Adoption studies of schizophrenia.

The observation that schizophrenia is more commonly observed among the relatives of individuals with schizophrenia than in the general population does not indicate the mechanism that produces such familiality occurs. Adoption designs permit evaluation of the role of genetic factors in schizophrenia independently of the influence of family environments. Results from studies of adoptees with schizophrenia and their biological and adoptive relatives indicate that genetic factors play a highly significant role in the risk for schizophrenia. This genetically mediated risk to relatives includes an increased prevalence of both schizophrenia and a nonpsychotic syndrome analogous to schizophrenia, but does not represent a general liability to other forms of psychopathology. Although adoption studies have convincingly demonstrated an important role for genetic factors in schizophrenia, the necessity and specificity of such factors, their precise identity, and their interaction with environmental influences remain unknown.

Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Replication of the Copenhagen Study in the rest of Denmark.

BACKGROUND: Our previous investigation of the prevalence of mental illness among the biological and adoptive relatives of schizophrenic adoptees in Copenhagen, Denmark, showed a significant concentration of chronic schizophrenia (5.6%) and what Bleuler called "latent schizophrenia" (14.8%) in the biological relatives of chronic schizophrenic adoptees, indicating the operation of heritable factors in the liability for schizophrenic illness. METHODS: We now report the results of a replication of that study in the rest of Denmark (the "Provincial Sample"). RESULTS: In this sample, the corresponding prevalences were 4.7% and 8.2%. In the combined "National Sample" of adoptees with chronic schizophrenia, that disorder was found exclusively in their biological relatives and its prevalence overall was 10 times greater than that in the biological relatives of controls. CONCLUSIONS: This study and its confirmation of previous results in the Copenhagen Study speak for a syndrome that can be reliably recognized in which genetic factors play a significant etiologic role. These findings provide important and necessary support for the assumption often made in family studies: observed familial clustering in schizophrenia is an expression of shared genetic factors.

The measurement of cerebral blood flow by means of inert diffusible tracers.

The author presents his development of the techniques for the measurement of total and regional cerebral blood flow, based on the principles that describe the exchange of inert diffusible tracers between blood and tissue. From the recognition that the uptake and distribution of such tracers would be independent of metabolism and neural function, but dependent instead on blood flow and purely physical factors such as diffusion and solubility, it was possible to transform equations of Fick, Bohr, and Krogh developed to describe steady states of oxygen distribution, to the dynamic processes involved in the distribution and equilibration of inert gases and other diffusible and nonmetabolized substances. The equations thus developed made possible the quantitative measurement of total and local blood flow in the brains of animals and man, and ultimately, the imaging of functional activity in the human brain through the coupling between activity and perfusion described 100 years ago by Roy and Sherrington.

Genetic transmission and improved diagnosis of schizophrenia from pedigrees of adoptees.

In previous investigations of the prevalence of schizophrenic illness among the biological relatives of schizophrenic adoptees in Copenhagen and the remainder of Denmark, the operation of heritable spectrum illness was clearly implicated. The findings supporting that conclusion are briefly summarized. Classical chronic schizophrenia was found almost exclusively in the biological relatives of chronic schizophrenic probands and its prevalence was ten times greater than that in the biological relatives of controls. These were global diagnoses, made without knowledge of the relationships and family histories of the subjects, and based upon the descriptions of dementia praecox or schizophrenia by Kraepelin and Bleuler. They showed considerably greater sensitivity and at least equal specificity in comparison with diagnoses made on the same material in accordance with operational criteria as exemplified by DSM-III. The prevalence of a disorder in the biological relatives of adoptees with that disorder in comparison with biological relatives of control adoptees offers a useful test for the expression of genetic factors in the disorder, but also a much needed evaluation of the validity of diagnoses based on clinical observation.

Schizophrenic illness in the families of schizophrenic adoptees: findings from the Danish national sample.

The prevalence of schizophrenic illness in the biological and adoptive relatives of schizophrenic adoptees has been examined in a total sample of adoptees in Denmark. The sample was studied in two stages, beginning with the Copenhagen sample of adoptions granted by the courts in the city and county of Copenhagen, and the results have been reported previously. The adoptions granted by the courts in the remainder of Denmark made up the Provincial sample, the preliminary results of which appear to confirm those obtained earlier. Chronic schizophrenia and milder syndromes described as latent, borderline, or uncertain schizophrenia, and in DSM-III as schizotypal personality disorder, were found in both samples to concentrate significantly in the biological relatives of schizophrenic adoptees as compared to their controls, but not in their adoptive relatives. These milder and marginal syndromes resembling schizophrenia occurring in the families of schizophrenic patients confirm the observations of Bleuler and others who succeeded him. Their presence in the biological families of schizophrenic adoptees indicates not only their familial, but also their genetic relationship to schizophrenia, although the specificity of that relationship has not been established.

The significance of genetic factors in the etiology of schizophrenia: results from the national study of adoptees in Denmark.

The prevalence of schizophrenic illness in the biological and adoptive relatives of schizophrenic adoptees has been examined for a total sample of adoptees in Denmark. The total sample was studied in two stages, beginning with the Copenhagen sample of adoptions granted by the courts in the city and county of Copenhagen, the results of which have been reported previously. The adoptions granted by the courts in the remainder of Denmark comprised the Provincial sample the preliminary results of which appear to confirm those obtained earlier. Chronic schizophrenia and milder syndromes described as latent, borderline, or uncertain schizophrenia were found in both samples to concentrate significantly in the biological relatives of schizophrenic adoptees as compared to their controls, but not in their adoptive relatives. These milder and marginal syndromes resembling schizophrenia occurring in the families of schizophrenic patients confirm the observations of Bleuler and others who succeeded him. Their presence in the biological families of schizophrenic adoptees indicates not only their familial but also their genetic relationship to schizophrenia.

Psychiatric disorders in the biological and adoptive families of adopted individuals with affective disorders.

To investigate the contribution of genetic and environmental factors in the etiology of mood disorders, a study was initiated to examine the frequency of psychiatric disorders in the biological and adoptive relatives of adult adoptees with mood disorders and in matched normal adoptees. Psychiatric evaluations of the relatives were made on the basis of independent blind diagnoses based on mental hospital and other official records. Analysis of the data showed an eightfold increase in unipolar depression among the biological relatives of the index cases and a 15-fold increase in suicide among the biological relatives of the index cases. These data demonstrate a significant genetic contribution to unipolar depression and suicide. They fail to disclose a significant contribution of family-associated transmission in the genesis of the mood disorders.

Regional cerebral blood flow: estimation by means of nonmetabolized diffusible tracers--an overview.

Visualization and measurement of functional activity throughout the human brain has been made possible by position emission tomography (PET) using tracers, the accumulation of which in the various regions of the brain are functions of regional blood flow or energy metabolism. Certain principles and mathematical expressions describing the exchange of diffusible, nonmetabolized substances between capillary and brain, published nearly 40 years ago, have been useful in this development.

Schizotypal personality disorder: an operational definition of Bleuler's latent schizophrenia?

In spite of the pressure for consensus that operational diagnoses exert, there remains considerable disagreement concerning the marginal syndromes which may be subtypes of schizophrenia or phenomenologically or genetically related. Some clarification of the question may result by returning to Bleuler's "latent schizophrenia," which he observed in the relatives of schizophrenics. Schizotypal personality disorder of DSM-III is only a first approximation of this, and its deficits in this respect are discussed briefly.

Mental illness in the biological and adoptive relatives of schizophrenic adoptees: findings relevant to genetic and environmental factors in etiology.

Previous studies by the author and his collaborators, Rosenthal, Wender, Schulsinger, and Jacobsen, of the biological and adoptive relatives of schizophrenic adoptees are reviewed in conjunction with more recent studies by Spitzer and Endicott and by Kendler, Gruenberg, and Strauss, who independently made operational diagnoses using the Research Diagnostic Criteria or DSM-III specifications, both of which showed good agreement with the authors' global diagnoses based on the descriptions in DSM-II. Both the DSM-III diagnoses and the authors' global diagnoses found a highly significant concentration of chronic, latent, and uncertain schizophrenia or schizotypal personality disorder in the biological relatives of adoptees who developed chronic schizophrenia. A response is made to recent criticisms published in this journal by Lidz and Blatt and by Abrams and Taylor.

Neurochemical and genetic bases of psychopathology: current status.

A review, which does not attempt to be exhaustive, is presented. Evidence for the operation of genetic factors in the etiology of mental disorders, including studies of natural families, twins, and adoptees and their biological and adoptive relatives, is briefly summarized and discussed. Environmental influences are also clearly involved, and observations bearing on their nature are described. Certain neurochemical correlates of psychopathology, particularly those related to chemical neurotransmitters, are discussed. Since schizophrenia and the affective disorders are phenomenological syndromes, it is likely that they represent heterogeneous collections of more specific disorders with common symptomatic features. Attempts to delineate more homogeneous subgroups in these disorders on the basis of morphological or biochemical features have achieved some success, and an example of each approach is described.