CLINICAL HANDBOOK OF SCHIZOPHRENIA

5. Neuropathology 53results, especially given the subtleties of the findings in schizophrenia. Third, differentgroups of investigators apply different methodologies to the analysis of data, even whenusing similar investigatory techniques and looking at presumably identical brain regions.This particular problem is to a certain extent due to the progress of knowledge in thefield. The increasing specificity of investigation is partly the product of ongoing confirmationof more generalized findings, and partly the consequence of advances in investigationaltechnology. In any event, the result is that comparing results or performing metaanalysesover time become problematic, because these variations make datasets uniqueand difficult to pool. Finally, small sample sizes remain problematic in schizophrenia research,increasing the likelihood of both false-positive and false-negative results.FUTURE DIRECTIONSWe began this chapter by stating that schizophrenia is likely an endophenotype. After thiscursory review of the neuropathology of schizophrenia, one can readily see the disparateand piecemeal nature of the evidence at hand. Subtle findings are the rule rather than theexception, and although conflicting results may represent technological differences, theymay also reveal different processes that lead to the same gross symptom picture in peoplewith schizophrenia. Research in this devastating disease is fraught with difficulty, fromthe vast variation in the nature of the clinical presentation to the current impossibility ofdividing schizophrenia into more homogenous subgroupings that further delineate differentbrain processes that may have gone awry in a particular patient. Treatment developmentremains hampered by this limitation as well, because etiology-driven treatments remainon the horizon so long as the nature of the disease remains elusive. As technologyadvances in brain imaging, as well as in microscopic analysis, so will our understandingof how to partition schizophrenia in ways that propel our understanding forward, ultimatelyleading to advances in treatment and perhaps even prevention.KEY POINTS• Schizophrenia is likely an endophenotype, in which differences in disease presentation andcourse may reflect distinct but potentially interrelated neuropathological deficits.• There are undoubtedly genetic and environmental contributions to the etiology of schizophrenia.The neurodevelopmental model of schizophrenia should be given substantialweight, and it should be noted that insults that occur early in life may not have consequencesuntil young adulthood.• The neuropathological findings in schizophrenia are subtle, and as technology progresses,we may find that many of the conflicts surrounding current findings are resolved more definitively.• Increased ventricle size, reductions in temporal lobe and frontal lobe structures, along withthalamic abnormalities, reflect some of the most robust findings in schizophrenia researchat this time.• White matter has a place in the study of schizophrenia. Alterations in connectivity that mayresult from alterations in myelin and oligodendrocytes seem to be worthy of serious considerationby the field.• At least portions of the neuroanatomical findings in schizophrenia research appear to beprogressive.• Both white matter and gray matter aberrations may make separate but intimately reciprocalcontributions to the schizophrenia syndrome.