The impact of psychosis on the course of cognition: a prospective, nested case-control study in individuals at clinical high-risk for psychosis

BACKGROUND: Although cognitive deficits in patients with schizophrenia are rooted early in development, the impact of psychosis on the course of cognitive functioning remains unclear. In this study a nested case-control design was used to examine the relationship between emerging psychosis and the course of cognition in individuals ascertained as clinical high-risk (CHR) who developed psychosis during the study (CHR + T). METHOD: Fifteen CHR + T subjects were administered a neurocognitive battery at baseline and post-psychosis onset (8.04 months, s.d. = 10.26). CHR + T subjects were matched on a case-by-case basis on age, gender, and time to retest with a group of healthy comparison subjects (CNTL, n = 15) and two groups of CHR subjects that did not transition: (1) subjects matched on medication treatment (i.e. antipsychotics and antidepressants) at both baseline and retesting (Meds-matched CHR + NT, n = 15); (2) subjects unmedicated at both assessments (Meds-free CHR + NT, n = 15). RESULTS: At baseline, CHR + T subjects showed large global neurocognitive and intellectual impairments, along with specific impairments in processing speed, verbal memory, sustained attention, and executive function. These impairments persisted after psychosis onset and did not further deteriorate. In contrast, CHR + NT subjects demonstrated stable mild to no impairments in neurocognitive and intellectual performance, independent of medication treatment. CONCLUSIONS: Cognition appears to be impaired prior to the emergence of psychotic symptoms, with no further deterioration associated with the onset of psychosis. Cognitive deficits represent trait risk markers, as opposed to state markers of disease status and may therefore serve as possible predictors of schizophrenia prior to the onset of the full illness

Substance use in clinical high risk for psychosis: a review of the literature

AimIn the literature, there is evidence suggesting an association between substance use and psychosis. However, little is known about substance use in those who may be in the pre-psychotic phase, that is, those who are putatively prodromal are considered to be at clinical high risk (CHR) of developing psychosis. MethodsWe conducted a review of publications measuring patterns and rates of substance use in CHR for psychosis individuals and the effects on the transition to psychosis. ResultsOf 5527 potentially relevant research papers, 10 met inclusion criteria of CHR subjects and specifically mentioned substance use in the sample. The results of these studies varied. Cannabis, alcohol and tobacco/nicotine were reported as the most commonly used substances. There was limited information on the changes in patterns of use over time. Two out of the ten studies found a significant association between the use of substances and subsequent transition to psychosis. In one of these studies, substance abuse was a predictor of psychosis when included as a variable in a prediction algorithm. In the other study, the abuse of cannabis and nicotine was associated with transition to psychosis. ConclusionsWe found limited evidence to suggest that increased rates of substance use may be associated with transition to psychosis. However, further prospective research examining the association between substance use and transition to psychosis is required before any firm conclusions can be made

The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia.

RATIONALE: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. OBJECTIVES: This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. METHODS: The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. RESULTS: The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. CONCLUSION: This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.This work was supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). The authors thank Charlotte Oomen for valuable comments on the manuscript.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-4007-

Psychosis Prevention: A Modified Clinical High Risk Perspective From the Recognition and Prevention (RAP) Program

OBJECTIVE: Early intervention and prevention of psychosis remain a major challenge. Prediction would be greatly advanced with improved ability to identify individuals at true risk, which, at present, is moderate at best. The authors tested a modified strategy to improve prediction by selecting a more homogeneous high-risk sample (attenuated positive symptom criteria only, age range of mid-teens to early 20s) than is currently standard, combined with a systematic selection of neurodevelopmental deficits. METHOD: A sample of 101 treatment-seeking adolescents (mean age, 15.9 years) at clinical high risk for psychosis were followed clinically for up to 5 years (mean follow-up time, 3.0 years, SD=1.6). Adolescents were included only if they exhibited one or more attenuated positive symptoms at moderate to severe, but not psychotic, severity levels. Cox regression was used to derive a risk index. RESULTS: The overall conversion rate to psychosis was 28.3%. The final predictor model, with a positive predictive validity of 81.8%, consisted of four variables: disorganized communication, suspiciousness, verbal memory deficits, and decline in social functioning during follow-up. Significant effects also suggest narrowing the risk age range to 15-22 years. CONCLUSIONS: Clinical high risk criteria that emphasize disorganized communication and suspiciousness while also including compromised verbal memory and declining social functioning have the potential to improve predictive accuracy compared with attenuated positive symptoms used alone. On the resulting risk index (a weighted combination of the predictors), low scores were interpreted as signifying minimal risk, with little treatment necessary, high scores as suggesting aggressive intervention, and intermediate scores, although less informative, as supporting psychosocial treatment

Contributions of early cortical processing and reading ability to functional status in individuals at clinical high risk for psychosis

Background: There is a growing recognition that individuals at clinical high risk need intervention for functional impairments, along with emerging psychosis, as the majority of clinical high risk (CHR) individuals show persistent deficits in social and role functioning regardless of transition to psychosis. Recent studies have demonstrated reduced reading ability as a potential cause of functional disability in schizophrenia, related to underlying deficits in generation of mismatch negativity (MMN). The present study extends these findings to subjects at CHR. Methods: The sample consisted of 34 CHR individuals and 33 healthy comparison subjects (CNTLs) from the Recognition and Prevention (RAP) Program at the Zucker Hillside Hospital in New York. At baseline, reading measures were collected, along with MMN to pitch, duration, and intensity deviants, and measures of neurocognition, and social and role (academic/work) functioning. Results: CHR subjects showed impairments in reading ability, neurocognition, and MMN generation, relative to CNTLs. Lower-amplitude MMN responses were correlated with worse reading ability, slower processing speed, and poorer social and role functioning. However, when entered into a simultaneous regression, only reduced responses to deviance in sound duration and volume predicted poor social and role functioning, respectively. Conclusions: Deficits in reading ability exist even prior to illness onset in schizophrenia and may represent a decline in performance from prior abilities. As in schizophrenia, deficits are related to impaired MMN generation, suggesting specific contributions of sensory-level impairment to neurocognitive processes related to social and role function. (C) 2015 Elsevier B.V. All rights reserved

The Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P): description and validation in a psychiatric sample and healthy controls

Objective: The aim of the present study was to investigate the psychometric properties of the Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P), the first specific interview for emerging bipolar disorder (BD) symptoms. Methods: A total of 205 youth aged 12-23 years and/or their caregivers underwent BPSS-P interviews: 129 patients with mood spectrum disorders [ depression spectrum disorder (n = 77), mood disorder not otherwise specified (NOS) (n = 27), BD-NOS (n = 14), bipolar I disorder (BD-I)/bipolar II disorder (BD-II)/cyclothymia (n = 11), 34 with non-mood spectrum disorders, and 42 healthy controls (HCs)]. We used Cronbach\u27s alpha to assess internal consistency; intra-class correlation (ICC) for inter-rater reliability; Spearman\u27s rho for convergent validity with the Young Mania Rating Scale (YMRS), General Behavior Inventory-10-item Mania Form (GBI-M-10), and Cyclothymic-Hypersensitive Temperament (CHT) scale; and analysis of variance for discriminatory power between diagnostic groups. Results: Internal consistency was good to very good for the BPSS-P Mania (Cronbach\u27s alpha = 0.87), Depression (Cronbach\u27s alpha = 0.89), and General Symptom indices (Cronbach\u27s alpha = 0.74). Inter-rater reliability was high for the BPSS-P Total score (ICC = 0.939), and BPSS-P Mania (ICC = 0.934), Depression (ICC = 0.985), and General (ICC = 0.981) indices. Convergent validity was large (rho \u3e= 0.50) between the BPSS-P Mania Index and YMRS, GBI-M-10, and CHT; BPSS-P Depression Index and Montgomery-Asberg Depression Rating Scale (MADRS) and CHT; and BPSS-P General Index and GBI-M-10 and CHT. Expectedly, convergent validity was small (rho = 0.10 to \u3c 0.30) between the BPSS-P Mania Index and MADRS, and BPSS-P Depression Index and YMRS. Furthermore, the BPSS-P and its subscales discriminated each patient group from HCs and from non-mood spectrum patients (except for the BPSS-P General Index). Moreover, the BPSS-P Total score discriminated BD-I/BD-II/cyclothymia from depression spectrum patients, and the BPSS-Mania Index differentiated all three bipolar spectrum groups from depression spectrum patients. Conclusions: The BPSS-P has good to excellent psychometric properties. Its use across multiple settings and predictive validity requires further investigation

Association of Thalamic Dysconnectivity and Conversion to Psychosis in Youth and Young Adults at Elevated Clinical Risk

IMPORTANCE: Severe neuropsychiatric conditions, such as schizophrenia, affect distributed neural computations. One candidate system profoundly altered in chronic schizophrenia involves the thalamocortical networks. It is widely acknowledged that schizophrenia is a neurodevelopmental disorder that likely affects the brain before onset of clinical symptoms. However, no investigation has tested whether thalamocortical connectivity is altered in individuals at risk for psychosis or whether this pattern is more severe in individuals who later develop full-blown illness. OBJECTIVES: To determine whether baseline thalamocortical connectivity differs between individuals at clinical high risk for psychosis and healthy controls, whether this pattern is more severe in those who later convert to full-blown illness, and whether magnitude of thalamocortical dysconnectivity is associated with baseline prodromal symptom severity. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, 2-year follow-up, case-control study, we examined 397 participants aged 12-35 years of age (243 individuals at clinical high risk of psychosis, of whom 21 converted to full-blown illness, and 154 healthy controls). The baseline scan dates were January 15, 2010, to April 30, 2012. MAIN OUTCOMES AND MEASURES: Whole-brain thalamic functional connectivity maps were generated using individuals\u27 anatomically defined thalamic seeds, measured using resting-state functional connectivity magnetic resonance imaging. RESULTS: Using baseline magnetic resonance images, we identified thalamocortical dysconnectivity in the 243 individuals at clinical high risk for psychosis, which was particularly pronounced in the 21 participants who converted to full-blown illness. The pattern involved widespread hypoconnectivity between the thalamus and prefrontal and cerebellar areas, which was more prominent in those who converted to full-blown illness (t(173) = 3.77, P \u3c .001, Hedge g = 0.88). Conversely, there was marked thalamic hyperconnectivity with sensory motor areas, again most pronounced in those who converted to full-blown illness (t(173) = 2.85, P \u3c .001, Hedge g = 0.66). Both patterns were significantly correlated with concurrent prodromal symptom severity (r = 0.27, P \u3c 3.6 x 10(-8), Spearman rho = 0.27, P \u3c 4.75 x 10(-5), 2-tailed). CONCLUSIONS AND RELEVANCE: Thalamic dysconnectivity, resembling that seen in schizophrenia, was evident in individuals at clinical high risk for psychosis and more prominently in those who later converted to psychosis. Dysconnectivity correlated with symptom severity, supporting the idea that thalamic connectivity may have prognostic implications for risk of conversion to full-blown illness