Review article
Neuropsychopharmacology and the genetics of schizophrenia
A history of the diagnosis of schizophrenia
Thomas A. Ban
Department of Psychiatry, Vanderbilt University, Nashville, TN, USA
Accepted 10 May 2004 - Available online 25 July 2004
7. Psychopharmacology
Psychopharmacology deals with the detection of psychopathologic symptoms and syndromes, and the identification of nosologic entities that are affected by psychotropic drugs (Ban 1996, 1999). Its origin was in Moreau de Tours’ (1845) recognition of the differential effect of dawamsec, an electuary of hashish, in depressed and in regressed patients (Caldwell, 1970).
Early clinical psychopharmacological research focused attention on the heterogeneity in responsiveness to antipsychotic drugs within the diagnostic category of schizophrenia (Ban, 1969). But instead of developing a methodology for resolving this heterogeneity in the 1960s and 1970s, a methodology was developed for the demonstration of therapeutic effectiveness, a quite different proposition (Lehmann and Ban, 1997).
There are two essential prerequisites for the demonstration of therapeutic effectiveness; sensitive rating scales that can detect and document changes, such as the Brief Psychiatric Rating scale of Overall and Gorham (1962), and diagnostic endpoints that can be reliably identified, such as the diagnostic criteria of the DSM-III (American Psychiatric Association, 1980) and of other consensus-based classifications. With the two essential prerequisites for a generally acceptable methodology fulfilled, isolated clinical trials were replaced by centrally coordinated clinical investigations during the 1980s.
With the employment of the new methodology, many drugs were found to be therapeutically effective in schizophrenia, but none of the newer drugs were found to be consistently more effective than chlorpromazine or any of the others (Davis et al., 1980). In spite of isolated reports indicating that one or another of the second-generation antipsychotics - and especially of clozapine - is superior to first generation antipsychotics, the fact remains that regardless of which first- or second-generation antipsychotic is chosen, approximately 30% of schizophrenia patients remain refractory to the first line of treatment; 30% to 40% respond only partially and 20% to 30% (of the responders) relapse within two years (Kane, 1987, 1996).
Used in the conventionally recommended doses - which are usually higher than the pharmacologically required doses - typical antipsychotics can induce parkinsonism and other extrapyramidal signs in as much as 75% of the patients. Some of these drug-induced, iatrogenic manifestations, e.g., avolition, abulia, are virtually indistinguishable from schizophrenic psychopathology. Since atypical antipsychotics induce these iatrogenic manifestation to a considerably lesser extent, patients treated with atypical antipsychotics fare better than patients treated with typical neuroleptics in so far as negative symptoms and cognition are concerned (Kane and Meyerhoff, 1989; Leucht et al., 1999; Scherer et al., 1999).
The information collected in multicenter clinical investigations has not provided orientation points for resolving the heterogeneity of pharmacological responsiveness within schizophrenia. Attempts to identify the treatment-responsive forms of illness by linear regression equations, biological markers, pharmacological load tests, biochemical measures, neurophysiological indicators or brain images yielded in consistent findings (Ban, 1987). None of these means permitted prediction which schizophrenic patient would respond to treatment and which schizophrenic patient would remain refractory.
While focusing on objective measures, virtually no attention was paid to Astrup’s (1959) early report that patients with unsystematic schizophrenia within Leonhard’s (1957) classification of endogenous psychoses, responded more favorably to antipsychotic phenothiazines than patients with systematic schizophrenia. Astrup’s (1959) findings were confirmed and further substantiated in a study with a total of 474 patients conducted by Fish (1964), in which about four of five patients with unsystematic schizophrenia, and about one of five patients with systematic schizophrenia showed a marked to moderate favorable response to treatment. Responsiveness to phenothiazines in the systematic schizophrenias was consistently low, ranging from 0.9% in systematic catatonia, (schizophrenia, catatonic type in the DSM-IV), through 23% in systematic hebephrenia, (schizophrenia, disorganized type in the DSM-IV), to 40.3% in systematic paraphrenia (schizophrenia, paranoid type in the DSM-IV).
Yet responsiveness in the unsystematic schizophrenias was consistently high, ranging from 60% in periodic catatonia, through 78.5% in cataphasia, to 84.4% in affect-laden paraphrenia (in part schizophrenia, paranoid type, and in part schizoaffective disorder in the DSM-IV) (American Psychiatric Association, 1994). Affect-laden paraphrenia was identified as the most responsive form of illness to antipsychotic phenothiazines within the schizophrenias, with more than four of five patients showing a markedly to moderately favorable response to treatment.
The findings that in the systematic hebephrenias and systematic catatonias, antipsychotic phenothiazines are only marginally effective, if effective at all, are complemented by findings in the 1980s which indicate that in the population in which antipsychotic phenothiazines are ineffective, they can be harmful (Ban, 1990). A study of chronic hospitalized schizophrenic patients revealed that in the treatment responsive unsystematic schizophrenic population, tardive dyskinesia was present only in 4.5% of the patients, whereas in some of the unresponsive forms of systematic schizophrenia, such has manneristic catatonia and shallow hebephrenia, tardive dyskinesia was present from 28% to 53% of the patients (Guy et al., 1985, 1986).