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Background As efforts intensify to intervene early among those at risk for psychosis, examination of the relationship between presenting psychopathology and long-term functional outcome may guide treatment decision-making and offer a means to prevent or reduce chronic disability. Methods Data were collected through the Early Detection and Intervention for the Prevention of Psychosis Program (EDIPPP), a multisite national trial testing the efficacy of an early intervention for youth at risk of developing psychosis. Participants were followed prospectively and completed comprehensive evaluations at 6, 12, and 24 months, including the Structured Interview for Prodromal Syndromes (SIPS) and the Global Social and Role Functioning Scales. The present analyses included 327 participants and examined the relationships between baseline symptoms and longitudinal global social and role functioning using a linear mixed modeling approach. Results Higher baseline negative symptoms and deteriorated thought process predicted worse social and role functioning in the follow-up period. The effect of negative symptoms on social functioning, however, was moderated by positive symptoms, and the relationship between positive symptoms and social functioning changed over time. Baseline positive symptoms, distress, and level of symptom severity were not predictors of either social or role functioning. Conclusions Baseline negative symptoms and thought disorder appear to predict functional outcome for up to two years among adolescents and young adults at risk for psychosis. Developing effective interventions to target these symptoms may be critical to promote functional recovery among those experiencing attenuated symptoms or a first episode of psychosis.

The GABA deficit hypothesis remains one of the most compelling explanations for the information processing impairments in schizophrenia. However, much of the supportive evidence has been derived from post-mortem studies, whereas in vivo studies have largely yielded inconsistent results. We undertook this single voxel proton magnetic resonance (MRS) GABA study to test in a sample of recent onset patients the replicability of our prior finding of reduced early visual cortex GABA in schizophrenia. We also examined the possibility that antipsychotics could represent a significant confound by studying a small subsample of antipsychotic naive subjects. 23 adults with recent onset schizophrenia and a demographically matched sample of 31 healthy control subjects underwent MRS using a MEGA PRESS sequence on a 3T MR scanner to measure GABA concentration in early visual cortex. To control for in-scanner head movement confounding the results, we quantified the amount of head movement during GABA scans to identify and exclude from analysis scans with excessive movement. Patients demonstrated significantly reduced GABA levels compared to control subjects, p = 0.029. GABA levels did not differ significantly between patients who were antipsychotic naive (n = 7) and patients treated with antipsychotics. This replication in a recent onset sample suggest that diminished GABA in the visual cortex is a reliable finding, present in early phase of illness and not confounded by illness chronicity.

Background Although mental illness accounts for only 4% of aggressive behavior in the general population, there remains a modest association between aggressive behavior and psychotic disorders, particularly in the early stages of the illness. However, little is known about the specific factors associated to this increased risk. Aims The present study aims to assess the rates, characteristics and risk factors of aggressive behavior in first episode psychosis patients (FEP). Method We conducted a retrospective chart review of 449 FEP patients recruited from an outpatient early psychosis clinic. Aggressive behavior and clinical information were rated based upon information gathered from the chart review of data collected at baseline and after 6 months of follow-up. Results Rates of aggressive behavior were 54.3% in FEP patients. Aggressive behavior was significantly associated with higher rates of history of birth complications, neurodevelopmental delays, learning difficulties, alcohol use disorders, and the clinical domain of poverty symptoms. In addition to aggressive behavior, 16.7% of FEP patients exhibited suicidal ideation or behaviors and 11.4% exhibited non-suicidal self-injurious behavior (NSSIB). In contrast to baseline, aggressive behaviors at 6 months follow up were almost entirely absent. Conclusions Patients at early stages of psychosis have high rates of aggressive and suicidal behavior prior to contact with clinical services. Neurodevelopmental adversities, alcohol use disorders and poverty symptoms are associated to higher risk of aggression in early psychosis. Participation in early psychosis specialty care resulted in a dramatic reduction in aggressive behavior.

This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H₃ receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.

Individuals with autism and schizophrenia exhibit atypical language and social symptoms. The extent to which these symptoms are evident during development and in current functioning is unclear.Three groups of patients aged 11-20 diagnosed as clinical-high-risk for psychosis (CHR; n=15), first episode psychosis (FEP; n=16), and autism spectrum disorders (ASD; n=20), plus typically developing individuals (TYP; n=20) were compared on common autism parent-report questionnaires assessing social and language development and current functioning including the Social Communication Questionnaire, the Children's Communication Checklist, and the Social Reciprocity Scale.All clinical groups demonstrated atypical social and language development, with social impairment highest in ASD. Twenty percent of participants with CHR and FEP met diagnostic criteria for ASD as assessed by parent-report. ASD exhibited greater current syntactic, and pragmatic language symptoms including delayed echolalia, pedantic speech, and deficits in appreciating irony and sarcasm. All clinical groups exhibited current deficits in social functioning. CHR and FE had similar and intermediate levels of functioning relative to ASD and TYP, with CHR generally scoring closer to TYP, providing construct validity for the CHR diagnostic label.The results of this study suggest that ASDs, CHR, and FEP share common features of atypical neurodevelopment of language and social function. Evidence of impaired social reciprocity across both disorders and distinct language symptoms in ASDs provides important information for differential diagnosis and psychosis prevention, as well as leads for future investigations of comparative genetics and pathophysiology.

Background: Recent research on schizophrenia indicates that cognitive deficits in this illness are important predictors of functional outcome, highlighting the need for treatments that have a positive impact on cognitive function. Here we explore the hypothesis that acute administration of d-amphetamine can improve cognitive function in individuals with schizophrenia who are well-treated with typical antipsychotics, as well as in healthy controls performing under dual task conditions designed to elicit performance deficits analogous to those found in schizophrenia. Methods: Ten individuals with schizophrenia taking haldol or prolixin and 22 healthy controls performed spatial working memory, language production, and Stroop tasks under both placebo and 0.25 mg/kg of d-amphetamine. Results: d-Amphetamine improved reactions times on the spatial working memory and Stroop tasks for both individuals with schizophrenia and controls, and improved working memory accuracy in schizophrenia. In addition, d-amphetamine improved language production for both individuals with schizophrenia and controls. Conclusions: These results provide support for the hypothesis that the adjunctive administration of dopamine agonist can improve cognitive in individuals with schizophrenia taking typical antipsychotics. The results are discussed in terms of their implications for understanding the nature of working memory deficits in schizophrenia, and potential future avenues for cognitive enhancement in this illness. D 2005 Elsevier B.V. All rights reserved.

Patients with schizophrenia frequently demonstrate hypofrontality in tasks that require executive processing; however questions still remain as to whether prefrontal cortex dysfunctions are specific to schizophrenia, or a general feature of major psychopathology. Context processing is conceptualized as an executive function associated with attention and working memory processes. Impairment in the ability of patients with schizophrenia to represent and maintain context information has been previously reported in a number of studies. To examine the question of the specificity of a context processing deficit to schizophrenia, we used functional MRI and an expectancy AX continuous performance task designed to assess context processing in a group of healthy controls (n=9), depressed patient controls (n=10), and patients with schizophrenia (n=7). The behavioral performance was consistent with a context processing deficit in patients with schizophrenia, but not those with depression. The imaging data replicate previous results in showing abnormal activity in the right middle frontal gyrus (BA9) in schizophrenia patients related to context processing. D 2005 Published by Elsevier B.V.

Objective Suicide is highly-prevalent and the most serious outcome in schizophrenia, yet the disturbances in neural system functions that confer suicide risk remain obscure. Circuits operated by the prefrontal cortex (PFC) are altered in psychotic disorders, and various PFC changes are observed in post-mortem studies of completed suicide. We tested whether PFC activity during goal-representation (an important component of cognitive control) relates to long-term suicide risk in recent-onset schizophrenia. Method 35 patients with recent-onset of DSM-IV-TR-defined schizophrenia (SZ) were evaluated for long-term suicide risk (using the Columbia Suicide Severity Rating Scale) and functional MRI during cognitive control task performance. Group-level regression models associating control-related brain activation with suicide risk controlled for depression, psychosis and impulsivity. Results Within this group, past suicidal ideation was associated with lower activation with goal-representation demands in multiple PFC sectors. Among those with past suicidal ideation (n = 18), reported suicidal behavior was associated with lower control-related activation in premotor cortex ipsilateral to the active primary motor cortex. Conclusions This study provides unique evidence that suicide risk directly relates to PFC-based circuit dysfunction during goal-representation, in a major mental illness with significant suicide rates. Among those with suicidal ideation, the overt expression in suicidal behavior may stem from impairments in premotor cortex support of action-planning as an expression of control. Further work should address how PFC-based control function changes with risk over time, whether this brain–behavior relationship is specific to schizophrenia, and address its potential utility as a biomarker for interventions to mitigate suicide risk.

Impaired functional connectivity has been hypothesized as a potential source of the cognitive deficits routinely observed in patients with schizophrenia. Additionally, these deficits may be manifestations of the genetic liability to schizophrenia and present in the non-psychotic first-degree relatives of that group. However, no study has examined task-based functional connectivity in schizophrenia relatives using independent component analysis (ICA). We employed group ICA to test the hypothesis that the unexpressed genetic liability to schizophrenia is reflected in the functional connectivity between brain regions during a task measuring context processing. We compared 20 schizophrenia patients and 32 patients' first-degree relatives to 22 controls demographically matched to the patients and 28 controls' relatives, respectively. The group ICA showed differential connectivity between patients and controls in a task-related network constituting right middle frontal gyrus (MFG) and right posterior parietal lobe. A network constituting left MFG and left posterior parietal, which was also related to the context processing task, did not differ between groups. These findings demonstrate that connectivity abnormalities associated with the genetic liability to schizophrenia are most strongly expressed in a right lateralized executive fronto-parietal network, and that these abnormalities are linked to context processing impairments.

This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H₃ receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.

Encoding semantic relationships between items on word lists (semantic processing) enhances true memories, but also increases memory distortions. Episodic memory impairments in schizophrenia (SZ) are strongly driven by failures to process semantic relations, but the exact nature of these relational semantic processing deficits are not well understood. Here, we used a false memory paradigm to investigate the impact of implicit and explicit semantic processing manipulations on episodic memory in SZ. Thirty SZ and 30 demographically matched healthy controls (HC) studied Deese/Roediger-McDermott (DRM) lists of semantically associated words. Half of the lists had strong implicit semantic associations and the remainder had low strength associations. Similarly, half of the lists were presented under “standard” instructions and the other half under explicit “relational processing” instructions. After study, participants performed recall and old/new recognition tests composed of targets, critical lures, and unrelated lures. HC exhibited higher true memories and better discriminability between true and false memory compared to SZ. High, versus low, associative strength increased false memory rates in both groups. However, explicit “relational processing” instructions positively improved true memory rates only in HC. Finally, true and false memory rates were associated with severity of disorganized and negative symptoms in SZ. These results suggest that reduced processing of semantic relationships during encoding in SZ may stem from an inability to implement explicit relational processing strategies rather than a fundamental deficit in the implicit activation and retrieval of word meanings from patients’ semantic lexicon.

Context-processing deficits have been shown in schizophrenia during first-episode, medication-naïve status, that persist after short-term antipsychotic treatment and also in first-degree relatives of individuals with schizophrenia. To confirm longer term persistence of deficits, we examined schizophrenia patients (n=63) during first-episode, medication-naïve status through to one-year follow-up, compared to healthy control (n=83) and non-schizophrenia psychosis comparison (n=47) groups, as well as unaffected first-degree relatives of individuals with schizophrenia (n=31). Context-processing ability assessed by performance on the AX-CPT (Continuous Performance Test) at baseline, 8 weeks, 6 months, and 1 year (relatives only at baseline). Reaction time, error rates and signal detection indices (d′-context) of context processing were analyzed. Linear discriminant analyses (LDA) on early timepoints (baseline, 8 weeks) were conducted to predict confirmatory diagnosis (schizophrenia vs. psychosis control) at 6 months. Schizophrenia patients showed evidence of impaired context-processing relative to both the healthy and psychosis comparator groups at baseline and continued through to 1 year. While context-processing impairments persisted in schizophrenia patients through one year, the impairments in psychosis controls, which were more modest at baseline, remitted at follow-up. First-degree relatives showed deficits that were intermediate between the schizophrenia and healthy control groups. LDA showed 67% classification rates for distinguishing schizophrenia from non-schizophrenia psychosis. The persistence, diagnostic specificity and association with genetic liability give support for context processing impairments serving as a cognitive endophenotype for schizophrenia and that evaluation of context processing could contribute to diagnostic assessments.

Thirty percent of individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder, particularly schizophrenia. We assessed attenuated positive, negative and disorganized symptoms of psychosis and clinical-high-risk syndromes in 20 adolescents with 22q11.2DS (median age 15.1 years) using the Structured Interview for Prodromal Symptoms (SIPS). Two participants met criteria for the Attenuated Positive Symptom Syndrome, while nine participants (45%) experienced positive symptoms rated in the “moderate” to “severe and psychotic” range on the SIPS. Almost all presented with moderate to severe symptoms in the negative, disorganized, and general symptom domains.

Background . There is evidence that, even during remission, schizophrenia (SZ) patients are especially vulnerable to de-compensate under stress, and that they tend to have a high baseline serum cortisol levels. This study was undertaken to determine whether raising serum cortisol by the infusion of hydrocortisone, in the absence of additional psychological stress, would result in different cerebral activity changes in schizophrenic patients compared to normal controls (CON). We were especially interested in cerebral activity in regions such as the medial temporal lobe and hippocampus, since structural abnormalities in these brain regions were frequent in association with schizophrenia. Methods . Serum cortisol levels were raised, by infusing hydrocortisone, in 8 pairwise-matched SZ patients and 8 CONs. The associated regional cerebral activity changes were analyzed using statistical parametric mapping (SPM). Results . There was increased regional cerebral activity in response to elevated cortisol in the left hippocampal region in the SZ group, while the controls showed evidence of decreased regional cerebral activity in the same anatomical location. For the rest of the brain regions, cerebral activity increases and decreases, in response to raised serum cortisol, in the SZ followed the same regional pattern as in the control group, but with a smaller overall magnitude of change. The blunted response in SZ was most marked in the regions that showed greatest regional cerebral activity changes in normal subjects. Conclusion . Patients with schizophrenia showed an abnormal increased regional cerebral activity response to cortisol infusion in the left hippocampal region, and similar but attenuated regional cerebral activity response in other regions, when compared to matched controls.

Studies using the single trial Stroop task consistently reveal increased reaction time (RT) facilitation effects among schizophrenia patients. One possible mechanism underlying this effect is increased automatic spreading activation in semantic networks. The current study was designed to test this hypothesis. We administered the Stroop task and two semantic priming tasks to the same subjects. Patients showed greater Stroop RT facilitation than controls, no evidence of increased semantic priming at short stimulus onset asynchronies (SOAs), and reduced semantic priming at long SOAs. In addition, abnormal Stroop performance was related to the severity of Disorganization symptoms. These results are inconsistent with the spreading activation hypothesis. Alternative hypotheses regarding the source of Stroop task performance deficits in schizophrenia are discussed.

In previous work using the Stroop task to examine cognitive function in schizophrenia, we have suggested that reaction time (RT) facilitation and error interference should be more sensitive measures of cognitive function than RT interference. We examined this hypothesis in 36 DSM-IV schizophrenia and schizoaffective patients, who performed both the Stroop and the Speaking Span, a measure of verbal working memory. The results supported our hypotheses, demonstrating that RT facilitation and error interference were associated more strongly with working memory performance than RT interference. The robust correlations between these measures of selective attention and Speaking Span performance has implications for understanding the nature and selectivity of cognitive dysfunction in schizophrenia. We present several different hypotheses that may explain this relationship, including: (1) a generalized deficit; (2) a common cognitive disturbance; and (3) a common neurobiological dysfunction.