ARTICLE

Schizophrenia is one of the most devastating human diseases. It afflicts about 1 in 100 people in the United States, generally becoming manifest in late adolescence or early adulthood and persisting thereafter (1). Because it begins so early and tends to interfere with education, employment, and marriage, schizophrenia is a great burden not only to those who suffer from it, but also to their families and to society; thus, the number of people who are seriously affected by this disease and the economic and personal cost to society are enormous.

Current treatments-which combine long-term medications with supportive care-usually alleviate the more florid symptoms of schizophrenia, such as paranoid delusions and hallucinations. However, most affected individuals have substantial lifelong impairment; indeed, more than one-half require continuous support whether living in the community or in long-term institutions. The chronic suffering of people with schizophrenia is highlighted by the fact that 10-15% of them ultimately commit suicide (2) and that many suffer homelessness. One-third of the nation's mental hospital beds are occupied by individuals with schizophrenia. The annual direct cost of their care was estimated to be $19 billion in 1991, with an additional indirect cost of $46 billion due to lost productivity (3).

Despite extensive study for many years and many initially promising, but ultimately disappointing hypotheses, we do not have a clear understanding of either the causes of schizophrenia or how the causative factors lead to the clinical features. But the striking recent advancement in our understanding of cellular, molecular, and integrative neuroscience, combined with the clear recognition that schizophrenia is a well-defined disease with documented changes in brain structure and function, present real opportunities for research into its causes and treatment. To that end, the National Academy of Sciences and the Institute of Medicine brought together experts in schizophrenia and specialists in other areas of the biological sciences in a workshop aimed at promoting the application of the latest biological information, technology, and experience to this clinical problem.

The workshop, held on November 29-30, 1995, paid particular attention to signs of pathology in the brains of people with schizophrenia, and to the possibility that this reflects an abnormality in brain development (4, 5) that eventually leads to the appearance of symptoms. The nonexperts in schizophrenia research at the meeting were senior and young scientists in a wide variety of fields, including cellular biology, biochemistry, receptor molecular biology, the neurobiology of model systems, neuropharmacology, control of cell growth and death, human genetics, and cognitive neuroscience. Most of these individuals had little prior knowledge of either the nature of schizophrenia or of the hypotheses regarding its causes. In addition to educating both experts and nonexperts about the disorder, the discussions were designed to identify some promising areas for interdisciplinary research in schizophrenia.

There was general consensus among the experts on the following points.

(i) Twin, family, and adoption studies suggest genetic factors are of substantial etiologic importance in schizophrenia (6, 7). Their role is complicated because single gene models do not fit current family transmission data. A reasonable interpretation of these data is that several genes (or, more precisely, variants of genes, i.e., alleles) act together. To date, none of the multiple genes that might contribute to schizophrenia has been identified, although scientists are presently focusing on regions of chromosomes 3, 6, 8, 9, 20, and 22.

(ii) Genes do not act alone to cause schizophrenia (6, 7). Environmental factors are also important (8), although their nature is not established. Environmental factors that have been proposed include obstetric complications, intrauterine abnormalities, and viruses. Although family and social factors causing stress may affect the course of the disease, there is no convincing evidence that they play a major causative role.

(iii) The brains of people with schizophrenia differ anatomically from the brains of normal people, and the differences can often be demonstrated by brain-imaging techniques (4) and by examination of postmortem brain specimens (4, 9-12). Although no anatomical change is shared by all affected individuals diagnosed with schizophrenia, there is a growing consensus from postmortem studies and from functional imaging of affected individuals that there is both a volume loss and cellular pathology in areas of the cerebral cortex. But there is overlap between normal and affected individuals, and there is no consensus about which, if any, of these differences are either characteristic of or essential for the development of schizophrenia.

(iv) The neuroanatomical findings, in many cases, are compatible with the presence of an abnormality in brain development (4, 5), possibly in fetal life. They are different from the anatomical changes seen in degenerative brain diseases, whether of genetic, infectious, or traumatic origin.

In brief, schizophrenia can be conceptualized as a complex biological disorder in which genes play a role (but not an exclusive one) and in which brain development is likely to be abnormal.

The nonexpert participants were stimulated and intrigued by their exposure to the details of this disease. For them, the following observations were especially useful for thinking about future research directions.

(i) Although psychological stress was once thought by some clinicians to cause schizophrenia, the consensus is that it is instead a disorder of brain function that is due to complex factorswith developmental processes, including the onset of puberty, thought of as possible triggers for the full display of the symptoms of the disease. In prospective studies, many affected people have been found to be somewhat developmentally delayed in childhood (13, 14), which is consistent with the subtle but detectable abnormalities in brain anatomy of people with schizophrenia, including those examined prior to treatment with antipsychotic medications. Twin studies provide evidence of a genetic contribution: if one identical twin gets the disease, the other has approximately a 30-40% chance of getting it (with a mean delay of 4 years), even if the two have been brought up in different families (15, 16). Nevertheless, the shared genes of identical twins are not sufficient to give rise to the disease in all instances, pointing to the participation of other factors.

(ii) People with schizophrenia may display a variety of patterns of aberrant behavior, raising the possibility that each pattern reflects a different form of the disorder due to a different cause. But even identical twins who both have schizophrenia, and who are presumed to have been afflicted because of shared causative factors, often have different patterns of symptoms. Therefore, the variability in symptoms does not appear to be a basis for distinguishing between schizophrenia due to different causes.

(iii) The unusual time course of appearance and development of the symptoms of schizophrenia is an important characteristic that should guide research strategies. The fact that most cases arise in early adulthood is an important clue with respect to pathophysiology, because developmental changes may continue to occur in the brain during this period. The onset of the illness, with subsequent progression of symptoms during the first few years and later stabilization for the remaining years, makes schizophrenia very unusual among brain disorders. Evidence that schizophrenia is not a degenerative brain disease is the absence of gliosis, the proliferation of nonneuronal brain cells that accompanies central nervous system injury.

(iv) Brain imaging studies suggest that people with schizophrenia have abnormalities in the prefrontal, temporal, and anterior cingulate regions known to be involved in cognition and affective integration, as well as in midline regions of the brain. Moreover, memory problems resembling those produced by lesions of the frontal lobe in monkeys and humans are evident in schizophrenia (17) and may account for the cardinal symptoms of disorganization in thinking, planning, and expressing thoughts.

The Workshop

There was a consensus among experts and nonexperts that understanding schizophrenia would ultimately require a much deeper understanding of many aspects of brain structure and function. Because schizophrenia is widely believed to result from abnormalities in brain development, interest was expressed in the study of genes that control brain development. These include homeobox genes that control the formation of specific brain regions and genes that encode proteins that control the processes of cell adhesion and cell migration responsible for the precise cellular connections in the brain.

The participants expressed great interest in extending basic physiological and anatomical studies of neuronal circuits in the temporal and frontal lobes and midline regions that control aspects of cognition and emotion, because these regions and functions appear to be affected in schizophrenia. If more were learned about the details of such neuronal circuits, mechanisms of specific functional defects in schizophrenia should be easier to unravel. Study of these circuits at the anatomical level would be greatly facilitated by detailed mapping of key proteins involved in neurotransmission in the human brain. Several participants expressed interest in a national program to develop a library of sections of regions of human brain suitable for histochemical examination that could be made available to all qualified investigators. The ability to image brain function in living individuals should also be very informative, especially as the resolution of this technology increases. It would be particularly useful to understand the changes that occur as the disease develops, e.g., in initially unaffected twins who later develop schizophrenia or individuals presenting symptoms early in the course of their disorder.

A major focus of the workshop was on evidence of microscopic pathology in postmortem specimens of the brains of people with schizophrenia. Most participants were convinced by the evidence that is suggestive of a defect in interneuronal connectivity in the frontal and temporal cortical and related subcortical regions of the brains of individuals with schizophrenia. Although it is not certain whether the defect is primary or secondary to the disease, the evidence of cortical volume loss in first-episode patients indicates that it may play a causative role. There was a consensus that the disease does not reflect a classical neurodegenerative condition, in that it is not accompanied by the changes in glial cells that are typically found with neurodegeneration. The evidence of a defect in connectivity may be a reflection of either an abnormality in brain development or of the later onset of atrophic changes in the frontal and temporal cortex. The histological data that can be interpreted as indicating abnormal migration of cortical cells to their normal destinations is consistent with a failure of normally programmed death of these cells during brain development, but is seen in only a fraction of the cases. Immunohistochemical and in situ hybridization techniques are providing more specific evidence of neuroanatomical abnormalities, but this work is still in its early stages.

Accurate assessment of the microscopic pathology of the brains of people with schizophrenia depends on the availability of properly preserved specimens from well-characterized affected individuals. There is a national program to collect such specimens, but several participants expressed dissatisfaction with either the quality of some of the material or its availability. Some participants expend a great deal of effort in collecting specimens on their own. The national program would be greatly facilitated by cooperative collection, better characterization, preservation, and distribution of brain tissue. All agreed that a reference collection of material would be particularly valuable, making possible direct correlations of observations on tissue from the same cases by different investigators.

Despite the great importance of medications in the treatment of schizophrenia, the workshop steered away from issues of drug development because they are already under intensive investigation by the pharmaceutical industry and at academic centers. Nevertheless, strong support was expressed for refinement of available drugs to minimize side effects while retaining therapeutic effects. To achieve this goal it may be necessary to find drugs with much greater specificity for particular neurotransmitter receptors. Because there is a suspicion that the therapeutic efficacy of currently used drugs is based on their interactions with more than one receptor, appropriate combinations of several specific drugs might best target the relevant receptors without the side effects caused by additional interactions.

There was also strong support for continuing basic research on the molecular and physiological basis of neurotransmission. Even though drugs targeted to dopamine receptors and to the mesolimbic and mesocortical dopaminergic pathways have proven to be highly effective in alleviating many symptoms of schizophrenia, drugs directed to other targets may also produce some symptomatic relief. Therefore, additional work on other neurotransmitters and receptors should help in the development of new classes of drugs.

Another promising subject for detailed study is the unaffected identical twin of a co-twin newly diagnosed with schizophrenia, who often will subsequently develop the disease, with a mean delay of 4 years. A research project focused on a close observation of large numbers of as-yet-unaffected twins during this period of vulnerability could detail the progression of the disease, and test possible preventive therapies. As one example, repeated imaging of the brains of both twins could reveal whether the brains of those twins that develop the disease show reproducible changes as their status changes from normal to schizophrenic.

Because of the availability of genetic maps with a high density of markers and the development of new statistical approaches that facilitate the identification of multiple genetic loci responsible for human diseases, the rate-limiting factor in finding the alleles that predispose to schizophrenia is the availability of families with sufficient numbers of rigorously diagnosed cases. Some participants expressed concern that even the existing cooperative programs established by the National Institute for Mental Health might not provide adequate material, since very large samples may be needed to find relevant genes for a disorder that probably involves interaction of a number of genes, and that also may be genetically heterogeneous. For this reason it may be necessary to collect thousands of DNA samples from groups of relatives with schizophrenia, including pairs of siblings who are both affected, to provide sufficient material for genetic studies.

Despite the consensus that genes are important in schizophrenia, there was strong interest in also encouraging other avenues of investigation. Even when relevant genes are found, interpretation of their actions could be difficult because of our limited understanding of fundamental aspects of brain functional organization and development.

Conclusions

This workshop was designed to facilitate the application of biological sciences to a very challenging and complicated medical problem of immense personal and social significance. The conclusion of all the participants was that many aspects of the problem could, in fact, be approached by applying the explosive growth of knowledge and techniques derived from fundamental research in neuroscience and molecular biology. In fact, one main goal of the workshop was to help stimulate the interest of a new generation of basic and clinical scientists in schizophrenia. For even though there has been an impressive growth of knowledge about this devastating disorder, there was general agreement that we are still far from understanding its cause and pathogenesis.

There was also a consensus that multiple approaches would be required to understand this disease. Clearly, a major focus should be on the search for predisposing genes. But even though all agreed that the availability of (and continuing improvements in) the necessary technology make this a very valuable approach, there was lively disagreement on the degree of emphasis that it warranted relative to other approaches. The advocates of the genetic approach felt that it should be central because identification of the relevant genes would open up so many other avenues of research by providing aids to diagnosis, clues to new treatments, and reagents (such as nucleic acid probes and monoclonal antibodies) for more-detailed studies of the microscopic pathology of schizophrenia. Others felt that this approach should not draw resources away from work in other areas. And even the strongest advocates of genetic studies of schizophrenia agreed that parallel research in basic neurobiology, neurophysiology, microscopic neuroanatomy of the brain, and integrative neuroscience, as well as a continued search for environmental factors, will be essential for understanding the actions of the relevant genes and for devising new treatments.