In this issue, the last of the schizophrenia series, Drs Robert Bilder and Carol Tamminga address 2 important new topics: understanding neurocognition (1) and specifying the action of drugs (2).

Dr Bilder, chief of clinical neuropsychology at Hillside Hospital in Glen Oaks, New York, sets himself the difficult task of speculating about how the individual cognitive impairments associated with schizophrenia might be addressed by specifically tailored therapeutic agents. Despite earlier promise, symptom clusters or specific syndromes within the schizophrenia rubric have not proven especially helpful in identifying which neuroleptic to use for which patient at what time and at what dose. The pattern of individual cognitive impairments, reflective at least in theory of actual neural circuitry defects, may prove to be a better guide to specific treatments. The pattern of these defects in thinking may help determine pharmacological directions, and they may also, in the future, open new doors to cognitive habilitation strategies, which as yet are in embryonic development.

Although up to 80% of schizophrenia patients “respond favourably” to initial treatment, it is essentially the psychotic symptoms that recede; suffering and functional impairment too often continue. The neuropsychological deficits in schizophrenia remain pervasive and relatively severe across a broad array of cognitive domains. Although such questions are far from settled, it appears that schizophrenia carries the risk of diffuse, generalized impairments in brain functioning rather than localized deficits. The possibility exists, however, that additional, more functionally specific deficits characterize certain subgroups of patients. Should such pathologic heterogeneity be possible to delineate, different treatments, both pharmacological and psychological, could theoretically be devised, each one targeted toward individual impairments. Dr Bilder illustrates such future possibilities, based on current theoretical constructs and on the classes of drugs currently available.

The review also describes how neurocognitive parameters can be usefully considered both as outcome predictors and as measures of outcome. Additionally, they can be viewed as process variables that modify outcome. Not generally known is that neuropsychological test results early in the course of illness can, to some extent, predict long-term rehabilitation potential, service utilization, and vocational success. Though not perfect predictors, they are better for this purpose than initial symptoms, which bear no relation to long-term outcome. Perhaps paradoxically, acute treatment response is more difficult to predict by means of neurocognitive testing than longer-term outcome.

This review also clarifies the effects of medications on cognition and, with the newer generation of antipsychotic drugs, introduces the hope for cognitive repair. Dr Bilder outlines promising areas of research in this area, including the potential inherent in new technologies.

Dr Tamminga, chief of inpatient services at the Maryland Psychiatric Research Center, provides a masterful, in-depth review of the new generation of antipsychotic drugs. She addresses the challenge of identifying a proxy measure of antipsychotic action in humans. This is important for the development of effective new drugs and also for treatment monitoring and treatment decision making when individuals with schizophrenia fail to respond fully or relapse despite treatment.

One such measure is striatal dopamine (D₂) receptor occupancy visualized by positron emission tomography (PET). The striatum is, at present, the locus of measurement because that is where the strongest binding signals take place. With the development of new, higher-affinity radioactive dopamine receptor ligands, it may be possible to measure occupancy in other brain regions that are perhaps more relevant to treatment response. Another measure of response is functional brain activity secondary to receptor occupancy, for instance, differential regional glucose utilization in various brain circuits following drug administration. PET measurements are an important research tool but are not likely (as explained by Dr Bilder) to ever become clinically relevant.

Dr Tamminga discusses current strategies of new antipsychotic drug discovery and concentrates on todays paradigm finding clozapine-like drugs which encompass the benefits of clozapine (high efficacy for both positive and negative symptoms, efficacy in those who have failed to respond to previous drug treatments, that is, “chronic” patients; absence of extrapyramidal side effects; and reversal of existing extrapyramidal side effects) and which will not introduce their own intolerable, unwanted effects. She traces the development of clozapine, risperidone, olanzapine, sertindole, quetiapine, and ziprasidone, offering hope to those who suffer from schizophrenia and to research scientists who will find out more about the basis of disease and disease response through the study of individual drug action.

Dr Tamminga suggests that the search for effective new drugs needs to be expanded beyond the manufacture of clozapine look-alikes to the design of agents arising from speculative hypotheses about schizophrenia etiology and to the experimental application of agents perhaps in current use for other diseases which, through serendipitous clinical observation, will be shown to be effective antidotes to one or several of the many schizophrenia deficits.

These 2 excellent papers conclude the schizophrenia scholarly reviews for 1997. Because of the rapid pace of change in the understanding and treatment of schizophrenia, more updates will be certain to appear in the Journal before long.

References

Mary V Seeman, MDCM
Editor, Schizophrenia Series