Incidence of nondextrality in the NAS/NRC Twin Registry.

Genetic theories still flounder on the fact that similarity of hand preference is the same in monozygotic (MZ) and dizygotic (DZ) twins. Lateral preference on a well-designed set of 5 activities was obtained from 2,131 male pairs. On item analysis, only "throw" discriminated zygosity, attributable to "excess" nondextral MZ pairs. This item is remarkably free of the intense cultural bias against sinistrality.

The New York High-Risk Project: comorbidity for axis I disorders is preceded by childhood behavioral disturbance.

The relationship between childhood behavioral disturbance and comorbidity for adult psychiatric disorders has not been sufficiently investigated. Subjects of this report (N = 185) were offspring of parents with schizophrenia or affective disorder and of normal parents from the New York High-Risk Project. Data on childhood behavior at the mean age of 9.5 years were obtained in a parent interview at initial assessment in 1971-72. Adulthood outcomes were assessed through standardized interviews, and lifetime axis I diagnoses were based on Research Diagnostic Criteria. Subjects with comorbidity for axis I disorders exhibited significantly more behavioral problems as children, compared with those who developed either one or no psychiatric disorder in adulthood. This association was not biased by gender or parental diagnosis of psychiatric disorder. The findings emphasize that psychiatric comorbidity can be traced back to childhood and underline the importance of longitudinal observations in psychiatric research.

Relationship between childhood behavioral disturbance and later schizophrenia in the New York High-Risk Project.

OBJECTIVE: An association between childhood behavioral disturbance and adulthood schizophrenia has been seen previously in retrospective or follow-back studies and in prospective studies. The authors examined the relationship between childhood behavioral problems and adulthood schizophrenia-related psychoses. Because a high rate of childhood behavioral problems is known to be associated with adult substance abuse, these analyses controlled for substance abuse. METHOD: The subjects of this investigation (N = 185) were offspring of parents with schizophrenia or affective disorder and of normal parents from the New York High-Risk Project (sample A). Data on childhood behavioral problems were obtained in a parent interview at initial assessment in 1971-1972. Adulthood outcomes (schizophrenia-related psychoses, affective disorders, anxiety disorders, substance abuse) were based on lifetime axis I diagnoses according to the Research Diagnostic Criteria. RESULTS: Substance abuse had a significant interaction with the clinical outcome groups. In subjects without substance abuse, those with schizophrenia-related psychoses had exhibited significantly more behavioral problems as children than had adult offspring with affective or anxiety disorder or with substance abuse only or no disorder. CONCLUSIONS: These results support the view that schizophrenia-related psychoses can be followed back to early behavioral disturbances. The confounding effects of substance abuse should be statistically controlled in studies of longitudinal associations between childhood behavioral disturbance and axis I outcomes.

Negative and positive dimensions of schizotypal personality disorder.

The positive (perceptual-cognitive) and negative (social-interpersonal) dimensions of schizotypal personality traits were examined in biological relatives of individuals with Axis I disorder. The subjects were young adult offspring from three contrasting parental groups, including schizophrenic disorder, affective disorder, and normal controls. Cognitive correlates, including digit span (presumed to assess working memory) and P3 amplitudes, were also examined. Preliminary results showed that positive and negative dimensions were distinguished by different prevalence patterns in the offspring subjects, and by a different pattern of correlations with cognitive measures. Negative dimensions were more frequent in offspring from the schizophrenic parental group than in the offspring from affective disorder and normal control parental groups. Digits forward and backward, and P3 amplitude decrements, characterized a subset of offspring with negative features from the schizophrenic parental group. Positive dimensions did not differ between the psychiatric parental groups, and did not covary with digit span or P3 amplitude assessments. These results support the view that positive and negative dimensions may reflect separable pathophysiologic processes.

The New York High-Risk Project. Prevalence and comorbidity of axis I disorders in offspring of schizophrenic parents at 25-year follow-up.

BACKGROUND: The New York High-Risk Project is a study of offspring of patients with schizophrenia (HRSz group) or affective illness (HRAff group) and psychiatrically normal parents (NC group) observed prospectively from childhood to adulthood. We herein present lifetime prevalence and comorbidity rates of Axis I disorders in subjects and their siblings from sample A of the project. METHODS: Schedule for Affective Disorders and Schizophrenia-Lifetime Version interviews conducted with the offspring in adulthood were used to obtain diagnoses of Axis I disorders. RESULTS: Schizophrenia and unspecified psychoses occurred only in the HRSz group. However, schizoaffective and psychotic affective disorders occurred equally in the HRSz and HRAff groups. Total rates of psychosis in these groups were significantly higher than in the NC group. All groups had similar rates of nonpsychotic affective and substance abuse disorders. The HRAff group, however, had significantly more total affective illness than the NC group and tended to have more anxiety disorders than the other groups. Comorbidity rates in the HRSz and HRAff groups were nearly twice those of the NC group. CONCLUSIONS: The familial liabilities to schizophrenia and affective disorders show specificities and commonalities, differing markedly from each other in their expression of some disorders and sharing others. Patterns of comorbidity are generally, although not entirely, similar to these liabilities.

Eye-tracking dysfunction in offspring from the New York High-Risk Project: diagnostic specificity and the role of attention.

Eye tracking abnormalities were studied in the offspring of schizophrenic, unipolar depressed and bipolar probands from the New York High-Risk Project to examine their familial specificity. Offspring of schizophrenic and depressed probands both had significant global performance deficits based on spectral purity measurements, but only the offspring of schizophrenic probands had an increased rate of intrusive anticipatory saccades. The greater specificity of high anticipatory saccade rate than global performance impairment suggests that this eye movement abnormality may provide a more specific biological marker of risk for schizophrenia than the global measure of eye tracking performance used in this study. Attention facilitation effectively normalized all performance deficits in the offspring of schizophrenic patients, suggesting that a problem sustaining focused visual attention may contribute to eye tracking deficits observed in the relatives of schizophrenic probands.

The temporal lobes, reversed asymmetry and the genetics of schizophrenia.

Mechanisms determining temporal lobe structural asymmetries may be involved in the pathogenesis of schizophrenia. To investigate the temporal lobes in familial schizophrenia, computed tomographic scans were obtained from 51 subjects (seven families). Enlargement of sylvian fissures and temporal lobe sulcal spaces was observed in family members with schizophrenia. The posterior one-third of the sylvian fissure was larger on the left side in subjects with schizophrenia, and larger on the right side in unaffected individuals. This disturbed pattern of posterior sylvian fissure asymmetry suggests that adjacent language regions may be affected in schizophrenia. An intermediate degree of disturbance in subjects who had schizophrenia-related illnesses or were obligate carriers suggests that genetic factors may be important determinants of temporal lobe asymmetries in familial schizophrenia.

The New York High-Risk Project. Psychoses and cluster A personality disorders in offspring of schizophrenic parents at 23 years of follow-up.

BACKGROUND: We herein present lifetime prevalence rates of psychoses and DSM-III-R cluster A personality disorders in sample A of the New York High-Risk Project, a prospective study following offspring of parents with schizophrenia (HRSz subjects) and affective illness (HRAff subjects) and of psychiatrically normal parents (NC subjects) from midchildhood to adulthood. METHODS: We interviewed the offspring in adulthood with the Schedule for Affective Disorders and Schizophrenia, Lifetime Version, for Axis I disorders and the Personality Disorder Examination for Axis II disorders. RESULTS: Lifetime prevalence rates (+/- SE) of schizophrenia and unspecified psychosis were 11.1% +/- 4.3% and 5.6% +/- 3.1%, respectively, in the HRSz group and 0% in the HRAff and NC groups. Rates of schizoaffective disorder subclassified as mainly schizophrenic, however, were highest in the HRAff group. Rates of psychotic affective disorders did not differ between the HRSz and other groups. Age-corrected morbidity risks were similar to lifetime prevalence rates. Rates of the three cluster A personality disorders did not differ among the groups, but the combined rate was greater in the HRSz and HRAff groups than in the NC group. CONCLUSIONS: Our data strongly support a specific familial liability to narrowly defined schizophrenia that is not shared by families of probands with affective disorder. Schizoaffective disorder and cluster A personality disorders, however, occur in families of both schizophrenic probands and probands with affective disorder. Psychotic affective disorders, which are not increased in HRSz subjects, do not appear to be an expression of the liability to schizophrenia.

Developmental abnormalities and cortical sulcal enlargement in psychosis.

Neurodevelopmental abnormalities and cortical sulcal enlargement both occur in schizophrenia. To test the hypothesis that these abnormalities were related, CT scans from 164 psychotic patients (80 with schizophrenia) were reviewed. Neurodevelopmental abnormalities were observed in 11%. Abnormalities were equally prevalent in schizophrenia and other psychotic disorders. Cortical sulcal enlargement was observed in 39% of patients with schizophrenia, and was not associated with developmental abnormalities. Different mechanisms may contribute to distinct structural abnormalities.

Results of computerised tomography during first admission for psychosis.

A cohort of 168 psychotic patients underwent computerised tomography (CT) during their first admission. Cortical atrophy was present in 40% of patients. The frequency of atrophy increased with age, but did not differ between patients with schizophrenia, schizoaffective disorder, bipolar disorder or psychotic depression. Other CT findings of note were present in 6.6% of patients, and included four infarctions, three arachnoid cysts, and one each of venous angioma, colloid cyst, cavum vergae and post-traumatic changes. The frequency of CT findings other than atrophy was increased in the psychotic depression group. The findings support the proposal of the onset of psychosis being an indication for CT.

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 (ERPs) as indicators of risk for schizophrenia.

Evidence is reviewed concerning the viability of cognitive event-related potential (ERP) indices to serve as psychophysiological markers for liability to schizophrenia and schizophrenia-related disorders. Methodologic problems that hinder the establishment of ERPs as such markers are also detailed. The ERP data from prospective high-risk and family-transmission paradigms were subjected to criteria that have been used to establish the marker status of a psychobiological variable. It is concluded that (1) there is a clear need for more studies of ERP component stability and of transmission of ERP parameters within normal families; (2) multiple tasks (in addition to the oddball experiment) must be used to probe the range of information-processing deficits in the schizophrenic syndrome; (3) investigators should pay greater attention to the scalp distribution of ERP components; and (4) profiles of multiple ERP indices may be required to enhance the probability of achieving diagnostic specificity.

A longitudinal study relating P3 amplitude to schizophrenia spectrum disorders and to global personality functioning.

Auditory and visual event-related potentials (ERPs) were recorded from first-degree relatives (adolescent offspring) of index cases with schizophrenic disorder, affective disorder, or no psychiatric disorder (normal controls) at a mean age of 15 years. Nearly a decade later, these subjects (at a mean age of 25 years) were evaluated for Research Diagnostic Criteria Schizophrenic Disorder, Schizoaffective Disorder, Unspecified Functional Psychosis, and for DSM-III-R Axis II schizophrenia-related traits and disorders including schizotypal, schizoid, and paranoid features. It was hypothesized, based on Duncan et al (1987a, Duncan 1988), that reduction of P3 amplitude in the auditory (but not the visual) modality would predict subsequent schizophrenic-related outcomes in subjects from the schizophrenic disorder parental group. This specific expectation was not statistically supported. An unanticipated and statistically robust result linking P3 decrements (in both auditory and visual modalities) with poorer Global Personality Functioning was observed for offspring from both psychiatric parental groups and the offspring of the normal control group. These data are consistent with the results of a large number of clinical studies of the P3 component that have demonstrated reductions in P3 amplitude in individuals expressing a wide range of behavioral dysfunctions. Their importance lies in the fact that these P3 amplitude decrements were detected long before the overt behavioral symptoms were identified, and were nonspecific with respect to parental psychiatric diagnostic group.

Early life precursors of psychiatric outcomes in adulthood in subjects at risk for schizophrenia or affective disorders.

In the New York High-Risk Project (NYHRP), 186 offspring of schizophrenic, affectively ill, and psychiatrically normal parents have been followed prospectively from 1971-72 to the average age of 27 years in 1990 with the goal of identifying early precursors of later psychopathology. In this report, we use path analyses to examine the relationship of several life-history variables to three pathological outcomes in the offspring: namely, psychosis, psychiatric hospitalization, and psychological dysfunction. The chief direct relationship with these outcomes is the effect of having a schizophrenic parent. The latter effect is also mediated indirectly by IQ.

The assessment of schizotypal features over two points in time.

The expression of schizotypal personality traits was assessed in mid-adolescence and again in young adulthood for three groups of offspring defined by the psychiatric diagnosis of their parents. Parental diagnoses included schizophrenic disorder (47 offspring), affective disorder (39 offspring), and 'no psychiatric disorder', or normal controls (82 offspring). Initially, schizotypal traits were assessed from video-taped semi-structured psychiatric interviews, subsequently rated by trained psychiatrists blind to the parental psychiatric status of the subjects, and/or direct clinical interviews (Schedule for Affective Disorders-Lifetime Version (SADS-L)). The second assessment was conducted by trained social workers and psychologists by means of a semi-structured interview specifically for DSM-III-R personality disorders (Personality Disorder Examination) and sections of the SDS-L where indicated. These interviewers were blind to the parental status and to previous psychiatric assessments of the offspring. The rates of stability of features or the rates of progression to axis I psychotic disorders (Schizophrenia, Schizoaffective Disorder, and Unspecified Functional Psychosis) were evaluated. Concordance of assessments over time is reported as a function of threshold for expression of traits at initial evaluation, i.e., two or more, three or more, or four or more features present. Concordance increases as the threshold for expression increases, as expected. The effect of comorbid clinical status, e.g., the coexistence of schizotypal traits and anxiety and/or depressive features on the concordance pattern, is also examined by parental diagnostic group status. The offspring of affective disorder parents exhibited higher rates of anxiety and/or depressive features at both points in time, exhibited higher concordance for anxiety and/or depressive features, and exhibited higher rates of 'transformation' of initial schizotypal features to anxiety and/or depressive features at the second assessment.

Report of a workshop on genetic linkage studies in schizophrenia.

A workshop on genetic linkage studies in schizophrenia was held at Columbia University's Arden House Conference Center in October 1989. This report summarizes the contents of invited talks by Drs. Arno Motulsky and T. Conrad Gilliam and the discussions at the five workshop sessions. Topics of the workshop sessions were (1) diagnostic boundaries and hierarchies in schizophrenia, (2) genetic models and linkage parameters, (3) selection and ascertainment of pedigrees, (4) future extensions of molecular genetics strategies, and (5) possibilities for future collaboration.

Measuring the inflation of the lod score due to its maximization over model parameter values in human linkage analysis.

A computer-simulation method is presented for determining and correcting for the effect of maximizing the lod score over disease definitions, penetrance values, and perhaps other model parameters. The method consists of simulating the complete analysis using marker genotypes randomly generated under the assumption of free recombination. It is applicable as a "post-treatment" to linkage analyses of any trait with an uncertain mode of inheritance and/or disease definition. When the method is applied to a linkage analysis of schizophrenia versus chromosome 5 markers, we find that, in this specific case, the P-value associated with a maximum lod score of 3 is equal to 0.0003. We also find that a lod score of 3.0 should be "deflated" by approximately 0.3 to 1 units, and, by tentative extrapolation, the observed lod score of 6.5 should be "deflated" by 0.7 to 1.5 units.

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.