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1.  Prediction of conversion to psychosis: review and future directions 
This article reviews recent findings on predictors of conversion to psychosis among youth deemed at ultra high risk (UHR) based on the presence of subpsychotic-intensity symptoms or genetic risk for psychosis and a recent decline in functioning. Although transition rates differ between studies, the most well powered studies have observed rates of conversion to full psychosis in the 30–40% range over 2–3 years of follow-up. Across studies, severity of subthreshold positive symptoms, poorer social functioning, and genetic risk for schizophrenia appear to be consistent predictors of conversion to psychosis, with algorithms combining these indicators achieving positive predictive power ≥ 80%. Nevertheless, a substantial fraction of UHR cases do not convert to psychosis. Recent work indicates that UHR cases who present with lower levels of negative symptoms and higher levels of social functioning are more likely to recover symptomatically and no longer meet criteria for an at-risk mental state. In general, it appears that about 1/3 of UHR cases convert to psychosis, about 1/3 do not convert but remain symptomatic and functionally impaired, and about 1/3 recover symptomatically and functionally. Continued efforts to detect early risk for psychosis are critical for informing early intervention and provide increasing promise of delaying or even preventing the onset of psychosis.
PMCID: PMC4098037  PMID: 22286564
psychosis; prodrome; prediction; conversion; functional outcome
2.  Altered Age-Related Trajectories of Amygdala-Prefrontal Circuitry in Adolescents at Clinical High Risk for Psychosis: A Preliminary Study 
Schizophrenia research  2011;134(1):1-9.
Emotion processing deficits are prominent in schizophrenia and exist prior to the onset of overt psychosis. However, developmental trajectories of neural circuitry subserving emotion regulation and the role that they may play in illness onset have not yet been examined in patients at risk for psychosis. The present study employed a cross-sectional analysis to examine age-related functional activation in amygdala and prefrontal cortex, as well as functional connectivity between these regions, in adolescents at clinical high risk (CHR) for psychosis relative to typically developing adolescents. Participants (n=34) performed an emotion processing fMRI task, including emotion labeling, emotion matching, and non-emotional control conditions. Regression analyses were used to predict activation in the amygdala and ventrolateral prefrontal cortex (vlPFC) based on age, group, sex, and the interaction of age by group. CHR adolescents exhibited altered age-related variation in amygdala and vlPFC activation, relative to controls. Controls displayed decreased amygdala and increased vlPFC activation with age, while patients exhibited the opposite pattern (increased amygdala and decreased vlPFC activation), suggesting a failure of prefrontal cortex to regulate amygdala reactivity. Moreover, a psychophysiological interaction analysis revealed decreased amygdala-prefrontal functional connectivity among CHR adolescents, consistent with disrupted brain connectivity as a vulnerability factor in schizophrenia. These results suggest that the at-risk syndrome is marked by abnormal development and functional connectivity of neural systems subserving emotion regulation. Longitudinal data are needed to confirm aberrant developmental trajectories intra-individually and to examine whether these abnormalities are predictive of conversion to psychosis, and of later deficits in socioemotional functioning.
doi:10.1016/j.schres.2011.10.005
PMCID: PMC3245800  PMID: 22056201
psychosis; brain development; emotion; amygdala; prefrontal cortex; fMRI
3.  Elucidating a Magnetic Resonance Imaging-Based Neuroanatomic Biomarker for Psychosis: Classification Analysis Using Probabilistic Brain Atlas and Machine Learning Algorithms 
Biological psychiatry  2009;66(11):1055-1060.
Background
No objective diagnostic biomarkers or laboratory tests have yet been developed for psychotic illness. Magnetic resonance imaging (MRI) studies consistently find significant abnormalities in multiple brain structures in psychotic patients relative to healthy control subjects, but these abnormalities show substantial overlap with anatomic variation that is in the normal range and therefore nondiagnostic. Recently, efforts have been made to discriminate psychotic patients from healthy individuals using machine-learning-based pattern classification methods on MRI data.
Methods
Three-dimensional cortical gray matter density (GMD) maps were generated for 36 patients with recent-onset psychosis and 36 sex- and age-matched control subjects using a cortical pattern matching method. Between-group differences in GMD were evaluated. Second, the sparse multinomial logistic regression classifier included in the Multivariate Pattern Analysis in Python machine-learning package was applied to the cortical GMD maps to discriminate psychotic patients from control subjects.
Results
Patients showed significantly lower GMD, particularly in prefrontal, cingulate, and lateral temporal brain regions. Pattern classification analysis achieved 86.1% accuracy in discriminating patients from controls using leave-one-out cross-validation.
Conclusions
These results suggest that even at the early stage of illness, psychotic patients present distinct patterns of regional cortical gray matter changes that can be discriminated from the normal pattern. These findings indicate that we can detect complex patterns of brain abnormality in early stages of psychotic illness, which has critical implications for early identification and intervention in individuals at ultra-high risk for developing psychosis/schizophrenia.
doi:10.1016/j.biopsych.2009.07.019
PMCID: PMC3192809  PMID: 19729150
Classification; cortical pattern matching; MRI; psychosis; PyMVPA; schizophrenia
4.  Structural and Functional Brain Abnormalities in Schizophrenia 
Schizophrenia is associated with changes in the structure and functioning of a number of key brain systems, including prefrontal and medial temporal lobe regions involved in working memory and declarative memory, respectively. Imaging techniques provide an unparalleled window into these changes, allowing repeated assessments across pre- and post-onset stages of the disorder and in relation to critical periods of brain development. Here we review recent directions in structural and functional neuroimaging research on schizophrenia. The view emerging from this work is that schizophrenia is fundamentally a disorder of disrupted neural connectivity, the sources of which appear to be genetic and environmental risk factors influencing brain development both prenatally and during adolescence.
doi:10.1177/0963721410377601
PMCID: PMC4235761  PMID: 25414548
schizophrenia; structural MRI; diffusion tensor imaging; connectivity; development; adolescence
5.  Prediction of Psychosis in Youth at High Clinical Risk 
Archives of general psychiatry  2008;65(1):28-37.
Context
Early detection and prospective evaluation of individuals who will develop schizophrenia or other psychotic disorders are critical to efforts to isolate mechanisms underlying psychosis onset and to the testing of preventive interventions, but existing risk prediction approaches have achieved only modest predictive accuracy.
Objectives
To determine the risk of conversion to psychosis and to evaluate a set of prediction algorithms maximizing positive predictive power in a clinical high-risk sample.
Design, Setting, and Participants
Longitudinal study with a 2½-year follow-up of 291 prospectively identified treatment-seeking patients meeting Structured Interview for Prodromal Syndromes criteria. The patients were recruited and underwent evaluation across 8 clinical research centers as part of the North American Prodrome Longitudinal Study.
Main Outcome Measure
Time to conversion to a fully psychotic form of mental illness.
Results
The risk of conversion to psychosis was 35%, with a decelerating rate of transition during the 2½-year follow-up. Five features assessed at baseline contributed uniquely to the prediction of psychosis: a genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Prediction algorithms combining 2 or 3 of these variables resulted in dramatic increases in positive predictive power (ie, 68%–80%) compared with the prodromal criteria alone.
Conclusions
These findings demonstrate that prospective ascertainment of individuals at risk for psychosis is feasible, with a level of predictive accuracy comparable to that in other areas of preventive medicine. They provide a benchmark for the rate and shape of the psychosis risk function against which standardized preventive intervention programs can be compared.
doi:10.1001/archgenpsychiatry.2007.3
PMCID: PMC3065347  PMID: 18180426
6.  Reduced Dysbindin Expression Mediates NMDA Receptor Hypofunction and Impaired Working Memory Performance 
Biological psychiatry  2010;69(1):28-34.
Schizophrenia is a substantially heritable disorder associated with disrupted neural transmission, as well as dysfunction of brain systems involved in higher cognitive processes. Among the several putative candidate genes for schizophrenia, the gene encoding dystrobrevin-binding-protein-1 (aka dysbindin) is associated with cognitive impairments, including memory and attention deficits, in both schizophrenia patients and non-schizophrenic individuals. The mechanism underlying these deficits is thought to be based in changes in glutamatergic and dopaminergic function within corticostriatal networks, circuitry known to be critical for schizophrenia. Recent support for this hypothesis derives from the study of mice with a null mutation in the dysbindin gene that exhibit memory dysfunction and abnormalities in excitatory neurotransmission in prefrontal and hippocampal networks. At a cellular level, dysbindin is thought to mediate pre-synaptic glutamatergic transmission. Here, we investigated whether loss of dysbindin expression also affects postsynaptic NMDA receptor function. We show that decreases in dysbindin are associated with specific decreases in NMDA-evoked currents in prefrontal pyramidal neurons, as well as decreases in expression of the obligatory NMDA receptor subunit (NR1). Furthermore, the degree of NR1 expression directly correlates with performance on a spatial working memory task, providing a mechanistic explanation for cognitive changes previously associated with dysbindin expression. These data show a significant down-regulation of NMDA receptors due to dysbindin deficiency and illuminate molecular mechanisms mediating the association between dysbindin insufficiency and cognitive impairments associated with schizophrenia, encouraging study of the dysbindin/NR1 expression association in humans with and at risk for the disease.
doi:10.1016/j.biopsych.2010.09.012
PMCID: PMC4204919  PMID: 21035792
dysbindin; DTNBP1; NMDA; glutamate; schizophrenia; working memory
7.  Progressive Brain Structural Changes Mapped as Psychosis Develops in ‘At Risk’ Individuals 
Schizophrenia research  2009;108(1-3):85-92.
Background
Schizophrenia and related psychoses are associated with brain structural abnormalities. Recent findings in ‘at risk’ populations have identified progressive changes in various brain regions preceding illness onset, while changes especially in prefrontal and superior temporal regions have been demonstrated in first-episode schizophrenia patients. However, the timing of the cortical changes and their regional extent, relative to the emergence of psychosis, has not been clarified. We followed individuals at high-risk for psychosis to determine whether structural changes in the cerebral cortex occur with the onset of psychosis. We hypothesized that progressive volume loss occurs in prefrontal regions during the transition to psychosis.
Methods
35 individuals at ultra-high risk (UHR) for developing psychosis, of whom 12 experienced psychotic onset by 1-year follow-up (‘converters’), participated in a longitudinal structural MRI study. Baseline and follow-up T1-weighted MR images were acquired and longitudinal brain surface contractions were assessed using Cortical Pattern Matching.
Results
Significantly greater brain contraction was found in the right prefrontal region in the ‘converters’ compared with UHR cases who did not develop psychosis (‘non-converters’).
Conclusions
These findings show cortical volume loss is associated with the onset of psychosis, indicating ongoing pathological processes during the transition stage to illness. The prefrontal volume loss is in line with structural and functional abnormalities in schizophrenia, suggesting a critical role for this change in the development of psychosis.
doi:10.1016/j.schres.2008.11.026
PMCID: PMC2670732  PMID: 19138834
schizophrenia; MRI; brain mapping; longitudinal; prodrome; ultra-high risk
8.  Decreased neurotrophic response to birth hypoxia in the etiology of schizophrenia 
Biological psychiatry  2008;64(9):797-802.
Background
Obstetric complications, particularly fetal hypoxia, are associated with increased risk for schizophrenia later in life. Such factors are also related to increased severity of certain neuropathological features of schizophrenia, including hippocampal and cortical gray matter reduction, among individuals with a genetic susceptibility to the disorder. However, the molecular mechanisms underlying these associations are unknown. Here we sought to determine whether neurotrophic factors, which are stimulated as part of a neuroprotective response to fetal distress, are differentially expressed in cord blood samples at the time of birth following fetal hypoxia, maternal hypertension/small for gestational age status, and/or prematurity among individuals who developed schizophrenia as adults, as compared with controls.
Methods
One hundred and eleven cases with psychotic disorders (70 with schizophrenia) and 333 controls matched for gender, race, and date of birth, were drawn from the Philadelphia cohort of the National Collaborative Perinatal Project, in a nested case-control study. Brain derived neurotrophic factor (BDNF) was assayed from cord and maternal blood samples taken at delivery and stored at −20 C for 45–50 years.
Results
Among controls, birth hypoxia was associated with a significant (10%) increase in BDNF in cord samples, while among cases, hypoxia was associated with a significant (20%) decrease in BDNF. This differential response to fetal hypoxia was specific to schizophrenia and was not explained by other obstetric complications or by the BDNF Val66Met polymorphism.
Conclusions
These findings provide serologically based prospective evidence of disrupted neurotrophic signaling in response to birth hypoxia in the molecular pathogenesis of schizophrenia.
doi:10.1016/j.biopsych.2008.04.012
PMCID: PMC2655104  PMID: 18486103
Schizophrenia; Hypoxia; Brain Derived Neurotrophic Factor; Neuroprotection
9.  Cortisol Levels and Risk for Psychosis: Initial Findings from the North American Prodrome Longitudinal Study 
Biological psychiatry  2013;74(6):410-417.
Background
Studies of biomarkers of hypothalamic-pituitary-adrenal (HPA) activity indicate that psychotic disorders are associated with elevated cortisol. This study examined cortisol levels in healthy controls and individuals who meet clinical high risk (CHR) criteria for psychosis. It was hypothesized that cortisol levels would be; a) elevated in the CHR group relative to controls, b) positively correlated with symptom severity, and c) most elevated in CHR patients who transition to psychotic level severity.
Methods
Baseline assessments were conducted at eight centers in the North American Prodrome Longitudinal Study (NAPLS). The present CHR sample included 256 individuals meeting Structured Interview for Prodromal Syndromes (SIPS) criteria, and 141 controls, all of whom underwent baseline assessment and measurement of salivary cortisol.
Results
Consistent with previous reports, there was an effect of age on cortisol, with increases through the adolescent/early adult years. Analysis of covariance (ANCOVA) showed a main effect of diagnostic group, with the CHR group showing higher cortisol. There were modest, positive correlations of cortisol with baseline symptom severity, and ANCOVA revealed higher baseline cortisol in those who transitioned to psychotic level symptoms when compared to healthy controls and CHR subjects who remitted.
Conclusions
The present findings add to accumulating evidence of heightened cortisol secretion in CHR individuals. The findings also indicate nonspecific associations between cortisol levels and symptom severity, as well as symptom progression. The role of HPA activity in prediction of conversion to psychosis, and its relation with other biomarkers of risk, should receive attention in future research.
doi:10.1016/j.biopsych.2013.02.016
PMCID: PMC3707958  PMID: 23562006
psychosis; prodrome; high-risk; stress; cortisol; longitudinal
10.  North American Prodrome Longitudinal Study: A Collaborative Multisite Approach to Prodromal Schizophrenia Research 
Schizophrenia Bulletin  2007;33(3):665-672.
This article presents the rationale, design, and preliminary findings of the North American Prodrome Longitudinal Study (NAPLS), a collaborative, multisite investigation into the earliest phase of psychotic illness. We describe how 8 independently conceived research projects were integrated methodologically, how diagnostic reliability was achieved across sites on the Structured Interview for Prodromal Syndromes, and how baseline and follow-up data were aggregated for 888 at risk and comparison subjects. Data are presented describing the demographic, academic/work, and diagnostic characteristics of 3 relevant subgroups: persons at heightened clinical risk for psychosis, help-seeking comparison subjects, and nonpsychiatric controls. The NAPLS data set will be used to explore a series of questions related to prodromal psychosis, including the descriptive phenomenology of currently accepted diagnostic criteria, conversion rates over a 30-month period, predictors of psychosis onset and functional disability, and the impact of early treatment on the course of prodromal symptoms.
doi:10.1093/schbul/sbl075
PMCID: PMC2526151  PMID: 17255119
psychosis; prodrome; schizophrenia; consortium; early detection; prevention; NAPLS
11.  Preliminary Findings for Two New Measures of Social and Role Functioning in the Prodromal Phase of Schizophrenia 
Schizophrenia Bulletin  2007;33(3):688-702.
Introduction: Research on prediction and prevention of schizophrenia has increasingly focused on prodromal (prepsychosis) social and role dysfunction as developmentally early, stable, and treatment-resistant illness components. In this report, 2 new measures, Global Functioning: Social and Global Functioning: Role, are presented, along with preliminary findings about psychometric properties and course of social and role (academic/work) functioning in the prodromal phase of psychosis. Methods: Subjects included 69 participants from the Recognition and Prevention program and 52 from the Center for the Assessment and Prevention of Prodromal States. Ages ranged from 12 to 29 years, and all met criteria for Attenuated Positive Symptom syndrome. Retrospective (past year) and baseline data are reported for all 121 prodromal subjects and for 44 normal controls (NCs). Prospective follow-up data are reported for a subsample of patients reevaluated at both 6 and 12 months (N = 44). Results: For both scales, interrater reliability was high, and preliminary data supported construct validity. Relative to NCs, prodromal individuals displayed impaired social and role functioning at baseline. Analyses of change over time indicated that role functioning declined over the year before ascertainment and improved over 12-month follow-up, presumably with treatment. Social impairment, by contrast, was constant across time and predicted later psychosis (P = .002). Discussion: Using 2 new global measures, social functioning was found to be a stable trait, unchanged by treatment, with considerable potential to be a marker of schizophrenia. Role functioning, by contrast, may be a more direct barometer of clinical change and may be responsive to treatment and environmental change.
doi:10.1093/schbul/sbm029
PMCID: PMC2526147  PMID: 17440198
RAP; CAPPS; functional predictors; prodromal schizophrenia; outcome; psychosis; scale validation; Global Functioning: Social; Global Functioning: Role
12.  Editor's Introduction: The Empirical Status of the Ultra High-Risk (Prodromal) Research Paradigm 
Schizophrenia Bulletin  2007;33(3):661-664.
Given the growth of prodromal research in the past 15 years, the time seems right for assessing whether the ultra high-risk (UHR) research paradigm has delivered on its promise as an approach to identification of individuals at risk for imminent onset of psychosis and as a platform for studies assessing protective benefits of early interventions and for elucidating predictive markers. As demonstrated by the 8 articles on this theme in the present issue, the empirical basis of the prodromal research area has advanced significantly. While there is a lower risk for transition to psychosis in recent studies compared with initial studies, most recent studies still show a 30%–35% risk for psychosis within 1–2 years of follow-up, a rate that is substantially higher than the incidence rate of psychosis among transition age youth in the general population. Moreover, the means with which to improve this predictive equation is rapidly developing, enabled by the collaborative integration of data across multiple sites, the employment of multivariate risk algorithms, and a longitudinal perspective on symptoms, cognition, and functioning. All the initial intervention studies have produced encouraging findings, albeit with small sample sizes and relatively large attrition rates. Nevertheless, the findings in this issue, together with others like them appearing at an increasing rate in the world literature, indicate that the prodromal research area is increasing in maturity and sophistication, providing a useful heuristic for early detection and intervention in those at risk for psychosis.
doi:10.1093/schbul/sbm031
PMCID: PMC2526144  PMID: 17470445
psychosis; prodrome; prevention
13.  Decreased Birth Weight in Psychosis: Influence of Prenatal Exposure to Serologically Determined Influenza and Hypoxia 
Schizophrenia Bulletin  2012;39(5):1037-1044.
Background: Decreased birth weight (BW) is associated with later psychosis, but the sources of decreased BW for those at risk for psychosis remain unclear. Aim: To determine whether fetal exposure to influenza and/or hypoxia accounts for BW decreases among psychotic cases and controls. Method: Subjects were 111 cases diagnosed with schizophrenia or affective psychosis and 333 matched controls from the Collaborative Perinatal Project. Psychiatric diagnoses were ascertained from medical records. Influenza and hypoxia were determined from maternal and cord sera collected at birth. Results: Cases exposed to severe fetal hypoxia or influenza had significantly lower BW compared with unexposed cases and controls, regardless of exposure status. No significant differences in BW were observed among controls based on exposure status. Conclusions: Decreased BW appears to be a risk factor for psychosis only in the presence of other teratogens. Liability to psychosis likely renders fetuses vulnerable to decreased fetal growth in response to hypoxia and influenza.
doi:10.1093/schbul/sbs084
PMCID: PMC3756769  PMID: 22966148
obstetric complications; pregnancy; schizophrenia
14.  Genetic Risk for Schizophrenia, Obstetric Complications, and Adolescent School Outcome: Evidence for Gene-Environment Interaction 
Schizophrenia Bulletin  2012;39(5):1067-1076.
Low birth weight (LBW) and hypoxia are among the environmental factors most reliably associated with schizophrenia; however, the nature of this relationship is unclear and both gene-environment interaction and gene-environment covariation models have been proposed as explanations. High-risk (HR) designs that explore whether obstetric complications differentially predict outcomes in offspring at low risk (LR) vs HR for schizophrenia, while accounting for differences in rates of maternal risk factors, may shed light on this question. This study used prospectively obtained data to examine relationships between LBW and hypoxia on school outcome at age 15–16 years in a Finnish sample of 1070 offspring at LR for schizophrenia and 373 offspring at HR for schizophrenia, based on parental psychiatric history. Controlling for offspring sex, maternal smoking, social support, parity, age, and number of prenatal care visits, HR offspring performed worse than LR offspring across academic, nonacademic, and physical education domains. LBW predicted poorer academic and physical education performance in HR offspring, but not in LR offspring, and this association was similar for offspring of fathers vs mothers with schizophrenia. Hypoxia predicted poorer physical education score across risk groups. Rates of LBW and hypoxia were similar for LR and HR offspring and for offspring of fathers vs mothers with schizophrenia. Results support the hypothesis that genetic susceptibility to schizophrenia confers augmented vulnerability of the developing brain to the effects of obstetric complications, possibly via epigenetic mechanisms.
doi:10.1093/schbul/sbs098
PMCID: PMC3756777  PMID: 22941745
low birth weight; hypoxia; high risk; academic; physical education
15.  Between Site Reliability of Startle Prepulse Inhibition Across Two Early Psychosis Consortia 
Neuroreport  2013;24(11):626-630.
Prepulse inhibition (PPI) and reactivity of the acoustic startle response are widely used biobehavioral markers in psychopathology research. Previous studies have demonstrated that PPI and startle reactivity exhibit substantial within-site stability; between-site stability, however, has not been established. In two separate consortia investigating biomarkers of early psychosis, traveling subjects studies were performed as part of quality assurance procedures in order to assess the fidelity of data across sites. In the North American Prodromal Longitudinal Studies (NAPLS) Consortium, 8 normal subjects traveled to each of the 8 NAPLS sites and were tested twice at each site on the startle PPI paradigm. In preparation for a binational study, 10 healthy subjects were assessed twice in both San Diego and Mexico City. Intraclass correlations between and within sites were significant for PPI and startle response parameters, confirming the reliability of startle measures across sites in both consortia. There were between site differences in startle magnitude in the NAPLS study that did not appear to be related to methods or equipment. In planning multi-site studies, it is essential to institute quality assurance procedures early and establish between site reliability to assure comparable data across sites.
doi:10.1097/WNR.0b013e3283637845
PMCID: PMC4135529  PMID: 23799460
Endophenotype; Reliability; Startle; Prepulse Inhibition
16.  Negative symptoms in individuals at clinical high risk of psychosis 
Psychiatry research  2012;196(0):220-224.
Negative symptoms are present in the psychosis prodrome. However, the extent to which these symptoms are present prior to the onset of the first episode of psychosis remains under-researched. The goal of this study is to examine negative symptoms in a sample of individuals at clinical high risk (CHR) for psychosis and to determine if they are predictive of conversion to psychosis. Participants (n=138) were all participants in the North American Prodrome Longitudinal Study (NAPLS 1) project. Negative symptoms were assessed longitudinally using the Scale of Prodromal Symptoms. The mean total negative symptom score at baseline was 11.0, with 82.0% of the sample scoring at moderate severity or above on at least one negative symptom. Over the course of 12 months, the symptoms remained in the above moderate severity range for 54.0% of participants. Associations between individual symptoms were moderate (r= 0.31 to r= 0.57, P<0.001) and a factor analysis confirmed that all negative symptoms loaded heavily on one factor. Negative symptoms were more severe and persistent over-time in those who converted to psychosis, predicting the likelihood of conversion (χ2 = 17.63, df= 6, P< 0.01, R2 = 0.21). Thus, early and persistent negative symptoms may represent a vulnerability for risk of developing psychosis.
doi:10.1016/j.psychres.2012.02.018
PMCID: PMC4119605  PMID: 22445704
psychosis prodrome; negative symptoms; conversion to psychosis; longitudinal study; NAPLS1 project
17.  Processing Speed and Neurodevelopment in Adolescent-Onset Psychosis: Cognitive Slowing Predicts Social Function 
Onset of psychosis may be associated with abnormal adolescent neurodevelopment. Here we examined the neurocognitive profile of first-episode, adolescent onset psychosis (AOP) as compared to typically developing adolescents, and asked whether neurocognitive performance varied differentially as a function of age in the cases compared with controls. A comprehensive neuropsychological battery was administered to 35 patients experiencing a first-episode of a DSM-IV psychotic disorder and to 31 matched controls. Clinicians also rated subjects’ social and role functioning, both at the time of neuropsychological assessment and 1 year later. Although patients displayed a wide range of impairments relative to controls, their most pronounced deficits included verbal memory, sensorimotor dexterity and cognitive processing speed. Among these, only processing speed showed a significant group-by-age interaction, consistent with an aberrant developmental course among AOP patients. Processing speed also accounted for substantial variance in other areas of deficit, and predicted social functioning 1 year later. AOP patients fail to show normal age-related increases in processing speed, which in turn predicts poorer functional outcomes. This pattern is consistent with the view that adolescent brain developmental processes, such as myelination, may be disrupted in these patients.
doi:10.1007/s10802-011-9592-5
PMCID: PMC4119229  PMID: 22134489
Schizophrenia; Adolescence; Neurodevelopment; Outcome; Cognitive processing speed
18.  Psychotropic Medication Use in Youth at High Risk for Psychosis: Comparison of Baseline Data from Two Research Cohorts 1998-2005 and 2008-2011 
Schizophrenia research  2013;148(0):10.1016/j.schres.2013.05.019.
Background
Antipsychotic medication use rates have generally been rising among youth with psychiatric disorders, but little is known about use rates of antipsychotics or other psychotropic medications in patients at high risk for psychosis.
Method
Baseline psychotropic medication use rates were compared in two research cohorts of patients at high risk for psychosis that enrolled between 1998-2005 (n=391) and 2008-2011 (n=346). Treatment durations and antipsychotic doses were described for cohort 2.
Results
Median age was 17 years in cohort 1 and 18 years in cohort 2. The rate of prescription of any psychotropic at baseline was roughly 40% for each cohort. Antipsychotic prescription rates were 24% among sites that permitted baseline antipsychotic use in cohort 1 and 18% in the cohort 2; the decline did not quite reach statistical significance (p=0.064). In cohort 2 the mean±sd baseline chlorpromazine-equivalent dose was 121±108 mg/d, and lifetime duration of antipsychotic treatment was 3.8±5.9 months.
Discussion
Although the rate of antipsychotic prescription among high-risk youth may have fallen slightly, the nearly one-in-five rate in the second cohort still constitutes a significant exposure. Mitigating factors were that doses and durations of treatment were low. As for other nonpsychotic conditions, it is incumbent on our field to develop alternative treatments for high-risk patients and to generate additional evidence for or against the efficacy of antipsychotics to help define their appropriate role if alternative treatments fail.
doi:10.1016/j.schres.2013.05.019
PMCID: PMC3867209  PMID: 23787224
psychosis; high risk; risk syndrome; psychotropic medication; antipsychotic medication
19.  Early Traumatic Experiences in those at Clinical High Risk for Psychosis 
Early intervention in psychiatry  2013;7(3):300-305.
Aim
Several lines of evidence suggest a possible association between a history of trauma in childhood and later psychosis or psychotic-like-experiences. The purpose of this study was to determine the extent of childhood trauma and bullying in young people at clinical high risk (CHR) of developing psychosis.
Methods
The sample consisted of 360 individuals who were at CHR of developing psychosis and 180 age and gender matched healthy controls. All participants were assessed on past trauma and bullying. The CHR participants were also assessed on a range of psychopathology and functioning.
Results
Individuals at CHR reported significantly more trauma and bullying than healthy controls. Those who had experienced past trauma and bullying were more likely to have increased levels of depression and anxiety and a poorer sense of self.
Conclusions
These results offer preliminary support for an association between a history of trauma and later subthreshold symptoms.
doi:10.1111/eip.12020
PMCID: PMC3754436  PMID: 23343384
clinical high risk; psychosis; trauma; prodrome; risk
20.  A randomized trial of family focused treatment for adolescents and young adults at risk for psychosis: study rationale, design and methods 
Early intervention in psychiatry  2011;6(3):283-291.
Aim
This article outlines the rationale for a family-focused psychoeducational intervention for individuals at risk for psychosis and explains the design of a randomized multisite trial to test its efficacy.
Methods
Adolescents and young adults that meet criteria for a psychosis risk syndrome at eight participating North American Prodromal Longitudinal Study sites are randomly assigned to a 6-month, 18-session family-focused treatment for prodromal youth or a 3-session psychoeducational enhanced care control intervention and followed over 1 year.
Results
The results will determine whether the use of a family intervention is able to significantly improve functional outcomes, decrease the severity of positive symptoms and possibly prevent the onset of full psychosis, compared with enhanced care alone. Levels of familial criticism at baseline are hypothesized to moderate responses to family intervention. Improvements in knowledge about symptoms, family communication and problem solving will be tested as mediators in the pathways between treatment assignment and clinical or psychosocial outcomes in high-risk youth.
Conclusions
The ongoing trial evaluates whether a non-invasive psycho-social approach can significantly enhance functional outcomes and prevent the ultra high risk patients from developing psychosis. The results will provide an important stepping stone in the movement of the field from refining early detection strategies to developing efficacious preventative treatments.
doi:10.1111/j.1751-7893.2011.00317.x
PMCID: PMC4106700  PMID: 22182667
family therapy; prodrome; psychosis; schizophrenia; treatment
21.  Obstetric complications and risk for conversion to psychosis among individuals at high clinical risk 
Early intervention in psychiatry  2009;3(3):226-230.
Aim
Examining risk factors among high-risk populations stands to inform treatment and to elucidate our understanding of the pathophysiology of schizophrenia. Despite substantial evidence implicating the incidence of obstetric complications (OCs) as a risk factor for schizophrenia, little is known about the relationship between OCs and risk for conversion among high-risk individuals.
Methods
We prospectively followed individuals at high-risk for developing psychotic disorders for a 2-year period to determine if a history of OCs is associated with conversion.
Results
Individuals who converted to psychosis had significantly more OCs when compared to non-converting participants; a history of OCs was associated with increased odds of conversion (OR=4.90, CI:1.04/22.20). OCs were positively associated with prodromal symptomatology.
Conclusions
To date, this report represents the first empirical evidence suggesting that OCs confer increased risk of conversion to psychosis. It is possible that OCs interact with brain maturational processes in the pathophysiology of schizophrenia and can serve as a risk marker.
doi:10.1111/j.1751-7893.2009.00137.x
PMCID: PMC4090059  PMID: 22640387
Obstetric Complications; Prodromal; Conversion; Schizophrenia; Psychosis
22.  Youth-caregiver Agreement on Clinical High-risk Symptoms of Psychosis 
Early identification of individuals who will go on to develop schizophrenia is a difficult endeavor. The variety of symptoms experienced by clinical high-risk youth make it difficult to identify who will eventually develop schizophrenia in the future. Efforts are being made, therefore, to more accurately identify at-risk individuals and factors that predict conversion to psychosis. As in most assessments of children and adolescents, however, both youth and parental report of symptomatology and resulting dysfunction are important to assess. The goals of the current study were to assess the extent of cross-informant agreement on the Structured Interview for Prodromal Symptoms (SIPS), a widely-used tool employed to determine clinical high-risk status. A total of 84 youth-caregiver pairs participated. Youth and caregiver raters displayed moderate overall agreement on SIPS-rated symptoms. Both youth and caregiver ratings of youth symptomatology contributed significantly to predicting conversion to psychosis. In addition, youth age and quality of youth-caregiver relationships appear to be related to cross-informant symptom ratings. Despite differences on individual SIPS domains, the majority of dyads agreed on youth clinical high-risk status. Results highlight the potential clinical utility of using caregiver informants to determine youth psychosis risk.
doi:10.1007/s10802-013-9809-x
PMCID: PMC4074879  PMID: 24092494
CHR; Clinical high risk; Assessment; Psychosis; Adolescents; Cross-informant agreement
23.  Cognitive Functioning Prior to the Onset of Psychosis: The Role of Fetal Exposure to Serologically Determined Influenza Infection 
Biological psychiatry  2009;65(12):1040-1047.
Background
Previous studies have linked prenatal influenza exposure to increased risk of schizophrenia; however, no study has examined the neurodevelopmental sequelae of this prenatal insult before the onset of psychotic symptoms using serological evidence of infection. This study sought to examine the contribution of prenatal influenza A and B exposure to cognitive performance among children who developed psychoses in adulthood versus nonpsychiatric control children.
Methods
Subjects were 111 cases (70 with schizophrenia and 41 with affective psychoses) and 333 matched control subjects followed from gestation until age 7 through the Collaborative Perinatal Project. The Wechsler Intelligence Scale for Children (age 7) was administered and adult psychiatric morbidity was assessed by medical records review and confirmed by a validation study. Assays were conducted from archived prenatal maternal sera collected at birth, and influenza infection was determined by immunoglobulin G (IgG) antibody titers >75th percentile.
Results
Significant decreases in verbal IQ and the information subtest, as well as similar nonsignificant reductions in full scale IQ scores and vocabulary, comprehension, digit span, and picture arrangement subtests were found among cases who were prenatally exposed to influenza B versus cases who were not exposed. Fetal exposure to influenza B did not lead to any significant differences in cognitive performance among control children.
Conclusions
Cumulatively, these findings suggest that a genetic and/or an environmental factor associated with psychosis rendered the fetal brain particularly vulnerable to the effects of influenza B, leading to poorer cognitive performance even before symptom onset.
doi:10.1016/j.biopsych.2008.12.015
PMCID: PMC4058882  PMID: 19195645
Collaborative Perinatal Project; cognitive outcomes; infection; influenza; IQ; obstetric complications; premorbid; psychosis; schizophrenia; serological
24.  Sexual dimorphisms and prediction of conversion in the NAPLS psychosis prodrome 
Schizophrenia research  2013;144(0):43-50.
Sex differences in age at onset, symptomatology, clinical course (see Walker, Walder, Lewine and Loewy, 2002) and functional impairment (Thorup et al., 2007) are well documented in psychosis. The general pattern of findings is that males manifest an earlier onset, more severe symptoms and poorer prognosis than females. Limited studies examining individuals at clinical high-risk (CHR) suggest a similar pattern of sexual dimorphism (Holtzman et al., in review; Corcoran et al., 2011). Specifically, high-risk males experienced more negative (Holtzman et al., in review; Corcoran et al., 2011) and disorganized symptoms at baseline whereas positive and mood symptoms were not sexually differentiated (Holtzman et al., in review). As part of the North American Prodrome Longitudinal Study (NAPLS), the current study examined sex differences in relationships among CHR symptoms, childhood (premorbid) academic and social functioning, baseline social and role functioning, and conversion to psychosis. Subjects included 276 (113F/163M) CHR NAPLS participants (ages 12–36.8 years). All measures/criteria were assessed at baseline except conversion status, assessed at 6-month intervals up to 30 months. Results show sex differences in baseline social and role functioning (though not in early childhood adjustment) that predate psychosis onset, with sexually dimorphic patterns in relation to prodromal symptoms. Among male (but not female) CHRs, baseline social functioning and positive prodromal symptoms predicted conversion. These findings have implications for understanding early course of vulnerability for, and etiology of, psychosis and highlight the importance of considering sexually differentiated predictors of course and outcome. In turn, this may maximize efforts at early identification and preventive intervention in a manner that is individually tailored to those in greatest need.
doi:10.1016/j.schres.2012.11.039
PMCID: PMC4045468  PMID: 23340377
schizophrenia; sex differences; adolescence; at-risk; prognosis; vulnerability
25.  Potential molecular mechanisms for decreased synaptic glutamate release in dysbindin-1 mutant mice 
Schizophrenia research  2013;146(0):254-263.
Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein encoded by DTNBP1, dysbindin-1, is expressed in forebrain neurons where it interacts with proteins mediating vesicular trafficking and exocytosis. It has been shown that loss of dysbindin-1 results in a decrease in glutamate release in the prefrontal cortex; however the mechanisms underlying this decrease are not fully understood. In order to investigate this question, we evaluated dysbindin-1 null mutant mice, using electrophysiological recordings of prefrontal cortical neurons, imaging studies of vesicles, calcium dynamics and Western blot measures of synaptic proteins and Ca2+ channels.
Dysbindin-1 null mice showed a decrease in the ready releasable pool of synaptic vesicles, decreases in quantal size, decreases in the probability of release and deficits in the rate of endo- and exocytosis compared with wild-type controls. Moreover, the dysbindin-1 null mice show decreases in the [Ca2+]i, expression of L- and N- type Ca2+ channels and several proteins involved in synaptic vesicle trafficking and priming. Our results provide new insights into the mechanisms of action of dysbindin-1.
doi:10.1016/j.schres.2013.01.037
PMCID: PMC3628687  PMID: 23473812
prefrontal cortex; calcium; dysbindin; synapsin; synaptotagmin; synaptic vesicles

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