The Consortium on the Genetics of Endophenotypes in Schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration.

Background: The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health-funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment.

Methods: The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping.

Successful multi-site measurement of antisaccade performance deficits in schizophrenia.

The antisaccade task is a promising schizophrenia endophenotype; it is stable over time and reflects neurophysiological deficits present in both schizophrenia subjects and their first-degree relatives. Meaningful genetic research requires large sample sizes that are best ascertained using multi-site study designs. To establish the criterion validity of the antisaccade task in a multi-site design, the Consortium on the Genetics of Schizophrenia (COGS) examined whether seven sites could detect previously reported antisaccade deficits in schizophrenia subjects.

Progress in the Prospective Study of the Schizophrenia Prodrome.

Further understanding of the schizophrenia spectrum has helped to define the prodrome of the illness, leading to hopes of earlier identification and intervention in susceptible, at-risk individuals. Given the heterogeneity and comorbidity observed in the clinically and demographically identified prodromal sample, it is essential that neurobiological markers that are more closely linked to brain function, and perhaps the ability to predict evolution of psychosis, be identified. Ultimately, it may be possible to identify an algorithm of risk factors that will combine clinical and demographic risk factors with vulnerability markers associated with later development of schizophrenia to better target at-risk individuals or preventative treatment.

Risk and protection in prodromal schizophrenia: ethical implications for clinical practice and future research.

Over the last decade schizophrenia researchers have turned their attention to earlier identification in the prodromal period of illness. A greater understanding of both risk and protective factors can lead to improved prevention and treatment strategies in this vulnerable population. This research, however, has far-reaching ethical implications.

P50 suppression in individuals at risk for schizophrenia: the convergence of clinical, familial, and vulnerability marker risk assessment.

Background: Identification of individuals at risk for the development of schizophrenia is important because it can lead to a greater understanding of the early stages of the illness. The aim of the present study was to determine whether individuals "at risk" for schizophrenia have deficits in P50 suppression, a preattentive measure of sensory gating.

Methods: Thirty-one at-risk and 21 normal comparison subjects were referred to the CARE (Cognitive Assessment and Risk Evaluation) Program at University of California San Diego.

How does studying schizotypal personality disorder inform us about the prodrome of schizophrenia?

An increasing emphasis in the schizophrenia literature has been on the prodromal phase of the illness. The study of schizophrenia spectrum illness, including schizotypal personality disorder, has added important insight into the etiology, neuropathology, and treatment of schizophrenia, which can facilitate early identification, intervention, and perhaps prevention of the illness. The heterogeneity of the schizophrenia spectrum makes its definition elusive at best.

Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability.

As the number of studies related to the early identification of and intervention in the schizophrenia prodrome continues to grow, it becomes increasingly critical to develop methods to diagnose this new clinical entity with validity. Furthermore, given the low incidence of patients and the need for multisite collaboration, diagnostic and symptom severity reliability is also crucial. This article provides further data on these psychometric parameters for the prodromal assessment instruments developed by the Prevention through Risk Identification, Management, and Education (PRIME) prodromal research team at Yale University: the Structured Interview for Prodromal Syndromes and the Scale of Prodromal Symptoms.

The use of the Ego Impairment Index across the schizophrenia spectrum.

The goal of this study was to assess perceptual and thought disturbance, as indexed by the Ego Impairment Index (EII; Perry & Viglione, 1991), a Rorschach-derived measure, across the schizophrenia spectrum. We hypothesized that there would be an increase in EII scores (indicating increased disturbance) across the spectrum from nonpatients to severely disturbed, hospitalized schizophrenia patients. Normal comparison participants (n = 66), students with elevated scores on either the Perceptual Aberration/Magical Ideation or the Physical Anhedonia Scales (n = 24), first-degree relatives of schizophrenia patients (n = 36), participants diagnosed with Diagnostic and Statistical Manual of Mental Disorders (4th ed.

Vulnerability markers in the schizophrenia spectrum: implications for phenomenology, genetics, and the identification of the schizophrenia prodrome.

A continuum of symptoms between "normality" and overt psychosis has been documented in relatives of schizophrenia patients, SPD, and individuals who may be in the early stages of a psychotic illness with "subsyndromal" symptoms. The empirically derived criteria for SPD have been refined to define a clinical phenotype that is linked to schizophrenia. The clinical SPD symptoms define a heterogeneous group of individuals who are often comorbid for Axis I and II disorders, may or may not have a family history of schizophrenia, and are at risk for developing schizophrenia themselves.

Neurobiological measures of schizotypal personality disorder: defining an inhibitory endophenotype?

Objective: Subjects with schizotypal personality disorder demonstrate deficits in inhibition when assessed on prepulse inhibition, P50 suppression, and antisaccade paradigms. This study determined if distinct subgroups of subjects with schizotypal personality disorder could be identified on the basis of performance on these measures and whether endophenotypes could be defined for future genetic study by using measures of inhibitory function.

Method: Prepulse inhibition, P50 suppression, and antisaccade paradigms were assessed in 21 subjects with schizotypal personality disorder.

Dopamine agonist effects on startle and sensorimotor gating in normal male subjects: time course studies.

Rationale: Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is deficient in schizophrenia and in rodents treated with dopamine (DA) agonists. Reduced PPI is reported in normal humans treated with direct or indirect DA agonists. To facilitate future studies, we assessed the time course of DA agonist effects on PPI in humans, for both direct (bromocriptine: 1.

Lateralized perceptual organization deficits on the global-local task in schizotypal personality disorder.

Right and left hemisphere contributions to perceptual organization functions were examined using a divided-attention version of the global-local task in a sample of 21 unmedicated participants diagnosed with schizotypal personality disorder (SPD) and 20 controls. The SPD participants showed an abnormal global processing advantage. When the visual angle of the hierarchical stimuli was increased from 3 degrees to 9 degrees, the controls showed an increasing local processing advantage, but the SPD participants continued to show an abnormal global processing advantage.

Endophenotyping schizotypy: a prelude to genetic studies within the schizophrenia spectrum.

Schizophrenia is a complex genetic disease with a prevalence rate of 1% in the general population. Schizotypal personality disorder (SPD) occurs in up to 3% of the population, and these subjects are phenomenologically and perhaps genotypically related to schizophrenia. The diagnosis of SPD was empirically derived based on the symptoms of individuals with a genetic relationship to schizophrenia patients and SPD may be a more common phenotypic expression of a schizophrenia-related diathesis than is schizophrenia itself.

Saccadic inhibition among schizotypal personality disorder subjects.

Schizotypal personality disorder (SPD) is theoretically part of the schizophrenia spectrum both clinically and neurobiologically. A liability for developing schizophrenia may be associated with dysfunction of dorsolateral prefrontal cortex (DLPFC) and its cortical and/or subcortical circuitry. If so, abnormalities on tasks associated with DLPFC functioning among SPD subjects would support the thesis that SPD is neurobiologically related to schizophrenia.

Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia.

Schizophrenia patients have prominent deficits in information processing that can be detected by measures of prepulse inhibition (PPI) of the startle response. Deficient PPI in schizophrenia is thought to reflect a failure of brain-based information 'protective' mechanisms that normally inhibit responsivity for 30-500ms after a weak prepulse stimulus. The relationship between specific prepulse stimulus characteristics and PPI deficits in this study was examined in 31 schizophrenia patients and 34 normal comparison subjects.

Matching strategies for drug studies of prepulse inhibition in humans.

Prepulse inhibition (PPI), a measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders. Animal studies have revealed drug effects on PPI that may be relevant to understanding the biology of gating deficits in human populations. Recent efforts have examined similarities and differences in drug effects on PPI between rodents and humans.

Modulation of the startle response and startle laterality in relatives of schizophrenic patients and in subjects with schizotypal personality disorder: evidence of inhibitory deficits.

Objective: Patients with schizophrenia spectrum disorders have been shown to have deficits in sensorimotor gating as assessed by prepulse inhibition of the startle response. The authors hypothesized that nonschizophrenic relatives of patients with schizophrenia would also have prepulse inhibition deficits, thereby reflecting a genetically transmitted susceptibility to sensorimotor gating deficits.

Method: Twenty-five comparison subjects, 23 patients with schizophrenia, 34 relatives of the schizophrenic patients, and 11 subjects with schizotypal personality disorder were assessed in an acoustic startle paradigm.

Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications.

Objective: Patients with schizophrenia have deficits in attention, cognition, and information processing. Measures such as P50 suppression are used to study cognitive and attentional dysfunction among these patients. P50 suppression is an operational measure of sensory gating that can be assessed by averaging electroencephalographic responses to multiple pairs of auditory clicks separated by 500 msec.

Sensory gating deficits assessed by the P50 event-related potential in subjects with schizotypal personality disorder.

Objective: The schizophrenia spectrum includes individuals with schizophrenia, their relatives, and individuals with schizotypal personality disorder. Subjects in the schizophrenia spectrum have disorders of attention, cognition, and information processing. Attention and information processing can be assessed by testing suppression of the P50 event-related potential; the amplitude of the P50 wave is measured in response to each of two auditory clicks.

Sex differences in sensorimotor gating of the human startle reflex: all smoke?

Rationale: A recent report described sex differences in the effects of nicotine use and withdrawal on prepulse inhibition of acoustic startle (PPI), but no sex differences in PPI in non-smokers.

Objective: To determine whether previously reported male>female acoustic PPI reflect sex differences in smoking effects on PPI, rather than simple sex differences in the regulation of PPI. A retrospective analyses of >600 carefully screened normals tested over the past 12 years was completed.

Cognitive functions in schizotypal personality disorder.

Objective: Schizophrenia spectrum subjects have cognitive deficits in a variety of domains. Schizotypal personality disordered (SPD) subjects do not have many of the confounds seen in schizophrenic patients, but may have the same pattern of cognitive deficits in attention and executive functioning.

Hypothesis: We hypothesized that SPD subjects would have impairments on measures of attention, abstract reasoning, cognitive inhibition, working memory and verbal recognition memory when compared to normal subjects, and that these deficits would be intermediate to those observed in schizophrenic patients.

Prepulse inhibition and habituation of the startle response are stable neurobiological measures in a normal male population.

Prepulse inhibition (PPI) and habituation of the startle response are operational measures of sensorimotor gating and information processing. Changes in the normal inhibition and habituation of the startle response may provide trait markers for illnesses such as schizophrenia that have altered neurotransmitter control of the neural circuitry that modulates these measures. The stability of PPI and habituation was assessed in 10 normal male subjects.

Transient versus sustained visual channels in the visual backward masking deficits of schizophrenia patients.

Background: Schizophrenia patients have information-processing deficits that can be quantified using visual backward masking. The visual information processing system is divided functionally and structurally into transient and sustained visual channels. When visual stimuli are presented to a subject, the transient pathway detects the presence and location of the stimulus while the sustained pathway is involved in fine discrimination and identification of the stimulus.

Information processing deficits of schizophrenia patients: relationship to clinical ratings, gender and medication status.

Information processing deficits were explored in a large cohort of schizophrenia patients (N = 125) and non-psychiatric subjects (N = 52). Gender, medication status and symptom factors were assessed relative to measures of performance in critical stimulus duration (CSD), visual backward masking (VBM) and auditory reaction time (RT) paradigms. Schizophrenia patients exhibited significant impairments in measures of CSD, VBM and both RT speed and RT set.