An independent analysis of the Danish Adoption Study of Schizophrenia. VI. The relationship between psychiatric disorders as defined by DSM-III in the relatives and adoptees

In this report, modified DSM-III criteria were applied to all the available interviews with adoptees from the greater Copenhagen sample of the Danish Adoption Study of Schizophrenia. In the adoptees, reasonable agreement was found between our DSM-III diagnoses and the original diagnoses using global DSM-II-based criteria by Kety et al for their categories of chronic and acute, but not borderline, schizophrenia. Comparing DSM-III-based diagnoses in adoptees and relatives, schizophrenia, schizotypal personality disorder, and paranoid personality disorder were all significantly more common in the biologic relatives of schizophrenic v screened control adoptees. These three diagnoses, which together form a tentative "schizophrenia spectrum," were also significantly concentrated in the biologic relatives of adoptees with schizoaffective disorder, mainly schizophrenic subtype, and schizotypal personality disorder, but not in biologic relatives of adoptees with schizophreniform disorder or atypical psychosis.     

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 genetic relationship to schizophrenia.     

Defining the schizophrenia spectrum: issues for genetic linkage studies

Genetic linkage studies of schizophrenia depend on accurate psychiatric diagnosis of relatives within multiply affected families. Each investigator makes a series of explicit or implicit decisions to define which relatives will be assumed to share a schizophrenia-related genotype, that is, who is an "affected relative." In this article we delineate issues that we believe should be considered in such studies and review the relevant literature. Issues include criteria for selecting probands; whether broader criteria should be used to select affected relatives; approaches to including or excluding diagnoses for which family study data suggest a relationship to schizophrenia or to affective disorders or other psychiatric disorders; clarification of diagnostic hierarchy; and issues related to substance abuse and neurological disorders. Also discussed are whether relatives without spectrum diagnoses should be considered unaffected or undiagnosed in linkage analyses, how bilateral familial affectedness should be defined, and provision for independent review of study diagnoses. As an illustration, the clinical model for the authors' schizophrenia linkage study is described.     

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.     

Adoption studies in functional psychosis

Summary The scientific rationale of the adoptive methods in genetic studies has been discussed. Three strategies have been employed in psychiatric research. In the adoptee's study method, one examines the adopted away offspring of biological parents, known to be affected by the disorder. A higher prevalence of the disorder among adoptees born to affected biological parents indicates that genetic factors are important. In the adoptee's relatives method, one starts with adoptees known to be disturbed, and then continues by investigating their biological and adoptive families. Comparisons of prevalence rates between relatives of the biological and the rearing index and control families permits one to estimate the influence of the genetic factors. A third method is crossfostering, which is rarely employed. Children of normals who are cross-fostered to adoptive parents who later became ill, are studied. Adoption studies in the field of schizophrenia and manic depressive illness are more specifically discussed. Taken all together, the family, twin and adoption studies support the genetic etiology in schizophrenia and manic depressive illness, although it must be admitted that we need replications to arrive at firm conclusions in the last group of disorder.     

Changes in VA diagnosis of schizophrenic and affective disorders after DSM-III

DSM-III tightened the criteria for diagnosis of schizophrenia by excluding patients who exhibit a full affective syndrome before the onset of psychotic symptoms; such patients are to receive a diagnosis of affective disorder. The impact of this change on psychiatric diagnostic practices in Veterans Administration facilities before and after publication of DSM-III was assessed. Diagnoses of schizophrenia increased about half as much as would be expected based on the overall increase in psychiatric diagnoses, while diagnoses of affective disorders rose about two and a half times as much as would be expected. Patients whose diagnoses were changed from schizophrenic to affective disorders after publication of DSM-III had significantly fewer hospitalizations in both time periods than patients who retained diagnoses of schizophrenia. However, greater diagnostic inconsistency was found after implementation of DSM-III.     

Genetic boundaries of the schizophrenia spectrum: evidence from the Finnish Adoptive Family Study of Schizophrenia

OBJECTIVE: Identification of the genetically related disorders in the putative schizophrenia spectrum is an unresolved problem. Data from the Finnish Adoptive Family Study of Schizophrenia, which was designed to disentangle genetic and environmental factors influencing risk for schizophrenia, were used to examine clinical phenotypes of schizophrenia spectrum disorders in adopted-away offspring of mothers with schizophrenia spectrum disorders. METHOD: Subjects were 190 adoptees at broadly defined genetic high risk who had biological mothers with schizophrenia spectrum disorders, including a subgroup of 137 adoptees at narrowly defined high risk whose mothers had DSM-III-R schizophrenia. These high-risk groups, followed to a median age of 44 years, were compared diagnostically with 192 low-risk adoptees whose biological mothers had either a non-schizophrenia-spectrum diagnosis or no lifetime psychiatric diagnosis. RESULTS: In adoptees whose mothers had schizophrenia, the mean lifetime, age-corrected morbid risk for narrowly defined schizophrenia was 5.34% (SE=1.97%), compared to 1.74% (SE=1.00%) for low-risk adoptees, a marginally nonsignificant difference. In adoptees whose mothers had schizophrenia spectrum disorders, the mean age-corrected morbid risk for a schizophrenia spectrum disorder was 22.46% (SE=3.56%), compared with 4.36% (SE=1.51%) for low-risk adoptees, a significant difference. Within the comprehensive array of schizophrenia spectrum disorders, schizotypal personality disorder was found significantly more often in high-risk than in low-risk adoptees. The frequency of the group of nonschizophrenic nonaffective psychoses collectively differentiated high-risk and low-risk adoptees, but the frequencies of the separate disorders within this category did not. The two groups were not differentiated by the prevalence of paranoid personality disorder and of affective disorders with psychotic features. CONCLUSIONS: In adopted-away offspring of mothers with schizophrenia spectrum disorders, the genetic liability for schizophrenia-related illness (with the rearing contributions of the biological mothers disentangled) is broadly dispersed. Genetically oriented studies of schizophrenia-related disorders and studies of genotype-environment interaction should consider not only narrowly defined, typical schizophrenia but also schizotypal and schizoid personality disorders and nonschizophrenic nonaffective psychoses.     

Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients. A family study using DSM-III criteria

This report examines the risk for psychiatric illness in 723 first-degree relatives of schizophrenics and 1,056 first-degree relatives of matched surgical control patients. Diagnoses in patients and relatives were made "blind" to one another, using DSM-III criteria. Information on relatives was obtained from personal interview and/or hospital records. Results were analyzed using two levels of diagnostic certainty and with or without relatives on whom only hospital records were obtained. In all analyses, the risk for schizophrenia was significantly greater (at least 18-fold) in the relatives of schizophrenics v controls. Evidence was also found for an increased risk in relatives of schizophrenics for schizoaffective disorder, paranoid disorder, and atypical psychosis but not for unipolar disorder, anxiety disorder, or alcoholism. As defined by DSM-III, schizophrenia is a familial disorder; however, the increased risk for psychotic illness in relatives of schizophrenics does not appear to be confined to schizophrenia alone.     

Who seeks mental health care in China? Diagnoses of Chinese outpatients according to DSM-III criteria and the Chinese classification system

The authors gave DSM-III diagnoses to 116 Chinese psychiatric outpatients in Shanghai and compared them with the diagnoses of the same patients made by a Chinese psychiatrist according to Chinese criteria. Affective disorders were the most common DSM-III diagnoses, accounting for 26.7% of the sample. A full range of psychopathology, including schizophrenia, organic mental disorders, adjustment disorders, anxiety disorders, and paranoid disorders, was seen. Some consistent differences in diagnosis by Chinese and Western standards, especially in the area of major depression, were found. The authors discuss the implications for interpreting psychiatric studies from China and for future cross-cultural research comparing U.S. and Chinese diagnoses.     

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.     

Clinical variables and genetic loading for schizophrenia: analysis of published Danish adoption study data

Schizophrenia shows considerable clinical variation, but the relationship between clinical variables and degree of genetic loading for schizophrenia is unclear. We investigated this by analyzing published data from the adoption study of Kety et al. (1994) in Denmark. We sought to determine which clinical variables in proband adoptees with chronic schizophrenia predicted risk of schizophrenia in their biological relatives, using logistic regression analysis. We found that risk of chronic schizophrenia in relatives was predicted by the presence of pervasive negative symptoms (odds ratio [OR] = 9.44, 95% confidence interval [CI] = 1.98-45.01) and absence of pervasive positive symptoms (OR = 0.09, 95% CI = 0.01-0.78) in probands. Pervasive negative symptoms were defined by the presence of all of the symptoms: social withdrawal, autistic behavior, poverty of thought/speech, and flat affect. Pervasive positive symptoms were defined by the presence of all of the symptoms: suspiciousness/ideas of reference, delusions, auditory hallucinations, and other hallucinations. These clinical variables may be useful for refining phenotypic definitions of schizophrenia in molecular genetic studies.     

Replicated psychometric correlates of schizophrenia

OBJECTIVE: The authors' goals are to use scales from the MMPI hypothesized in their previous research to be correlates of liability to schizophrenia to differentiate DSM-III schizophrenia from bipolar and unipolar affective illness and to cross-validate these correlates in an independently ascertained sample of patients with Research Diagnostic Criteria (RDC) schizophrenia or affective disorder. METHOD: The criterion sample consisted of 83 patients consecutively admitted to a state-operated community mental health center. Diagnosis of schizophrenia; bipolar disorder, manic; and major depression were assigned by using DSM-III. The replication sample consisted of 60 adults with RDC diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, and unipolar disorder who were parents of children in two samples collected for a study of offspring at high risk for schizophrenia and other psychopathology. After the patients in the criterion sample were classified by logistic regression analysis, the results were used to classify patients in the replication sample. RESULTS: The MMPI indicators had adequate sensitivity, specificity, and predictive power for classifying schizophrenia, and there was a moderately high rate of diagnostic agreement between the MMPI and DSM-III. Cross-validation in the replication sample was successful. Overall, the MMPI index was an adequate inclusion and exclusion criterion not only for DSM-III-defined but also for RDC-defined schizophrenia. CONCLUSIONS: A psychometric index composed of the paranoid schizophrenia, psychoticism, and manifest hostility scales from the MMPI would be a cost-effective measure to increase diagnostic efficacy in future schizophrenia research and clinical practice.     

Personality disorder in the families of depressed, schizophrenic, and never-ill probands

In a blind family study of 176 probands with nonpsychotic major depression, psychotic major depression, schizophrenia, or no history of DSM-III disorders, only the relatives of depressed probands with mood-incongruent psychotic features had a risk for personality disorders higher than that for the relatives of never-ill probands. The authors did not find a high rate of borderline personality in relatives of depressed probands or of schizotypal personality disorder in relatives of probands with schizophrenia or any psychosis. However, depressed probands with normal dexamethasone test results had a significantly higher familial loading for the DSM-III cluster of histrionic, antisocial, borderline, and narcissistic personality disorders.     

Clinical methods in psychiatric genetics. III. Environmental stratification may simulate a genetic effect in adoption studies

In adoption studies, the possibility of inadvertent matching between biological and adoptive parents for some environmental variable (known or unknown) correlated with illness must be considered. We examine such bias quantitatively and show how a genetic effect can be simulated. Existence of a genetic effect which is independent of environmental correlation can be accepted, when the frequency of a disease in adoptees who have a biological parent affected and no adoptive parents affected is significantly greater than the frequency of the disease in adoptees who have an adopted parent affected and no biological parents affected. The published data on schizophrenia, alcoholism, and criminality do not exclude the possibility of undetected environmental correlations simulating a genetic effect, according to this direct criterion.     

Finnish adoptive family study: sample selection and adoptee DSM-III-R diagnoses

OBJECTIVE: To evaluate the genetic contribution to schizophrenia using an adoption design that disentangles genetic and environmental factors. METHOD: Finnish hospital diagnoses of schizophrenic/paranoid psychosis in a nationwide sample of adopting-away women are compared with DSM-III-R research diagnoses for these mothers. DSM-III-R diagnoses of their index offspring are blindly compared with adopted-away offspring of epidemiologically unscreened control mothers. RESULTS: Primary sampling diagnoses of index mothers were confirmed using DSM-III-R criteria. Lifetime prevalence of typical schizophrenia in 164 index adoptees was 6.7% (age-corrected morbid risk 8.1%), significantly different from 2.0% prevalence (2.3% age-corrected morbid risk) in 197 control adoptees. When adoptees with diagnoses of schizoaffective disorder, schizophreniform disorder, schizotypal disorder and affective psychoses were added, the contrast between the index and control adoptees increased. CONCLUSION: The genetic liability to 'typical' DSM-III-R schizophrenia is decisively confirmed. Additionally, the liability also extends to a broad spectrum of other psychotic and non-psychotic disorders.     

Relationship of schizotypal personality disorder to schizophrenia: genetics

The adoptive, family, and twin studies show that schizotypal personality features are found among the relatives of schizophrenics. However, it has not been shown that there is a higher risk of schizophrenia among the relatives of schizotypals. An explanation may be that the current DSM-III criteria of schizotypal personality disorder do not adequately define schizotypals genetically related to schizophrenia. While some of the cases that meet DSM-III criteria are within the schizophrenia spectrum, others are unrelated to schizophrenia. There is reason to believe that schizotypals characterized by distant relationship to others, suspiciousness, eccentricity, peculiar communication, and dysfunctional school and work performance are within the schizophrenic sphere, while individuals with psychotic-like symptoms phenomenologically similar to schizophrenia and diagnosed as schizotypal personality disorders in DSM-III represent decompensation of other personality disorders.     

Schizo-affective disorder, manic type. A clinical, laboratory, and genetic study

We studied a sample of 111 Feighner manics divided into 42 'pure' manics without any schizophrenic features, 41 manics with one such feature, and 28 with two or more such features. The three groups did not significantly differ on any major demographic, clinical, historical, treatment response, laboratory, or familial variable tested. We also applied the DSM-III schizophrenia and schizophreniform criteria to these 111 Feighner manics. Only 1 manic had an index episode longer than 6 months (a necessary criterion for schizophrenia), whereas 13 (12%) satisfied the schizophreniform criteria. We compared these 13 Feighner manics satisfying DSM-III schizophreniform criteria with the remaining 97 Feighner manics and could find no major demographic, clinical, or laboratory differences between the two groups. Although not statistically significant, the morbidity risk for affective disorder in the first-degree relatives of the 97 Feighner manics was three times the risk in the relatives of the Feighner manics who also satisfied the DSM-III schizophreniform criteria. The morbidity risk for alcoholism in these relatives was one-half that of first-degree relatives of the 'schizophreniform' manics. The two groups did not differ in total risk for alcoholism and affective disorder.     

The value of DSM-III for psychotherapy. A feasibility study

Establishing the usefulness of DSM-III for psychotherapy will probably require numerous studies. This paper reports a feasibility study for one kind of investigation: the use of clinical records to survey the DSM-III diagnoses and therapy outcome of 30 patients who had outpatient psychotherapy. We were interested in what range of DSM-III diagnoses was represented by patients in outpatient therapy; whether judgments of diagnosis and outcome could be made reliably from clinical records; how well patients in the therapy fit DSM-III diagnoses; if patients did not fit well, why not? We found that an exploration of the relationship between DSM-III diagnosis and outcome from clinical records is feasible; a relatively wide range (13) of DSM-III diagnoses was represented by the 30 patients; 80% of the patients fit well or moderately well into a DSM-III diagnosis; most of the 20% who did not fit well represent the class of problems of living, which does not mean, however, that their problems were minor or unimportant; in some cases the diagnosis--even when it fit the patient well--did not express the essence of the problem for which he or she was to be treated; there was a small correlation (.19) between the patient's rating on axis V and therapy outcome. The findings are discussed in terms of the pro and con arguments that have been made about DSM-III.