Neuropsychopharmacology and the genetics of schizophrenia: a history of the diagnosis of schizophrenia.

Development of the diagnostic concept of schizophrenia (dementia praecox) is traced from the fourth edition of [Kraepelin, E., 1893. Ein Kurzes Lehrbuch der Psychiatrie. 4 Aufl. Barth, Lepzig] textbook to the DSM-IV [American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders. Fourth ed. American Psychiatric Association, Washington, 273-316]. The differences between the criteria used by Bleuler [Bleuler, E., 1911. Dementia Praecox oder Gruppe der Schizophrenien. Deuticke, Leipzig] and Schneider [Fortschr. Neurol. Psychiatr. 25 (1957) 487] in the diagnosis of schizophrenia are discussed. The nosologic contributions of Kleist [Klin. Wochenschr. 2 (1923) 962] and Leonhard [Leonhard, K., 1957. Aufteilung der endogenen Psychosen. Akademie, Berlin]--which split schizophrenia into two major classes of disease with several forms and subforms--are outlined. Epidemiological findings--which show wide variations in the prevalence of schizophrenia in the general population and in the admission rate of schizophrenics to psychiatric clinics--are presented. Findings in genetic studies are reviewed with special reference to family, twin, and adoption studies which have raised the possibility that heredity plays an important role in the etiology of schizophrenia; mathematical analyses are examined which have ruled out monogenic transmission, as well as molecular genetic investigations indicating that the schizophrenic population is genetically heterogeneous. The relevance of findings with endophenotypes to the genetics of schizophrenia is questioned. The history of pharmacotherapy, neuropharmacology, and psychopharmacology of schizophrenia is outlined. Attention is focused on findings which indicate that the schizophrenic population is pharmacologically heterogenous. It is emphasized that neuropsychopharmacology, through its unique capability of linking the effects of psychotropic drugs to brain structures--encoded by genes which have been identified--offers a pioneering methodology for bridging the gap between the genes and psychiatric nosology. It is pointed out that for the detection of subpopulations within schizophrenia, clinical investigations with antipsychotic drugs have to proceed beyond the demonstration of therapeutic efficacy to the identification of treatment-responsive form(s) of illness. Early findings by Fish [L'Encephale 53 (1964) 245] are presented which indicate that affect-laden paraphrenia, one of the three forms of unsystematic schizophrenia in Leonhard [Leonhard, K., 1957. Aufteilung der endogenen Psychosen. Akademie, Berlin] classification, is the treatment-responsive subpopulation within schizophrenia for typical antipsychotic drugs. It is suggested that if the findings of Fish [L'Encephale 53 (1964) 245] could be verified, affect-laden paraphrenia would qualify for molecular genetic research. Another possible subpopulation that might qualify for genetic research is systematic hebephrenia, one of the three forms of systematic hebephrenia. The paper concludes that resolving the heterogeneity of the schizophrenic population would open up a new perspective for genetic research and for the pharmacotherapy of the different illnesses covered up for a century by the diagnostic label of schizophrenia.