L. Erlenmeyer-Kimling

Family and twin strategies as a head start in defining prodromes and endophenotypes for hypothetical early-interventions in schizophrenia

In an effort to share the experiences of genotype-hunters-who have approached the difficult task of forecasting future schizophrenia in the young offspring or other relatives of index cases, in new samples guided by the prior probabilities of 15% in offspring or 50% in identical co-twins-with early-interventionists-who focus on purported prodromal symptoms in children who would be treated pharmacologically to prevent the development of schizophrenia-we provide a focused review that emphasizes the hazards of false positives in both approaches. Despite the advantages prospective high-risk strategies have had from clinical and laboratory findings that implicate some prodromal signs and endophenotypes, e.g. attention, memory, and information processing evaluations, the yields are not sufficient for practical applications involving antipsychotic drugs for undiagnosed children. Even more caution than usual is required, given the suggestions that the developing neocortex is vulnerable to dopaminergic exposure.

A summary of attentional findings in the New York high-risk project

We summarize here our findings with respect to attentional impairment among offspring of schizophrenic, affectively ill, and normal parents followed from childhood to adulthood during the two decades of the New York High-Risk Project (NYHRP). We review our data first, on childhood attentional performance in each of our two independent samples of such subjects and, second, on the relationship of early dysfunctions observed in this domain to psychopathological outcomes in adolescence and adulthood. Our cumulative results contribute strong support to the contention that global attentional dysfunctions may be viewed as a biobehavioral marker for the genetic liability to schizophrenic disorders.

A taxometric analysis of cognitive and neuromotor variables in children at risk for schizophrenia.

A taxometric model was applied to detect a subgroup or taxon of children conjectured to be at highest risk for developing schizophrenia or related disorders in a sample of offspring of schizophrenic, depressed, and normal parents. Measures of cognitive and neuromotor performance in childhood were used as indicator tests in the analyses. A taxon consisting chiefly of children of schizophrenic parents was detected. Forty-seven percent of those children were assigned to the taxon, compared with 16% of the children of depressed parents and 4% of the children of normal parents. Assignment to the taxon is assessed in relation to the current functional status of the subjects in young adulthood.

DSM-III-R SCHIZOTYPAL PERSONALITY TRAITS IN OFFSPRING OF SCHIZOPHRENIC DISORDER, AFFECTIVE DISORDER, AND NORMAL CONTROL PARENTS

The aggregation of disorder in families identified by a schizophrenic disorder proband (index case) has provided indirect clues to the question of diagnostic boundaries of schizophrenic spectrum categories. The Danish Adoption Studies provided quasi-experimental evidence for the range of expression of a putative schizophrenic spectrum disorder which was subsequently denoted schizotypal personality disorder (STPD) in DSM-III-R. It has been hypothesized that such schizophrenic spectrum categories bear a genetic relationship to schizophrenic disorder and thus are continuous with schizophrenia in terms of etiology and pathogenesis. For meaningful use of such spectrum categories in genetic analyses, i.e., linkage analysis, it is important that rates of spectrum traits and disorder in normal control and in psychiatric control populations are known. The rate of DSM-III-R schizotypal traits and disorder was assessed in three offspring groups (ages 18-29) defined by parental diagnoses, including schizophrenic disorder (N = 90), affective disorder (N = 79), and no parental disorder (N = 161). The assessment was conducted by trained social workers and psychologists by means of a direct interview (Personality Disorder Examination). The interviewers were blind to the parental status and to previous psychiatric assessments of these offspring. The rates of three, four and five schizotypal features were elevated in the offspring with parental psychiatric disorder in contrast to the offspring with no parental psychiatric disorder. However, the rates between the offspring of the schizophrenic disorder parental group and the offspring of the affective disorder parental group did not differ significantly, thus failing to support the assumption of diagnostic specificity.

The New York High-Risk Project: attention, anhedonia and social outcome.

In the New York High-Risk Project we have followed two samples of subjects (Sample A and Sample B) at risk for schizophrenic or affective disorders and low-risk controls from childhood to adulthood, in an attempt to identify early predictors of later psychopathology. We administered a large number of cognitive, psychometric and other types of measures to both samples as possible psychopathology predictors, including an index of attentional deviance assessed in childhood, the Physical Anhedonia Scale in adolescence, and three measures of social outcome in adulthood (Suspicious Solitude, Social Insecurity, and Lack of Empathy), derived from the Personality Disorders Examination. In the analysis of the combined samples, parental diagnostic group, gender, attentional deviance in childhood, and physical anhedonia in adolescence were used to predict three measures of social outcome in adulthood. While only physical anhedonia was directly related to all three social outcome measures, with the strongest relationship to Suspicious Solitude, attention deviance successfully predicted two of the three outcomes. Subjects at risk for affective disorder did not show increased levels of attention deviance, physical anhedonia, or social dysfunction, relative to the normal control subjects. Attention deviance appears to be a key neurobiological indicator and physical anhedonia appears to be a potentiating factor mediating the relationship between risk for schizophrenia and later social dysfunction.

Wisconsin Card Sorting deficits in the offspring of schizophrenics in the New York High-Risk Project

It has been suggested that performance on the Wisconsin Card Sorting Test (WCST) may be an indicator of vulnerability to schizophrenia. WCST deficits have been demonstrated in schizophrenic patients and their relatives, but not as yet in their offspring. This study aimed to further establish the indicator potential of WCST deficits by analyzing data collected as part of the New York High-Risk Project (NYHRP), a longitudinal study of attention, cognition and clinical functioning in the offspring of schizophrenic (HRSz, n=73), affective disordered (HRAff, n=61) and normal comparison (NC, n=120) parents. Parental Research Diagnostic Criteria diagnoses were established by semi-structured interview (SADS-L). WCST testing was carried out when offspring were in their mid-20s. HRSz subjects performed significantly more poorly on the WCST than HRAff and NC subjects. High-risk subjects who developed psychotic symptoms prior to or shortly after testing did not differ significantly from HRSz subjects who did not become ill. Thus, WCST performance in the offspring of schizophrenics resembles that of schizophrenic patients and may distinguish HRSz from offspring at risk for nonschizophrenic illness. WCST deficits may be a specific familial indicator of vulnerability, but appear not to distinguish between those subjects at risk for schizophrenia who do or do not become ill.

The New York high-risk project: social and general intelligence in children at risk for schizophrenia

UNLABELLEDnSocial deficits, as well as low performance on intelligence tests, are known early symptoms of schizophrenia. We studied whether impairment of social intelligence can be detected before the outbreak of the disorder. In the New York High-Risk Project, children at risk for schizophrenia (HRSz) or affective disorder (HRAff) and a normal control group (NC) were studied over the past 26 years. The children are now in mid-adulthood, with known psychiatric outcomes. Developmental and clinical data from childhood can now be related to adulthood diagnoses. We compared mean WISC (or WISC-R) and WAIS (or WAIS-R) scores from childhood and adolescence, and change of IQ, between the risk groups, as well as between the adulthood outcomes. We were specifically interested in the development of social intelligence (the Picture Arrangement and Comprehension subtests). We used logistic regression analyses to generate a model predicting adulthood schizophrenia.nnnRESULTSnIQ at age 9,7 was lower in children with HRSz than with HRAff. Adulthood schizophrenia, compared with major depressive disorder and no psychiatric diagnosis could not be related conclusively to low IQ. This may be a result of the study design, since children with IQ below 70 or behavioral problems were not eligible as study subjects. There was no evidence of lower scores or more decline in social intelligence related to age or group membership (risk or outcome). Subtest-Scatter, a nondirectional measure of the differences between all subtests and Vocabulary, reflecting a lesser difference between crystallized and fluid intelligence, was identified as a significant predictor of adulthood schizophrenia, in the whole group as well as in the HRSz group alone.

Latent structure of DSM-III-R Axis II psychopathology in a normal sample.

The Personality Disorder Examination was administered to 302 normal controls in the New York High-Risk Project in order to elicit Axis II diagnoses (revised 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 1987) and quantitative dimensions of psychopathology. LISREL confirmatory factor analysis was used to evaluate the Axis II hypothesis of 3 orthogonal factors. There was considerable overlap among personality disorders. The best fitting LISREL model was of 3 oblique factors that were different for male and female subjects. Given that our choice of variables to constrain in order to mathematically identify our models was partially based on analysis of intercorrelations in our data set, our methods were not purely confirmatory. We present our results not to confirm specific hypotheses but to generate explicit hypotheses that can be tested in independent samples.

Event-related potentials in children at risk for schizophrenia during two versions of the continuous performance test

Event-related potentials (ERPs) were recorded from children of schizophrenic parents, children of parents with affective disorders, and children of parents without a history of psychiatric illness. ERPs were elicited during two versions of the continuous performance test (CPT), which differed in their level of processing complexity. The data were recorded from electrodes located at midline frontal, central, parietal, and occipital scalp sites. Diagnostic assessments of the parents were performed using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version and Research Diagnostic Criteria. Clinical assessments of the children were made with a modified version of the Global Assessment Scale. ERP amplitudes for six electrophysiological events were compared among groups for target and nontarget stimuli using analyses of variance of both factor score and baseline to peak measures. There was one isolated between-group finding: frontal negative slow wave recorded at FZ was of greater magnitude in the high risk (HR) than in either the psychiatric (PC) or normal control (NC) groups. Since only a small percentage of children at risk will eventually develop schizophrenia, ERP amplitude deviance and frequency distribution analyses were also performed and compared among groups. ERP component amplitudes did not distinguish the groups when each component was considered separately. Deviance analyses, using a combination of the amplitudes of the six ERP components, also did not provide evidence of a deviant subgroup within any of the three groups. There appeared to be no relationship between ERP component amplitudes and behavioral adjustment in adolescence. Some evidence of a relationship between deviant attentional functioning and ERP component amplitude was found, but the pattern of findings within the attentionally deviant HR subgroup was opposite to that found for the HR group as a whole and more consistent with the pattern found for the NC group.

Positive and negative thought disorder and psychopathology in childhood among subjects with adulthood schizophrenia

UNLABELLEDnThe New York High-Risk Project (NYHRP) is a longitudinal study of offspring of parents with schizophrenia or affective disorder and normal controls. Neuropsychological deficits had been observed at about age 9 in subjects with adulthood schizophrenia. We explored whether in these subjects, early signs of clinical schizophrenia-related symptoms, such as thought disorder or behavioral abnormalities, could also be observed.nnnMETHODSnWe rated thought disorder and symptoms from videotaped interviews at age 9, using the Scale for the Assessment of Thought, Language and Communication (TLC), and the Mental Health Assessment Form (MHAF). With factor analyses we examined the structure of the ratings, and from interpretable factors, scales were assembled. MANOVAs were used to examine the effect of parental risk and adulthood psychiatric diagnosis (schizophrenia-related psychosis (SRP), major affective disorder (MAD), no disorder/other (NoDx/other)) as independent variables (IV) on thought disorder and symptoms as dependent variables.nnnRESULTSnGlobal, positive and negative thought disorder, and negative symptoms were significantly higher in subjects with adulthood schizophrenia-related psychosis than both comparison groups. A significant interaction between the two IVs was effective with respect to positive thought disorder. This scale was particularly elevated among subjects with adulthood schizophrenia-related psychosis at parental risk for affective disorder (all of whom had adulthood schizoaffective disorder).nnnCONCLUSIONSnWe were able to show that global, negative and positive thought disorder and negative symptoms were present in subjects with adulthood schizophrenia already at mid-childhood, years before onset of psychosis. Further, we found a particularly high propensity to positive symptoms in subjects with adulthood schizophrenia who have also an affective component in their symptoms. This association, previously reported in acute schizophrenia, was here observed years before the first psychotic episode.