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590 Schizotypal Personality Disorder: An Operational Definition of Bleuler's Latent Schizophrenia? by Seymour S. Kety Abstract 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 to this, and its deficits in this respect are discussed briefly. In 1962, when we learned about our mutual interest in the ability of adoption to separate the usually entangled genetic and environmental influences which had confronted studies on the etiology of schizophrenia, David Rosenthal, Paul Wender, and I decided to pool our efforts in the compilation of a total sample of adoptions as large as we could muster. We entered this collaboration from different vantage points and with different aims. Rosenthal saw an adoption study as a better means of evaluating a diathesis:stress model of schizophrenia (Rosenthal 1963). Wender recognized in the adoptive parents of schizophrenic patients a valuable means of testing parental schizophrenogenic hypotheses without genetic interference. For me, it permitted an examination of the prevalence of schizophrenia in the biological and adoptive families of schizophrenic adoptees in order to learn how much of the well-known familial tendency of schizophrenia might be accounted for by genetic or environmental factors (Kety 1959). When, with the invaluable collaboration of Fini Schulsinger, the Danish Adoption Registers were compiled, first for Greater Copenhagen and more recently for all of Denmark, we were able to pursue these aims using the diligently maintained Danish records, exhaustive interviews by Danish psychiatrists, and our research design developed to minimize ascertainment, selective, and subjective bias. In the study of adoptees born of a schizophrenic parent (Rosenthal et al. 1968), diagnosis was not an overriding issue since the aim was to elicit the psychological characteristics of the inherited diathesis. In the study of the types and prevalence of mental illness in the relatives of schizophrenic adoptees (Kety et al. 1968), however, the issue of diagnosis was a major one which had to be settled before we could select the probands. For defining schizophrenia, which was the subject of our study, there was no DSM-IH to make operational diagnoses economically on the basis of a small number of criteria. Instead, we had the exhaustive descriptions of Kraepelin and Bleuler of the syndrome they had defined and the designations and sketches in DSM-I and the International Classification of Mental Disorders (ICD) to denote accretions to the original concepts. Our individual definitions of schizophrenia varied widely by virtue of our training and experience, from a substantial reliance on Kraepelin and Bleuler to the broader psychodynamic concepts which were taught in the 1950s. Although not all of us accepted psychoses with acute onset and prompt remission as forms of schizo- Reprint requests should be sent to Dr. S.S. Kety, Intramural Research Program, NIMH, Bldg. 10, Rm. 4C-110, 9000 Rockville Pike, Bethesda, MD 20205. VOL 11, NO. 4, 1985 phrenia, we agreed to retain the putative subgroup "acute schizophrenia," which was listed in DSM-I and the ICD. We readily agreed to include a latent form of schizophrenia, which we called "latent" or "borderline" interchangeably since Bleuler had recognized it, and the ICD had retained and widened it to include latent, pseudoneurotic and pseudopsychopathic schizophrenia. The proband schizophrenic adoptees represented the gamut of schizophrenia diagnoses—chronic, acute, and latent—accepted at that time by the profession. In the case of the relatives, a category called "uncertain schizophrenia" had to be added if relatives with less certain diagnoses were not to be lost. In addition two nonschizophrenic disorders most resembling schizophrenia, schizoid and inadequate personality, were included in the spectrum of disorders to be examined. I doubt that any of us believed that all of these disorders would be found to be related to schizophrenia, but it would have been inappropriate to exclude any prematurely. Furthermore, if we kept the different components separate, we might eventually be able to evaluate the relationship of each to paradigmatic schizophrenia. The hypothesis to be tested in the 1968 study was stated as follows: "If schizophrenia were to some extent genetically transmitted, there should be a higher prevalence of disorders in the schizophrenia spectrum among the biological relatives of the index cases than in those of their controls." Blind consensus diagnoses based on detailed abstracts of hospital records found a prevalence of that spectrum in the biological index relatives of 8.7 percent compared to 1.9 percent in the biological relatives of the control adoptees (p = .0072), the prevalence in the adoptive index relatives being no higher than that in their controls. 591 Without the inclusion of the two personality disorders, the prevalence of schizophrenia in the biological index and control relatives was 7.3 percent vs. 1.9 percent (p = .022), and the hypothesis was upheld. Although there were insufficient cases to permit testing individual components of the spectrum with any reliability, we noted an absence of any schizophrenic disorders in the 30 biological relatives of the 7 adoptees diagnosed as acute schizophrenia, while 10 of the 13 spectrum disorders in the index biological relatives were latent or uncertain schizophrenia— our first indication that Bleuler was correct in rejecting acute schizophrenia but asserting the existence and prevalence of latent or borderline forms of schizophrenia. To come closer to defining the boundaries of schizophrenia, it was necessary to enlarge the sample or obtain more information about the mental and behavioral states of the relatives. We decided to do both by extending the study to all of Denmark and by conducting exhaustive interviews with the relatives. We were fortunate when Bjorn Jacobsen joined our collaboration and spent the next 3 years interviewing the relatives in the Copenhagen sample. The structured interviews were more exhaustive than the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L), which was not yet available, extending to 36 or more pages with numerous checklists and extensive narrative elaborations. The interview was designed to elicit response on a complete range of psychiatric symptoms and manifestations, particularly those which had been recorded in schizophrenia and schizophrenia-like syndromes. Dr. Jacobsen succeeded in obtaining interviews with 90 percent of the relatives still alive and residing in Scandinavia and partial interviews or pertinent information in an additional 5 percent. The two recent reports of failure to find evidence for genetic transmission or even familial clustering in schizophrenia (Pope et al. 1982; Abrams and Taylor 1983) used such seriously inadequate means of ascertainment that negative results would be expected. The interviews were obtained by Dr. Jacobsen with minimal knowledge of the relationship of the subject to an index or control proband and were analyzed in the United States by three of us who were entirely ignorant of the relationships. In the cases where Dr. Jacobsen developed a hunch about that relationship, it was possible to show that his hunch did not influence the diagnoses made by the raters who read the interview, and excluding those cases entirely did not significantly alter the results (Kety et al. 1975). Analysis of the interviews amplified the results obtained in the same sample from hospital records alone. The original spectrum was significantly (p = .006) concentrated as before in the biological relatives of the schizophrenic adoptees, but now instead of two cases of schizoid or inadequate personality in the hospitalized relatives, 26 instances were found among the nonhospitalized relatives. These were divided evenly between index and control relatives. When these nondiscriminating personality disorders were excluded, the remaining diagnoses (which were forms of DSM-I and the new DSM-11 schizophrenia) were highly concentrated in the biological relatives of the schizophrenic adoptees (p = .0004). There were no diagnoses of chronic schizophrenia in the biological relatives of the controls but five cases of this most severe form in the biological relatives of the schizophrenic adoptees (p = .03). 592 There were, moreover, a large number of latent and uncertain schizophrenias among the biological relatives, highly concentrated in the index relatives (11.0 percent vs. 3.4 percent, p = .005). When only biological relatives of the 23 control adoptees who were interviewed and found to be free of schizoid or inadequate personality disorder were included, the preponderance of latent and uncertain schizophrenia in the biological relatives of schizophrenic adoptees was even more striking (11.0 percent vs. 0.9 percent, p = .0004) (Kety et al. 1975). The significance of those findings was not lost on us. The concept of latent schizophrenia had been vaguely defined by Bleuler, and our criteria for uncertain schizophrenia were equally ill defined— enough of the features of schizophrenia to make that the most likely diagnosis but not sufficiently severe or typical to be certain. Despite this vagueness, which could only increase the opportunity for error and make it more difficult to find a significant difference, these diagnoses, made blindly, were almost exclusively in the biological relatives of the schizophrenic adoptees. Bleuler's recognition of a mild form of the disorder in the relatives of severely ill schizophrenic patients and his observation that it was considerably more common in the severe form was confirmed, this time in relatives who grew up apart from the patient and could not have been influenced by the patients' thought processes and behavior. Although global diagnoses may have great sensitivity and even specificity as these results indicate, there is difficulty in describing the particular criteria used and communicating them to others. Wender attempted to characterize the diagnoses we used in the first study, SCHIZOPHRENIA BULLETIN with moderate success (Kety et al. 1968), particularly for chronic and acute schizophrenia. In the case of latent or borderline schizophrenia, Kendler (this issue) points out that we placed an emphasis on positive manifestations with an apparent neglect of primary or negative symptoms. It should be pointed out, however, that all of the diagnoses in that study, in relatives as well as the adoptees, were made on people whose mental disorder was severe enough to require hospitalization, and in those, positive symptoms would be expected to predominate. For our diagnoses made from interviews in the 1975 study, no characterizations were attempted. We used the DSM-II description of latent schizophrenia, schizoid and inadequate personality that was then in use and we also took into account Bleuler's description of the symptoms of latent schizophrenia as he observed them in the relatives of overt schizophrenic patients. Bleuler's description of latent schizophrenia actually was the most useful guide since only those observations, like ours, had been made on individuals not hospitalized or seeking treatment. Our diagnoses of latent and uncertain schizophrenia in the relatives, therefore, included a majority with flat affect, bizarre thinking, poor contact, and poor interpersonal relationships rather than the positive symptoms which appeared to characterize the hospitalized group. An opportunity to operationalize our diagnoses of latent and uncertain schizophrenia presented itself when Robert Spitzer and Jean Endicott offered to review the interviews in which we had made those diagnoses along with a comparable number in which we had not. From an original list of 17 items, they narrowed the list to 8 discriminators. These items became the DSM-lll criteria for schizotypal personality disorder, a category that combined the characteristics of our diagnoses of latent and uncertain schizophrenia. It is possible that the apparent neglect of negative symptoms in the eight criteria for schizotypal personality disorder arose not so much from our failure to observe them in the interviews and use them in our diagnoses as from a relative overemphasis on positive symptoms of schizophrenia on the part of Spitzer and his associates. The criteria for schizotypal personality disorder were based on all of our borderline and uncertain schizophrenia diagnoses (plus six diagnoses of schizoid personality) and confirmed by reference to the concepts of a large number of psychiatrists selected randomly (Spitzer, Endicott, and Gibbon 1979). Thus, they were not derived solely from the genetic relatives of schizophrenic patients, which would have given it some independent validity. It is, however, better able to discriminate the genotype than any previous descriptors. When Kendler and his associates asked to review Jacobsen's interviews for the possible relationship of anxiety disorder to schizophrenia, we asked them to include other DSM-lll diagnoses, particularly that of schizotypal personality disorder (Kendler, Gruenberg, and Strauss 1981). They found a prevalence of 13.6 percent for this syndrome in the biological relatives of 16 adoptees diagnosed by us and by Spitzer and associates as chronic schizophrenia using the Research Diagnostic Criteria compared to 2 percent in the biological relatives of unscreened control adoptees (Kety 1983). Our less operationalized diagnoses had given prevalence rates for latent and uncertain schizophrenia of 17.1 593 VOL. 11, NO. 4, 1985 percent and 6.1 percent, respectively, in the same populations. In their hands, DSM-III had greater specificity but less sensitivity than our global diagnoses. Later, when Kendler and Gruenberg (1984) made DSM-I11 diagnoses on the index probands, the difference in prevalence rates for schizotypal personality disorder between biological relatives of DSM-III schizophrenic adoptees and control biological relatives was even sharper. The genetic relationship of schizotypal personality disorder (or the latent and uncertain schizophrenias on which it was based) to paradigmatic schizophrenia is clearly demonstrated by their high prevalence in the biological relatives of adoptees with chronic schizophrenia. Although it may be true, as Torgersen (this issue) indicates, that the reverse is not the case, i.e., rarely is chronic schizophrenia found in the relatives of borderline schizophrenic probands, that is hardly a basis for rejecting a genetic relationship between the two. There are obvious statistical and genetic explanations for Torgersen's observation. If chronic schizophrenia is considerably more rare than schizotypal personality disorder, the likelihood of finding it in the relatives of latent schizophrenics is considerably diminished. In addition, it is easy to think of types of genetic transmission which would produce a similar phenomenon. It would be expected in polygenic transmission and in recessive forms, if monogenic. One would find numerous heterozygotes for phenylketonuria (PKU) in the families of PKU patients, but practically no PKU in the families of heterozygotes. Stone (1980) has reported finding an excess of chronic schizophrenia in the families of borderline schizophrenics, indicating that such occurrences may be rare but not nonexistent. The fact that chronic schizophrenic probands do have schizotypal twins and relatives is further assurance that there must be schizotypal individuals who have chronic schizophrenia in their families. Finally, I can think of no other explanation for the high prevalence of schizotypal personality disorder in the biological relatives of adopted chronic schizophrenics than that the two disorders are genetically associated. There is no reason to feel, however, that the eight criteria for schizotypal personality disorder in DSM-III represent the complete or the best possible description of Bleuler's latent schizophrenia. There are undoubtedly many more characteristics of the nonpsychotic genotypes of schizophrenia which remain to be noted and evaluated. The criteria should have been developed more explicitly within the biological relatives of schizophrenics, thus using the genetic association to contribute to the validity of the syndrome—an opportunity that is still rare in psychiatric nosology. The work of Kendler and his associates and that of Gunderson, Siever, and Spaulding (1983) have been important in further defining the syndrome and staking out its limits. The syndrome is in need of further improvement, however, as is the DSM-III definition of schizophrenia (Kety 1985). The interviews now being completed in the adoption sample outside of Greater Copenhagen will soon be available for evaluating improved concepts and operational diagnoses of the components of the schizophrenia spectrum which can now be validated. References Abrams, R., and Taylor, M.A. The genetics of schizophrenia: A reassessment using modern criteria. American Journal of Psychiatry, 140:171-175, 1983. Gunderson, J.G.; Siever, L.J.; and Spaulding, E. The search for a schizotype. Archives of General Psychiatry, 40:15-22, 1983. Kendler, K.S., and Gruenberg, A.M. 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. Archives of General Psychiatry, 41:555-564, 1984. Kendler, K.S.; Gruenberg, A.M.; and Strauss, J.S. An independent analysis of the Copenhagen sample of the Danish adoption study of schizophrenia: II. The relationship between schizotypal personality disorder and schizophrenia. Archives of General Psychiatry, 38:982-984, 1981. Kety, S.S. Biochemical theories of schizophrenia: Part 2. Science, 129:1590-1596, 1959. Kety, S.S. Mental illness in the biological and adoptive relatives of schizophrenic adoptees: Findings relevant to genetic and environmental factors in etiology. American Journal of Psychiatry, 140:720-727, 1983. Kety, S.S. The concept of schizophrenia. In: Alpert, M., ed. Controversies in Schizophrenia. New York: Guilford Press, 1985. pp. 3-11. Kety, S.S.; Rosenthal, D.; Wender, P.H.; and Schulsinger, F. The types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics. In: Rosenthal, D., and Kety, S.S., eds. The Transmission of Schizophrenia. Oxford: Pergamon Press, 1968. pp. 345-362. Kety, S.S.; Rosenthal, D.; Wender, P.H.; Schulsinger, F.; and Jacobsen, SCHIZOPHRENIA BULLETIN 594 B. Mental illness in the biological and adoptive families of adoptive individuals who have become schizophrenic: A preliminary report based on psychiatric interviews. In: Fieve, R.R.; Rosenthal, D.; and Brill, H., eds. Genetic Research in Psychiatry. Baltimore: Johns Hopkins University Press, 1975. pp. 147-165. Pope, H.G., Jr.; Jonas, J.M.; Cohen, B.M.; and Lipinski, J.F. Failure to find evidence of schizophrenia in first-degree relatives of schizophrenic probands. American Journal of Psychiatry, 139:826-828, 1982. Videotapes on Schizophrenia Available Rosenthal, D., ed. The Genain Quadruplets. New York: Basic Books, 1963. Rosenthal, D.; Wender, P.H.; Kety, S.S.; Schulsinger, F.; Welner, J.; and Ostergaard, L. Schizophrenics' offspring reared in adoptive homes. In: Rosenthal, D., and Kety, S.S., eds. The Transmission of Schizophrenia. Oxford: Pergamon Press, 1968. pp. 377-391. Spitzer, R.L.; Endicott, J.; and Gibbon, M. Crossing the border into borderline personality and borderline schizophrenia: The development of criteria. Archives of General Psychiatry, 36:17-24, 1979. Stone, M.H. The Borderline Syndromes. New York: McGraw Hill, 1980. The Video Center of the George Warren Brown School of Social Work, in cooperation with several community and mental health organizations, has produced four videotapes on the following topics relating to survival issues for chronically mentally ill persons and their families in the community. Coping With a Chronically Mentally 111 Relative in the Community—The two videotapes on this topic were produced in cooperation with the Alliance for the Mentally 111, St. Louis Chapter. Each videotape presents the experiences of a family which has had some success surviving the multiple problems arising from caring for a mentally ill relative in the community. The videotapes are intended for an audience of parents and relatives of chronically mentally ill persons who could benefit from a vicarious sharing of experiences with the families on the videotapes. Psychosocial Rehabilitation: Two Agencies Based on the Fountain House Model—These two videotapes were produced in cooperation with the Missouri Department of Mental Health, Independence Center, and Places for People, St. Louis, MO. Each videotape presents a psychosocial rehabilitation agency from the point of view of its members. The tapes are intended for professional audiences as well as for families and mentally ill persons who could benefit from knowing what it's like to experience psychosocial rehabilitation "from the inside." For more information about the rental or purchase of these videotapes, please contact: Dr. David Katz, Video Center, Box 1196, Washington University, St. Louis, MO 63130. The Author Seymour S. Kety, M.D., is Emeritus Professor of Neuroscience, Harvard University, and Senior Science Advisor, National Institute of Mental Health, Alcohol, Drug Abuse, and Mental Health Administration, Rockville, MD 20857.