DISCUSSION: Our findings show experiential negative symptoms to predict multiple areas of real-life functioning and quality of life, while expressive negative symptoms exert a modest influence on the functional prognosis of CHR individuals. Experiential negative symptoms may therefore constitute an important treatment target in intervention approaches aimed at enhancing the functional outcome of CHR individuals.

Assessing social skills in individuals at ultra-high risk for psychosis: Validation of the High Risk Social Challenge task (HiSoC).

BACKGROUND: Individuals at ultra-high risk (UHR) for psychosis exhibit deficits in social functioning that may relate to efficacy of social skills performance. There is, though, a scarcity of objective measures assessing social skills performance in the UHR state. This study assessed the psychometric properties of a relatively new social skills measure, the High Risk Social Challenge Task (HiSoC), in an UHR population. METHODS: Exploratory factor analysis was used to assess the factor structure of the HiSoC task in 102 UHR individuals and 66 healthy controls (HC). Convergent and discriminant validity of the HiSoC was assessed. RESULTS: Our findings revealed a three-factor structure comprising the factors "Affect", "Odd Behaviour and Language", and "Social-Interpersonal". The test showed excellent inter-rater reliability (ICC between 0.88 and 0.98). The HiSoC correlated significantly, as expected, with measures of global and social functioning demonstrating construct validity and utility as a social skills assessment tool in the UHR population. The HiSoC task discriminated between UHR and HC with large effect sizes (Cohen's d range=1.40-1.94). DISCUSSION: Our findings provide evidence for a three-factor structure of the HiSoC task corresponding to the original American version of the task. Additionally, our findings reveal the HiSoC to be sensitive to social skills impairments in the UHR population and suggest it to be a suitable screening tool for social skills deficits in UHR states. The robust correlations with real-life functioning indicate social skills to be an important target for assessment and intervention within the UHR population.

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

BACKGROUND: Studies 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: An 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.

Emotion recognition latency, but not accuracy, relates to real life functioning in individuals at ultra-high risk for psychosis.

BACKGROUND: Emotion recognition deficits are essential features of psychotic disorders and the ultra-high risk state of psychosis (UHR), that are known to relate to functional outcome. The potential associations between aspects of emotion recognition deficits and functioning are, however, understudied in UHR individuals. METHOD: Emotion recognition accuracy and latency were assessed in 132 UHR individuals and 60 healthy controls using the CANTAB emotion recognition task along with multiple measures of real life functioning. Multiple regression analyses assessed the potential relations between emotion recognition accuracy, latency, and measures of functioning. RESULTS: A consistent finding was that emotion recognition latency, but not accuracy, was associated with the four observer-rated measures of functioning (ß in the range -1.57 to -16.20), which remained significant on one measure after controlling for neurocognitive processing speed. Neither emotion recognition accuracy, nor latency related to real life functioning in healthy controls. DISCUSSION: The results suggest that processing speed of social cognitive information is an important correlate to real-life functioning in UHR individuals which may be a relevant target in social cognitive remediation programs for patients at risk for psychosis.

The effect of cognitive remediation in individuals at ultra-high risk for psychosis: a systematic review.

Cognitive deficits are prominent features of the ultra-high risk state for psychosis that are known to impact functioning and course of illness. Cognitive remediation appears to be the most promising treatment approach to alleviate the cognitive deficits, which may translate into functional improvements. This study systematically reviewed the evidence on the effectiveness of cognitive remediation in the ultra-high risk population. The electronic databases MEDLINE, PsycINFO, and Embase were searched using keywords related to cognitive remediation and the UHR state. Studies were included if they were peer-reviewed, written in English, and included a population meeting standardized ultra-high risk criteria. Six original research articles were identified. All the studies provided computerized, bottom-up-based cognitive remediation, predominantly targeting neurocognitive function. Four out of five studies that reported a cognitive outcome found cognitive remediation to improve cognition in the domains of verbal memory, attention, and processing speed. Two out of four studies that reported on functional outcome found cognitive remediation to improve the functional outcome in the domains of social functioning and social adjustment. Zero out of the five studies that reported such an outcome found cognitive remediation to affect the magnitude of clinical symptoms. Research on the effect of cognitive remediation in the ultra-high risk state is still scarce. The current state of evidence indicates an effect of cognitive remediation on cognition and functioning in ultra-high risk individuals. More research on cognitive remediation in ultra-high risk is needed, notably in large-scale trials assessing the effect of neurocognitive and/or social cognitive remediation on multiple outcomes.