Specificity of Incident Diagnostic Outcomes in Patients at Clinical High Risk for Psychosis.

It is not well established whether the incident outcomes of the clinical high-risk (CHR) syndrome for psychosis are diagnostically specific for psychosis or whether CHR patients also are at elevated risk for a variety of nonpsychotic disorders. We collected 2 samples (NAPLS-1, PREDICT) that contained CHR patients and a control group who responded to CHR recruitment efforts but did not meet CHR criteria on interview (help-seeking comparison patients [HSC]). Incident diagnostic outcomes were defined as the occurrence of a SIPS-defined psychosis or a structured interview diagnosis from 1 of 3 nonpsychotic Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) groups (anxiety, bipolar, or nonbipolar mood disorder), when no diagnosis in that group was present at baseline. Logistic regression revealed that the CHR vs HSC effect did not vary significantly across study for any emergent diagnostic outcome; data from the 2 studies were therefore combined. CHR (n = 271) vs HSC (n = 171) emergent outcomes were: psychosis 19.6% vs 1.8%, bipolar disorders 1.1% vs 1.2%, nonbipolar mood disorders 4.4% vs 5.3%, and anxiety disorders 5.2% vs 5.3%. The main effect of CHR vs HSC was statistically significant (OR = 13.8, 95% CI 4.2-45.0, df = 1, P < .001) for emergent psychosis but not for any emergent nonpsychotic disorder. Sensitivity analyses confirmed these findings. Within the CHR group emergent psychosis was significantly more likely than each nonpsychotic DSM-IV emergent disorder, and within the HSC group emergent psychosis was significantly less likely than most emergent nonpsychotic disorders. The CHR syndrome is specific as a marker for research on predictors and mechanisms of developing psychosis.

Trajectories of premorbid childhood and adolescent functioning in schizophrenia-spectrum psychoses: A first-episode study.

Evidence of social and behavioral problems preceding the onset of schizophrenia-spectrum psychoses is consistent with a neurodevelopmental model of these disorders. Here we predict that individuals with a first episode of schizophrenia-spectrum psychoses will evidence one of three patterns of premorbid adjustment: an early deficit, a deteriorating pattern, or adequate or good social adjustment. Participants were 164 (38% female; 31% black) individuals ages 15-50 with a first episode of schizophrenia-spectrum psychoses. Premorbid adjustment was assessed using the Cannon-Spoor Premorbid Adjustment Scale. We compared the fit of a series of growth mixture models to examine premorbid adjustment trajectories, and found the following 3-class model provided the best fit with: a "stable-poor" adjustment class (54%), a "stable-good" adjustment class (39%), and a "deteriorating" adjustment class (7%). Relative to the "stable-good" class, the "stable-poor" class experienced worse negative symptoms at 1-year follow-up, particularly in the social amotivation domain. This represents the first known growth mixture modeling study to examine premorbid functioning patterns in first-episode schizophrenia-spectrum psychoses. Given that the stable-poor adjustment pattern was most prevalent, detection of social and academic maladjustment as early as childhood may help identify people at increased risk for schizophrenia-spectrum psychoses, potentially increasing feasibility of early interventions.

Current status specifiers for patients at clinical high risk for psychosis.

BACKGROUND: Longitudinal studies of the clinical high risk (CHR) syndrome for psychosis have emphasized the conversion vs non-conversion distinction and thus far have not focused intensively on classification among non-converters. The present study proposes a system for classifying CHR outcomes over time when using the Structured Interview for Psychosis-risk Syndromes and evaluates its validity. METHOD: The system for classifying CHR outcomes is referred to as "current status specifiers," with "current" meaning over the month prior to the present evaluation and "specifiers" indicating a set of labels and descriptions of the statuses. Specifiers for four current statuses are described: progression, persistence, partial remission, and full remission. Data from the North American Prodromal Longitudinal Study were employed to test convergent, discriminant, and predictive validity of the current status distinctions. RESULTS: Validity analyses partly supported current status distinctions. Social and role functioning were more impaired in progressive and persistent than in remitted patients, suggesting a degree of convergent validity. Agreement between CHR current statuses and current statuses for a different diagnostic construct (DSM-IV Major Depression) was poor, suggesting discriminant validity. The proportion converting to psychosis within a year was significantly higher in cases meeting progression criteria than in those meeting persistence criteria and tended to be higher than in those meeting full remission criteria, consistent with a degree of predictive validity. DISCUSSION: CHR syndrome current status specifiers could offer a potentially valid and useful description of current clinical status among non-converters. Study in additional samples is needed.

Functional development in clinical high risk youth: prediction of schizophrenia versus other psychotic disorders.

This study evaluates premorbid social and academic functioning in clinical high-risk individuals as predictors of transition to schizophrenia versus another psychotic disorder. Participants were 54 individuals enrolled in phase one of the North American Prodrome Longitudinal Study who over two and a half years of follow-up met criteria for schizophrenia/schizophreniform disorder (n=28) or another psychotic disorder (n=26). Social and academic functioning in childhood, early adolescence, and late adolescence was assessed at baseline using the Cannon-Spoor Premorbid Adjustment Scale. Social maladjustment in late adolescence predicted significantly higher odds of transition to schizophrenia versus another psychotic disorder independent of childhood and early adolescent adjustment (OR=4.02) and conveyed unique risk over academic maladjustment (OR=5.64). Premorbid academic maladjustment was not associated with psychotic disorder diagnosis. Results support diagnostic specificity of premorbid social dysfunction to schizophrenia in clinical high-risk youth and underscore an important role for social maladjustment in the developmental pathology of schizophrenia and its prediction.

Premorbid functional development and conversion to psychosis in clinical high-risk youths.

Deterioration in premorbid functioning is a common feature of schizophrenia, but sensitivity to psychosis conversion among clinical high-risk samples has not been examined. This study evaluates premorbid functioning as a predictor of psychosis conversion among a clinical high-risk sample, controlling for effects of prior developmental periods. Participants were 270 clinical high-risk individuals in the North American Prodrome Longitudinal Study-I, 78 of whom converted to psychosis over the next 2.5 years. Social, academic, and total maladjustment in childhood, early adolescence, and late adolescence were rated using the Cannon-Spoor Premorbid Adjustment Scale. Early adolescent social dysfunction significantly predicted conversion to psychosis (hazard ratio = 1.30, p = .014), independently of childhood social maladjustment and independently of severity of most baseline positive and negative prodromal symptoms. Baseline prodromal symptoms of disorganized communication, social anhedonia, suspiciousness, and diminished ideational richness mediated this association. Early adolescent social maladjustment and baseline suspiciousness together demonstrated moderate positive predictive power (59%) and high specificity (92.1%) in predicting conversion. Deterioration of academic and total functioning, although observed, did not predict conversion to psychosis. Results indicate early adolescent social dysfunction to be an important early predictor of conversion. As such, it may be a good candidate for inclusion in prediction algorithms and could represent an advantageous target for early intervention.

Diagnostic specificity of poor premorbid adjustment: comparison of schizophrenia, schizoaffective disorder, and mood disorder with psychotic features.

Individuals with schizophrenia have significant deficits in premorbid social and academic adjustment compared to individuals with non-psychotic diagnoses. However, it is unclear how severity and developmental trajectory of premorbid maladjustment compare across psychotic disorders. This study examined the association between premorbid functioning (in childhood, early adolescence, and late adolescence) and psychotic disorder diagnosis in a first-episode sample of 105 individuals: schizophrenia (n=68), schizoaffective disorder (n=22), and mood disorder with psychotic features (n=15). Social and academic maladjustment was assessed using the Cannon-Spoor Premorbid Adjustment Scale. Worse social functioning in late adolescence was associated with higher odds of schizophrenia compared to odds of either schizoaffective disorder or mood disorder with psychotic features, independently of child and early adolescent maladjustment. Greater social dysfunction in childhood was associated with higher odds of schizoaffective disorder compared to odds of schizophrenia. Premorbid decline in academic adjustment was observed for all groups, but did not predict diagnosis at any stage of development. Results suggest that social functioning is disrupted in the premorbid phase of both schizophrenia and schizoaffective disorder, but remains fairly stable in mood disorders with psychotic features. Disparities in the onset and time course of social dysfunction suggest important developmental differences between schizophrenia and schizoaffective disorder.

The nature of schizotypy among multigenerational multiplex schizophrenia families.

Identification of endophenotypes (Gottesman & Gould, 2003; Gottesman & Shields, 1972) that genetically correlate with schizophrenia and are genetically homogeneous is an important strategy for detecting genes that affect schizophrenia risk. Symptoms of schizotypy may familially correlate with schizophrenia; however, there are critical limitations of the current literature concerning this association. The present study examined the genetic architecture and genetic associations between schizotypy and schizophrenia among multigenerational, multiplex schizophrenia families. Genetic schizotypy factor scales were developed that genetically correlated with schizophrenia, although some relations were unexpected in direction suggesting minimization of "psychotic-like" symptoms. These genetic schizotypy factor scales did not genetically correlate with major depressive disorder or substance dependence indicating specificity to schizophrenia. The results highlight the possibility of significant response bias in schizophrenia families, particularly among close relatives, and suggest an important consideration when acquiring self-report information. This is a topic that deserves future study as the origins of this putative bias in relatives are unclear. In addition, the results support the identification of genetic schizotypy factors as a promising technique for maximizing genetic correlation of endophenotypes with schizophrenia.

A multivariate perspective on schizotypy and familial association with schizophrenia: a review.

Although generally accepted that schizotypal personality disorder diagnosis is more prevalent among relatives of individuals with schizophrenia and may be associated with genetic liability to schizophrenia, it seems likely that this diagnosis is itself heterogeneous and thus perhaps not as useful in identifying genes that affect schizophrenia risk (i.e. endophenotypes) as it could be. In contrast, symptoms and dimensions of schizotypal personality disorder may be more etiologically homogeneous, and thus more useful in genetic studies. The current review evaluated and consolidated evidence to date regarding specific symptoms and dimensions of schizotypal personality disorder among non-psychotic relatives of schizophrenia patients. Comparisons were made with relatives of affective disorder patients and non-psychiatric controls. Findings indicate strong support for elevation of social-interpersonal schizotypal symptoms among relatives of schizophrenia patients versus other groups along with moderate specificity. Results suggest only a small elevation of cognitive-perceptual and disorganized symptoms in relatives of schizophrenia patients and results for disorganized symptoms were inconsistent across studies. Thus, evidence to date supports further investigation of genetic associations between symptoms of schizotypal personality disorder and schizophrenia, and suggests that social-interpersonal symptoms may be particularly promising in genetic analyses of schizophrenia.

Development of social functioning in preschizophrenia children and adolescents: a systematic review.

Schizophrenia is associated with severe deficits in social functioning. Similar deficits may be present prior to psychosis onset, in childhood and adolescence. If so, then prepsychosis social deficits could provide clues to the development of pathological processes in preschizophrenia children and could potentially improve early identification of the disorder and suggest targets for intervention. Evidence is reviewed from birth cohort, case- control, and familial high-risk studies within distinct periods of development to clarify the nature, timing, and specificity of social deficits in preschizophrenia children and adolescents. The results indicate that poor social functioning does differentiate preschizophrenia children and adolescents from their peers and can be a sensitive and potentially specific predictor of schizophrenia, not just psychopathology in general. Furthermore, age (but not sex) appears to be an important moderator of the strength and specificity of the association between particular social deficits (e.g., externalizing, internalizing) and later schizophrenia. Results are discussed in the context of current developmental theories of timing and pathophysiology of schizophrenia involving hypothalamic- pituitary-adrenal dysregulation. Implications for the early identification and treatment of preschizophrenia individuals are also considered.

Spontaneous dyskinesia and familial liability to schizophrenia.

Several factors suggest that spontaneous dyskinesia may be a useful supplemental phenotype for further elucidating the specific nature of the genetic contribution to schizophrenia. For example, involuntary movement abnormalities have been observed in both medicated and unmedicated schizophrenia patients, in individuals with schizotypal personality disorder, and sometimes in siblings of schizophrenia patients. However, there are many inconsistencies present in the literature to date. The current study thus sought to investigate the existence of spontaneous dyskinesia in schizophrenia patient probands, their non-psychotic siblings, and healthy controls in order to clarify its potential value as an "endophenotype" in genetic studies of schizophrenia. Videotaped interviews were coded for the presence of spontaneous, involuntary movement abnormalities by a trained and reliable rater using computer assisted technology who was blind to group and family status. The results of this study indicated that siblings of schizophrenia patients did not display significantly more involuntary movements compared to controls, although tremor was observed in a few siblings. In contrast, schizophrenia patients did display significantly more involuntary movements compared to controls as well as their non-psychotic siblings. The lack of significant differences between siblings and controls argues against a strong association between spontaneous dyskinesia and an "unexpressed" genetic liability to schizophrenia. Thus, it appears that involuntary movement abnormalities may be limited in their utility as endophenotypes in genetic studies of schizophrenia, despite being associated with, and perhaps predictive of, schizophrenia itself.

Validating schizotaxia and its place in studies of preventing schizophrenia by psychopharmacological intervention.

Schizotaxia is a stable syndrome of neuropsychological deficits and negative symptoms found in relatives of schizophrenic patients. These may represent special vulnerability to schizophrenia. Five areas of deficit are enumerated and suggestions as to the potential value of pre-illness interventions are discussed.

Medial temporal and prefrontal lobe activation during verbal encoding following glucose ingestion in schizophrenia: A pilot fMRI study.

Verbal declarative memory is one of the most reliably impaired cognitive functions in schizophrenia. Important issues are whether the problem is reversible, and which brain regions underlie improvement. We showed previously that glucose administration improved declarative memory in patients with schizophrenia, and sought in this pilot study to identify whether glucose affects the location or degree of activation of brain regions involved in a verbal encoding task. Seven clinically stable and medicated patients with schizophrenia or schizoaffective disorder, who showed deficits on a clinical test of memory, participated in the study. Subjects served as their own controls in a double-blind, crossover protocol that consisted of two sessions about a week apart. In each session, subjects ingested a beverage flavored with lemonade that contained 50 g of glucose on one occasion, and saccharin on the other. Blood glucose was measured before and 15, 50, and 75 min after ingestion. After ingesting the beverage, they performed a verbal encoding task while undergoing brain functional magnetic resonance imaging. The results showed significantly greater activation of the left parahippocampus during novel sentence encoding in the glucose condition, compared to the saccharin condition, despite no change in memory performance. A trend towards greater activation of the left dorsolateral prefrontal cortex (p<.07) was also evident in the glucose condition. These pilot findings emphasize the sensitivity of both the medial temporal and prefrontal regions to effects of glucose administration during encoding, and are consistent with the hypothesis that these regions also participate in declarative memory improvements following glucose administration.

Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample.

Observations of impaired glucose regulation in schizophrenia are long-standing, although their pathological and etiological significance is uncertain. One approach to the issue that minimizes environmental variables (e.g., medication and diet) is to determine whether genes related to glucose regulation show genetic linkage to schizophrenia. We examined the potential role of glucose metabolism in schizophrenia through a genome scan of affection status in schizophrenia and an empirical method for deriving P-values. Data were utilized from the NIMH Genetics Initiative for Schizophrenia dataset, which comprises a total sample consisting of 71 pedigrees containing 218 nuclear families and 987 individuals. A genome scan with 459 markers spaced at an average of 10 cM intervals was conducted using the linkage analysis program Genehunter separately for European- and African-American groups. Enzymes that regulate glycolysis were identified and the genes regulating these enzymes were located through the Online Mendelian Inheritance in Man (OMIM) website. The focus in this study was on genes located near previously reported schizophrenia susceptibility regions. The genome-wide significance of these genes to schizophrenia was assessed using permutation testing. When results were adjusted for multiple testing within and across ethnic groups, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2; chromosome 1q32.2) achieved genome-wide significance (P = 0.04). In addition, hexokinase 3 (HK3; chromosome 5q35.3) was also suggestive of linkage (P = 0.09). For the European-American sample, PFKFB2 (1q32.2), hexokinase 3 (HK3; 5q35.3), and pyruvate kinase 3 (PK3; chromosome 15q23) achieved significance at the 0.05 level. None of the genes showed significance in the African-American sample. Our results provide further support for the view that genes that regulate glucose metabolism may also influence susceptibility to schizophrenia. More generally, they support the view that relationships between glucose dysregulation and schizophrenia are inherent to the disorder, and are not merely epiphenomena related to medication or other treatment factors.

An integration of schizophrenia with schizotypy: identification of schizotaxia and implications for research on treatment and prevention.

The liability to schizophrenia (schizotaxia) is associated with deficits in a variety of domains, including negative symptoms and neuropsychological deficits, even in the absence of psychosis or pre-psychotic prodromal symptoms. Conceptually, this view of schizotaxia is similar to negative schizotypy (i.e., schizotypal personality disorder minus the positive symptoms). It is broader than DSM-IV schizotypal personality disorder (SPD), however, in that more relatives of patients with schizophrenia show core symptoms of schizotaxia than meet the diagnostic criteria for SPD. Three lines of evidence support the validity of schizotaxia. First, evidence of concurrent validation was obtained by showing that schizotaxic subjects were more impaired than non-schizotaxic subjects on a variety of independent clinical scales. Second, schizotaxic subjects showed higher levels of negative symptoms on the Structured Interview for Schizotypy than non-schizotaxic subjects, but did not differ on positive symptoms. Third, subjects who met predetermined criteria for schizotaxia (i.e., negative symptoms and neuropsychological deficits) showed positive effects following treatment with low doses of risperidone (0.25-2.0 mg). Thus, clinical deficits in schizotaxia may be identifiable, and to a significant extent, reversible. Implications for the conception of schizotypy and the prevention of schizophrenia will be discussed.