Distinguishing Prodromal From First-Episode Psychosis Using Neuroanatomical Single-Subject Pattern Recognition

Background: The at-risk mental state for psychosis (ARMS) and the first episode of psychosis have been associated with structural brain abnormalities that could aid in the individualized early recognition of psychosis. However, it is unknown whether the development of these brain alterations predates the clinical deterioration of at-risk individuals, or alternatively, whether it parallels the transition to psychosis at the single-subject level. Methods: We evaluated the performance of an magnetic resonance imaging (MRI)-based classification system in classifying disease stages from at-risk individuals with subsequent transition to psychosis (ARMS-T) and patients with first-episode psychosis (FE). Pairwise and multigroup biomarkers were constructed using the structural MRI data of 22 healthy controls (HC), 16 ARMS-T and 23 FE subjects. The performance of these biomarkers was measured in unseen test cases using repeated nested cross-validation. Results: The classification accuracies in the HC vs FE, HC vs ARMS-T, and ARMS-T vs FE analyses were 86.7%, 80.7%, and 80.0%, respectively. The neuroanatomical decision functions underlying these discriminative results particularly involved the frontotemporal, cingulate, cerebellar, and subcortical brain structures. Conclusions: Our findings suggest that structural brain alterations accumulate at the onset of psychosis and occur even before transition to psychosis allowing for the single-subject differentiation of the prodromal and first-episode stages of the disease. Pattern regression techniques facilitate an accurate prediction of these structural brain dynamics at the early stage of psychosis, potentially allowing for the early recognition of individuals at risk of developing psychosis.Key words: at-risk mental state, early prediction of psychosis, voxel-based morphometry, multivariate analysis, machine learning, support vector machine     

A longitudinal study of neurocognitive function in individuals at-risk for psychosis

INTRODUCTION: Clinically defined prodromal diagnostic criteria identify at-risk individuals with a 35-40% likelihood of developing a psychotic disorder within a year. The time course and predictive value of cognitive deficits in the development of psychosis has not been established. METHODS: A comprehensive neurocognitive battery and clinical assessments were administered to 37 subjects meeting Criteria of Prodromal States (COPS) criteria for being at risk for psychosis, and two comparison groups: 59 first episode and 47 healthy subjects. Subjects were also evaluated at 6-month and 1-year follow-up periods. Primary analyses used a neurocognitive composite score derived from individual neurocognitive measures, including measures of vigilance, verbal memory, working memory, and processing speed. RESULTS: At-risk subjects performed more poorly than healthy subjects (t=2.93, P=0.01), but better than first episode subjects (t=4.72, p<0.0001). At-risk subjects were particularly impaired on measures of vigilance and processing speed. Cognitive composite scores were significantly lower in at-risk subjects who progressed to psychosis (N=11; z=-1.2), while those at-risk subjects who did not progress to psychosis (N=17) performed better (z=-0.5), and not significantly different from controls. Poor CPT performance combined with better WAIS-R digit symbol performance predicted progression to psychosis. Severity of neurocognitive deficits was not related to duration of prodrome or to time to development of psychosis and neurocognitive function improved in all subjects except those who progressed to psychosis. CONCLUSION: Neurocognitive impairment emerges early in the course of psychotic illness. Performance on tests of neurocognition may prove to be an early risk predictor for subsequent development of psychotic disorders.     

Aberrant Current Source-Density and Lagged Phase Synchronization of Neural Oscillations as Markers for Emerging Psychosis

Background:

Converging evidence indicates that neural oscillations coordinate activity across brain areas, a process which is seemingly perturbed in schizophrenia. In particular, beta (13-30 Hz) and gamma (30–50 Hz) oscillations were repeatedly found to be disturbed in schizophrenia and linked to clinical symptoms. However, it remains unknown whether abnormalities in current source density (CSD) and lagged phase synchronization of oscillations across distributed regions of the brain already occur in patients with an at-risk mental state (ARMS) for psychosis.

Methods:

To further elucidate this issue, we assessed resting-state EEG data of 63 ARMS patients and 29 healthy controls (HC). Twenty-three ARMS patients later made a transition to psychosis (ARMS-T) and 40 did not (ARMS-NT). CSD and lagged phase synchronization of neural oscillations across brain areas were assessed using eLORETA and their relationships to neurocognitive deficits and clinical symptoms were analyzed using linear mixed-effects models.

Results:

ARMS-T patients showed higher gamma activity in the medial prefrontal cortex compared to HC, which was associated with abstract reasoning abilities in ARMS-T. Furthermore, in ARMS-T patients lagged phase synchronization of beta oscillations decreased more over Euclidian distance compared to ARMS-NT and HC. Finally, this steep spatial decrease of phase synchronicity was most pronounced in ARMS-T patients with high positive and negative symptoms scores.

Conclusions:

These results indicate that patients who will later make the transition to psychosis are characterized by impairments in localized and synchronized neural oscillations providing new insights into the pathophysiological mechanisms of schizophrenic psychoses and may be used to improve the prediction of psychosis.Key words: schizophrenia, at-risk mental state (ARMS), resting state, EEG     

Multivariate patterns of brain-cognition associations relating to vulnerability and clinical outcome in the at-risk mental states for psychosis

Background: Neuropsychological deficits are a core feature of established psychosis and have been previously linked to fronto‐temporo‐limbic brain alterations. Both neurocognitive and neuroanatomical abnormalities characterize clinical at‐risk mental states (ARMS) for psychosis. However, structure–cognition relationships in the ARMS have not been directly explored using multivariate neuroimaging techniques. Methods: Voxel‐based morphometry and partial least squares were employed to study system‐level covariance patterns between whole‐brain morphological data and processing speed, working memory, verbal learning/IQ, and executive functions in 40 ARMS subjects and 30 healthy controls (HC). The detected structure–cognition covariance patterns were tested for significance and reliability using non‐parametric permutation and bootstrap resampling. Results: We identified ARMS‐specific covariance patterns that described a generalized association of neurocognitive measures with predominantly prefronto‐temporo‐limbic and subcortical structures as well as the interconnecting white matter. In the conversion group, this generalized profile particularly involved working memory and verbal IQ and was positively correlated with limbic, insular and subcortical volumes as well as negatively related to prefrontal, temporal, parietal, and occipital cortices. Conversely, the neurocognitive profiles in the HC group were confined to working memory, learning and IQ, which were diffusely associated with cortical and subcortical brain regions. Conclusions: These findings suggest that the ARMS and prodromal phase of psychosis are characterized by a convergent mapping from multi‐domain neurocognitive measures to a set of prefronto‐temporo‐limbic and subcortical structures. Furthermore, a neuroanatomical separation between positive and negative brain–cognition correlations may not only point to a biological process determining the clinical risk for disease transition, but also to possible compensatory or dysmaturational neural processes. Hum Brain Mapp 33:2104–2124, 2012. © 2011 Wiley Periodicals, Inc.     

Neurocognitive deficits in the (putative) prodrome and first episode of psychosis

OBJECTIVE: International research programs have contributed to the creation of operationally defined criteria to identify individuals at risk for schizophrenia. Although there has been substantial progress in the prospective study of the schizophrenia prodrome, the utility of current diagnostic criteria remains questionable because of the relatively low base rates of incident psychoses, the high false-positive rate and ethical concerns regarding the treatment of individuals at risk. The identification of brain based neurocognitive vulnerability markers for schizophrenia may contribute to the development of an at risk algorithm with greater predictive accuracy. METHODS: Forty subjects at risk (AR) for schizophrenia, 15 in their first episode (FE) of schizophrenia, and 36 healthy comparison (HC) subjects were administered a neurocognitive battery that assessed the domains of processing speed, working memory, verbal episodic memory, executive functioning and general intelligence. RESULTS: At baseline, AR subjects showed neurocognitive deficits across all domains compared to HC subjects that were less severe than those observed in the FE sample. In preliminary analyses, AR subjects who later converted to psychosis (N=5) had greater neurocognitive impairment at baseline evaluation compared to those individuals who remained "at risk" at follow-up. CONCLUSIONS: Neurocognitive deficits may be important in the pathogenesis of early psychosis and could help to define individuals at greatest risk for schizophrenia. Continued research in larger cohorts is needed to test the validity of this neurocognitive profile and its utility as a vulnerability marker.     

A longitudinal study of neurocognitive function in individuals at-risk for psychosis

IntroductionClinically defined prodromal diagnostic criteria identify at-risk individuals with a 35–40% likelihood of developing a psychotic disorder within a year. The time course and predictive value of cognitive deficits in the development of psychosis has not been established.MethodsA comprehensive neurocognitive battery and clinical assessments were administered to 37 subjects meeting Criteria of Prodromal States (COPS) criteria for being at risk for psychosis, and two comparison groups: 59 first episode and 47 healthy subjects. Subjects were also evaluated at 6-month and 1-year follow-up periods. Primary analyses used a neurocognitive composite score derived from individual neurocognitive measures, including measures of vigilance, verbal memory, working memory, and processing speed.ResultsAt-risk subjects performed more poorly than healthy subjects (t = 2.93, P = 0.01), but better than first episode subjects (t = 4.72, p < 0.0001). At-risk subjects were particularly impaired on measures of vigilance and processing speed. Cognitive composite scores were significantly lower in at-risk subjects who progressed to psychosis (N = 11; z = − 1.2), while those at-risk subjects who did not progress to psychosis (N = 17) performed better (z = − 0.5), and not significantly different from controls. Poor CPT performance combined with better WAIS-R digit symbol performance predicted progression to psychosis. Severity of neurocognitive deficits was not related to duration of prodrome or to time to development of psychosis and neurocognitive function improved in all subjects except those who progressed to psychosis.ConclusionNeurocognitive impairment emerges early in the course of psychotic illness. Performance on tests of neurocognition may prove to be an early risk predictor for subsequent development of psychotic disorders.     

Neurocognitive functioning in subjects at risk for a first episode of psychosis compared with first- and multiple-episode schizophrenia

Evidence from neurobiological studies suggests that schizophrenia arises from an early abnormality in brain development and possibly further progressive developmental mechanisms. Despite a delay between the acquisition of neuropathology and the triggering of psychosis, neurobiological susceptibility is likely to be expressed subclinically by biobehavioral markers in the premorbid stage. The exploratory study aims at identifying potential neurocognitive risk factors and investigating the unfolding of the illness within a cross-sectional design by comparing neurocognitive profiles in 179 healthy controls, 38 clinically identified subjects in an early initial prodromal state (EIPS) for psychosis, 90 subjects in a late initial prodromal state (LIPS), 86 first-episode patients with schizophrenia, and 88 multiple-episode patients. Subjects at risk were substantially impaired in verbal executive and verbal memory functions. Compared to EIPS subjects, LIPS subjects demonstrated additional attentional deficits. Both EIPS and LIPS subjects were superior to first-episode patients who presented a generalized neuropsychological deficit profile, and to multiple-episode patients who showed evidence for further decline. Although results were influenced by general intellectual abilities and demographic and clinical characteristics, they could not account for total group differences. Results support a neurodevelopmental model of psychosis with further progressive mechanisms and are consistent with a primary involvement of left frontotemporal networks in the prodromal phase.     

Neurocognitive performance in subjects at ultrahigh risk for schizophrenia: a comparison with first-episode schizophrenia

Objective

The aim of the present study was to explore the neurocognitive performance of patients at ultrahigh risk (UHR) compared with patients with first-episode (FE) schizophrenia and healthy control (HC) subjects.

Method

Twenty-seven subjects at UHR for schizophrenia, 25 patients in their FE of schizophrenia, and 33 HCs were included. All participants completed a neurocognitive battery, including tests of general intelligence, attention and working memory, executive function, and verbal and visual memory.

Results

Of the 3 groups, the FE subjects performed poorest at all neurocognitive tests, encompassing the broad range of impairments. The UHR subjects had a similar pattern of neuropsychological dysfunction but less severe than that of FE patients. The UHR subjects were particularly impaired on measures of attention and working memory, executive function, and verbal memory compared with the HCs.

Conclusion

These findings are consistent with the view that the neurocognitive impairments of schizophrenia are neurodevelopmental in nature and, although less severe, those impairments are mostly in place before the onset of the first frank psychotic episode. Neurocognitive impairments may play an important role in the pathogenesis of early psychosis and could help to clarify individuals at UHR for schizophrenia.     

Disorganization/Cognitive and Negative Symptom Dimensions in the At-Risk Mental State Predict Subsequent Transition to Psychosis

Objective:

The at-risk mental state (ARMS) is associated with a very high risk of psychosis, but it is difficult to predict which individuals will later develop psychosis on the basis of their presenting symptoms. We investigated psychopathological dimensions in subjects with an ARMS and examined whether particular symptom dimensions predicted subsequent transition to psychosis.

Method:

The sample comprised 122 subjects (aged 16–35 years) meeting Personal Assessment and Crisis Evaluation clinic criteria for the ARMS recruited through Outreach and Support in South London, a clinical service for people with an ARMS. A principal axis factor analysis was performed on symptom scores, obtained at presentation from the Comprehensive Assessment of the At-Risk Mental State, using Varimax rotation. The relationship between dimension scores and transition to psychosis during the following 24 months was then examined employing Cox regression analysis.

Results:

Factor analysis gave rise to a 5-factor solution of negative, anxiety, disorganization/cognitive, self-harm, and manic symptom dimensions, accounting for 37% of the total variance. Scores on the negative and on the disorganization/cognitive dimensions were associated with transition to psychosis during the follow-up period (P = 0.044 and P = 0.005, respectively).

Conclusion:

The symptoms of the ARMS have a dimensional structure similar to that evident in patients with schizophrenia except for the positive symptom dimension. The association between scores on the disorganization/cognitive and negative dimensions and later transition is consistent with independent evidence that formal thought disorder, subjective cognitive impairments, and negative symptoms are linked to the subsequent onset of psychosis.     

No associations between medial temporal lobe volumes and verbal learning/memory in emerging psychosis

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

Generalized and specific neurocognitive deficits in prodromal schizophrenia.

BACKGROUND: Neurocognitive deficits are considered to be central to the pathophysiology of schizophrenia, and the neurodevelopmental model suggests that such deficits precede full-blown psychosis. The present study examined performance on a broad neuropsychological battery of young subjects considered to be at clinical high risk for schizophrenia, who were subsequently followed to determine clinical outcome. METHODS: Subjects were 38 clinical high-risk patients (58% male patients; mean age = 16.5) and 39 sex- and age-matched healthy control subjects. At baseline, all high-risk patients had attenuated (subpsychotic) schizophrenialike positive symptoms. Clinical follow-up data of at least 6 months duration was available on 33 patients, of whom 12 developed nonaffective psychotic disorders. RESULTS: At baseline, clinical high-risk patients had significantly impaired global cognitive performance relative to control subjects and to estimates of their own prior intellectual functioning. Measures of verbal memory and executive functioning/working memory showed significantly greater impairments; visuospatial functioning was relatively spared. Prodromal patients who later developed psychosis had significantly lower verbal memory scores at baseline compared with patients who remained nonpsychotic. CONCLUSIONS: Verbal memory deficits may be an important risk marker for the development of schizophrenia-spectrum psychotic disorders, possibly indicating the presence of a prefrontal-hippocampal neurodevelopmental abnormality. Generalized neurocognitive impairment may be a nonspecific vulnerability marker.     

Impaired verbal memory in young adults with unipolar and bipolar depression

Aim: Early stages of severe mood disorders may be accompanied by neurocognitive changes. Specifically, deficits in verbal memory have been linked to depression in young people. This study examined whether young adults with unipolar compared with bipolar depression showed similar neurocognitive deficits. Methods: A total of 57 young adults (16–32 years) were assessed in this study. Twenty with unipolar and 20 with bipolar depression, all currently depressed, were compared with 17 healthy controls. Neuropsychological assessment included psychomotor speed, attention for routine mental operations, attentional switching, executive control and verbal learning and memory. Results: Both unipolar and bipolar subjects showed significant impairments in verbal memory and attentional switching compared with controls. Both mood disorder groups showed no impairments in psychomotor speed, attention for routine mental operations and executive control. Effects size calculations show that the unipolar and bipolar groups do not differ from each other across a range of neurocognitive measures. Conclusion: Neurocognitive deficits in young adults with current depressive syndromes appear to differ from those typically seen in older patients. In early adulthood, both unipolar and bipolar depression may be distinguished by poor verbal memory, despite intact speed of processing, attention and executive functions. This study suggests that there is utility in neuropsychological testing for young adults in the early stages of severe mood disorders. In order to prevent neurobiological changes inherent to the disease, pharmacological and non-pharmacological interventions that target verbal memory deficits may be optimally delivered early in the disease course.     

Different duration of at-risk mental state associated with neurofunctional abnormalities. A multimodal imaging study

Objectives: Neurofunctional alterations are correlates of vulnerability to psychosis, as well as of the disorder itself. How these abnormalities relate to different probabilities for later transition to psychosis is unclear. We investigated vulnerability‐ versus disease‐related versus resilience biomarkers of psychosis during working memory (WM) processing in individuals with an at‐risk mental state (ARMS). Experimental design: Patients with “first‐episode psychosis” (FEP, n = 21), short‐term ARMS (ARMS‐ST, n = 17), long‐term ARMS (ARMS‐LT, n = 16), and healthy controls (HC, n = 20) were investigated with an n‐back WM task. We examined functional magnetic resonance imaging (fMRI) and structural magnetic resonance imaging (sMRI) data in conjunction using biological parametric mapping (BPM) toolbox. Principal observations: There were no differences in accuracy, but the FEP and the ARMS‐ST group had longer reaction times compared with the HC and the ARMS‐LT group. With the 2‐back > 0‐back contrast, we found reduced functional activation in ARMS‐ST and FEP compared with the HC group in parietal and middle frontal regions. Relative to ARMS‐LT individuals, FEP patients showed decreased activation in the bilateral inferior frontal gyrus and insula, and in the left prefrontal cortex. Compared with the ARMS‐LT, the ARMS‐ST subjects showed reduced activation in the right inferior frontal gyrus and insula. Reduced insular and prefrontal activation was associated with gray matter volume reduction in the same area in the ARMS‐LT group. Conclusions: These findings suggest that vulnerability to psychosis was associated with neurofunctional alterations in fronto‐temporo‐parietal networks in a WM task. Neurofunctional differences within the ARMS were related to different duration of the prodromal state and resilience factors. Hum Brain Mapp 33:2281–2294, 2012. © 2011 Wiley Periodicals, Inc.     

A Stratified Model for Psychosis Prediction in Clinical Practice

Objective: Impaired cognition is an important dimension in psychosis and its at-risk states. Research on the value of impaired cognition for psychosis prediction in at-risk samples, however, mainly relies on study-specific sample means of neurocognitive tests, which unlike widely available general test norms are difficult to translate into clinical practice. The aim of this study was to explore the combined predictive value of at-risk criteria and neurocognitive deficits according to test norms with a risk stratification approach. Method: Potential predictors of psychosis (neurocognitive deficits and at-risk criteria) over 24 months were investigated in 97 at-risk patients. Results: The final prediction model included (1) at-risk criteria (attenuated psychotic symptoms plus subjective cognitive disturbances) and (2) a processing speed deficit (digit symbol test). The model was stratified into 4 risk classes with hazard rates between 0.0 (both predictors absent) and 1.29 (both predictors present). Conclusions: The combination of a processing speed deficit and at-risk criteria provides an optimized stratified risk assessment. Based on neurocognitive test norms, the validity of our proposed 3 risk classes could easily be examined in independent at-risk samples and, pending positive validation results, our approach could easily be applied in clinical practice in the future.Key words: prediction, psychosis, neurocognition, processing speed, at-risk criteria, risk estimation     

Neuropsychological Profiles in Different At-Risk States of Psychosis: Executive Control Impairment in the Early—and Additional Memory Dysfunction in the Late—Prodromal State

Impairments in neuropsychological functioning have been described in subjects clinically at high risk for psychosis, but the specific cognitive deficits in different clinical high-risk groups remain to be elucidated. The German Research Network on Schizophrenia employs a heuristic 2-stage model: a putatively late prodromal state (LPS), characterized by the onset of attenuated positive or brief psychotic symptoms, and an early prodromal state (EPS), mainly characterized by the presence of basic symptoms, which are predictive for psychosis within the next 10 years.A total of 205 subjects met the criteria for either an EPS or an LPS of psychosis and were assessed with a comprehensive neuropsychological test battery. Neurocognitive profiles of high-risk groups were compared with data of 87 healthy controls comparable with regard to gender, age, and premorbid verbal IQ.Patients in the LPS were impaired in all neurocognitive domains (memory/learning, executive control/processing speed, and working memory) examined, with memory being the worst. Deficits were less pronounced in patients in the EPS, with a specific deficit in the executive control/processing speed domain. Consistent with a progressive neurodevelopmental disorder, some cognitive abilities were already impaired in patients in the EPS, followed by further deterioration in the LPS. Specifically, deficits in executive control functioning were related to the presence of basic symptoms, indicating a vulnerability for psychosis. Memory deficits were associated with the onset of psychotic symptoms indicating further disease progression in the trajectory to psychosis and, thus, may be useful in predicting psychosis and targeting early intervention.     

Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers: Results From the FePsy Study

Background: Reliable prognostic biomarkers are needed for the early recognition of psychosis. Recently, multivariate machine learning methods have demonstrated the feasibility to predict illness onset in clinically defined at-risk individuals using structural magnetic resonance imaging (MRI) data. However, it remains unclear whether these findings could be replicated in independent populations. Methods: We evaluated the performance of an MRI-based classification system in predicting disease conversion in at-risk individuals recruited within the prospective FePsy (Früherkennung von Psychosen) study at the University of Basel, Switzerland. Pairwise and multigroup biomarkers were constructed using the MRI data of 22 healthy volunteers, 16/21 at-risk subjects with/without a subsequent disease conversion. Diagnostic performance was measured in unseen test cases using repeated nested cross-validation. Results: The classification accuracies in the “healthy controls (HCs) vs converters,” “HCs vs nonconverters,” and “converters vs nonconverters” analyses were 92.3%, 66.9%, and 84.2%, respectively. A positive likelihood ratio of 6.5 in the converters vs nonconverters analysis indicated a 40% increase in diagnostic certainty by applying the biomarker to an at-risk population with a transition rate of 43%. The neuroanatomical decision functions underlying these results particularly involved the prefrontal perisylvian and subcortical brain structures. Conclusions: Our findings suggest that the early prediction of psychosis may be reliably enhanced using neuroanatomical pattern recognition operating at the single-subject level. These MRI-based biomarkers may have the potential to identify individuals at the highest risk of developing psychosis, and thus may promote informed clinical strategies aiming at preventing the full manifestation of the disease.     

Deficit of theory of mind in individuals at ultra-high-risk for schizophrenia

BACKGROUND: Although a deficit in social cognition is regarded as an early indicator of schizophrenia, few studies have investigated social cognition in ultra-high-risk (UHR) individuals. METHODS: Our investigation involved subjects at UHR for psychosis (N=33) and an age- and IQ-matched healthy control (HC) group (N=36). Two types of theory of mind (ToM) tasks and a neuropsychological test battery were measured. RESULTS: Compared to the HC group, the UHR group performed significantly worse for ToM tasks, with the effect size at an intermediate level (0.64-0.68). Furthermore, the UHR group showed impaired performance in the executive and working memory tests, but not verbal memory tests. These deficits for ToM tests observed in the UHR group were significantly correlated with set-shifting tasks. CONCLUSIONS: Deficits in social cognition may be modest at the prodromal stage of schizophrenia and may be attributed to prefrontal dysfunction. To prevent or delay transition to psychosis, there is a need for specific preventive strategies targeting social functioning for the UHR group.     

The Palau Early Psychosis Study: neurocognitive functioning in high-risk adolescents

ObjectiveThe purpose of the present study was to evaluate both the independent and joint effects of genetic risk and clinical status on neurocognitive functioning in adolescents from a population isolate with an elevated risk for schizophrenia and strong familial aggregation of cases.MethodThe subjects were 310 non-help seeking, drug-naïve adolescents 14–19 years of age from the Republic of Palau. The sample comprised 98 Genetically High Risk (GHR) adolescents, 54 of whom were symptomatic, and 212 Genetically Low Risk (GLR) adolescents, including 113 Clinically High Risk (CHR) subjects who were symptomatic and 99 normal controls who were non-symptomatic. Neurocognitive testing was conducted after the clinical assessment and included Wechsler Memory Scale tests of logical, visual and working memory, the perceptual organization and processing speed subtests of the WISC-III, CPT-IP measures of sustained attention, and tests of fine and gross neuromotor function.ResultsGHR adolescents showed impairments in immediate logical memory, verbal working memory, CPT-IP performance, and fine motor skills. The only two cognitive components influenced by the presence of early psychosis symptoms were WISC-III perceptual organization and spatial working memory. Neurocognitive deficits did not increase with increasing levels of psychopathology. We found no significant interactive effects of genetic risk and clinical status on neurocognitive functioning.ConclusionsGenetic risk and clinical status exert independent effects on neurocognitive function in HR adolescents, and genetic risk has a broader impact than clinical status. Our results suggest that many of the neurocognitive impairments associated with early psychosis are genetically mediated and can occur in genetically vulnerable individuals regardless of their clinical status. However, visuospatial processing appears to be uniquely disrupted by emerging symptomatology.     

Stress biomarkers as predictors of transition to psychosis in at-risk mental states: Roles for cortisol,prolactin and albumin

Stress and inflammation are thought to play a role in the risk of developing a psychotic disorder. We aimed to identify stress-related biomarkers for psychosis transition in help-seeking individuals with an at-risk mental state (ARMS). We studied 39 ARMS subjects who were attending an Early Intervention Service. We included a control group of 44 healthy subjects (HS) matched by sex and age. Stressful life events and perceived stress were assessed. Stress-related biomarkers were determined in serum (cortisol, prolactin, C-reactive protein and albumin), plasma (fibrinogen) or saliva (morning cortisol, cortisol awakening response). All ARMS were followed-up at our Unit for at least one year. We divided the ARMS group into two subgroups based on the development of a psychotic disorder (ARMS-P, N = 10) or not (ARMS-NP, N = 29). ARMS-P reported more stressful life events and perceived stress than HS and ARMS-NP groups. In relation to baseline stress biomarkers, ARMS-P subjects had increased prolactin and lower albumin levels in serum, when compared to ARMS-NP and HS groups. These results did not change when repeated in a subsample of antipsychotic-naïve ARMS subjects. We also found significant differences between groups in the cortisol secretion after awakening. In a multinomial logistic regression adjusting for age, sex and life stress, prolactin was a predictor of psychosis transition whereas albumin levels had a protective effect. Our study underscores the role of stress and stress-related biomarkers (cortisol awakening response, prolactin and albumin) in the pathogenesis of psychosis.     

Neuropsychological functioning in early onset psychotic disorders

This paper examines whether neuropsychological profiles of youth with early onset psychotic disorders predicted diagnostic or clinical status. Youth with schizophrenia (n=27), bipolar disorder (n=22), and psychosis NOS (n=20) were included. Subjects received an extensive neuropsychological evaluation, including measures of general cognition, attention, memory, and executive functioning. Medication status was not controlled. No statistically significant neurocognitive differences across diagnostic groups were found. Compared to standardized norms, youth with schizophrenia demonstrated deficits in general cognition, verbal learning, recall, sustained effort, and social knowledge. Subjects with bipolar disorder and psychosis NOS exhibited deficits on measures of verbal learning, recall, and sustained effort similar to those of youth with schizophrenia. Neurocognitive deficits in memory and attention appeared to be common among youth with psychotic illnesses, regardless of diagnosis. Those with schizophrenia may have greater global cognitive deficits and problems with social knowledge. Across diagnoses, subjects demonstrated relative strengths on tests that provided them with immediate feedback, and performed most poorly on tests requiring delayed recall.