brain development across the lifespan), then little doubt exists that schizophrenia is at least partly neurodevelopmental. GLOBAL BRAIN FINDINGS Decreased Brain Volume Early research into brain volumes in schizophrenia, at least partially driven by theories that brain volume was related to mental illness, cognitive deficits, and low socioeconomic status, reach as far back as the early 1800s. Using postmortem tissue, the brains of pa- tients with schizophrenia have been found to be reduced in length, volume, and weight. In imaging studies, schizophrenia has been found to be associated with reduced global brain volumes; however, the majority of studies have not found significant differences be- tween patients with schizophrenia and controls. There are several explanations for these discrepant findings, and it is likely that each plays a part in this inconsistency. First, global brain volume is a somewhat imprecise and gross measure in and of itself. Second, controlling for brain size differences related to variations in head size rather than to schizophrenia is difficult to do. Third, sample sizes in schizophrenia studies are typically small, and the volume changes themselves are likely to be small, thus increasing the likeli- hood that subtle brain volume differences will be missed. Fourth, many of these studies did not separate patients by differences in symptom severity, age, or disease course, and it is possible, if not likely, that patients whose disease has a particularly severe progression would have more profound brain changes than those who have a relatively good outcome. When these heterogeneous groups are examined together, those with good outcome— who might have less brain pathology—may wash out the findings that would be seen if patients with poor outcome were examined separately. Last, and perhaps most impor - tant, schizophrenia may be better characterized as a disorder with regional aberrations. It is important to note that few diseases that have a profound effect on global brain volume are not only consistent with life but also allow those afflicted to function in society. Even though the schizophrenia symptom picture is devastating and debilitating, one must keep in mind that these changes are subtle in the grand scheme of self-maintenance and self- preservation; consequently, they might be better explained by regional neuropathology or dysconnectivity (both discussed below). All this having been said, meta-analyses have demonstrated small but significant reductions in total brain volume in schizophrenia. Ventricular Enlargement There is enlargement of the ventricles in schizophrenia. Data come from both imaging and postmortem investigations. Areas typically noted to be enlarged in patients with 46 I. CORE SCIENCE AND BACKGROUND INFORMATION TABLE 5.2. Limitations on Neuropathological Investigation Limitation Affects postmortem studies Affects imaging studies Postmortem index + – Variations in sample selection or delineation of region of interest ++ Differing methodologies for analysis + + Small sample sizes + + schizophrenia include the lateral ventricles as a whole, the temporal horn portion of the lateral ventricular system (particularly on the left), and the third ventricle (which is of particular importance given its proximity to the thalamus, discussed below). Rather than use an absolute measurement, ventricular size is often measured by ventricule–brain ratio (VBR), which adjusts for differences in subjects’ overall brain volumes. Schizophrenia has been associated with a wide range of increases in VBR, from 20 to 75%, with a recent re - view citing a median enlargement of 40%. Although estimates of the size of this increase remain somewhat variable, the enlargement of the ventricles in schizophrenia is a ubiqui - tous finding. There is a significant amount of overlap in VBR between subjects with schizophrenia and controls, so it is worth noting that VBR has no diagnostic or predictive ability. Although overall brain volumes have often been found to be reduced in schizo - phrenia as described earlier, this decrease has not been shown to correlate with the degree of VBR increase. Not only is the increase in VBR a common finding, but twin studies also lend support to the idea that this may be partially a predisposing factor and partially a disease-specific finding. On the one hand, in monozygotic twins discordant for schizophrenia, the ventri - cles of the affected twin are larger than those of the unaffected sibling, along with reduc - tions in cortical and hippocampal size. These findings suggest that increased VBR is part of a schizophrenia phenotype; in other words, this increase accompanies the presentation of the disease and does not merely reflect an underlying genetic vulnerability. On the other hand, family studies that examine patients with schizophrenia and their unaffected siblings demonstrate that unaffected siblings have smaller ventricles than their siblings with schizophrenia but larger ventricles than healthy controls who are not part of the family. This suggests, instead, that at least some aspect of ventricular size in schizophre- nia may be under genetic influence. CORTICAL FINDINGS Prefrontal Cortex The prefrontal cortex is a region of interest in schizophrenia, because it is believed to modulate many cognitive and behavioral tasks at which patients with schizophrenia are deficient. Postmortem studies have shown prefrontal abnormalities, and although imag - ing studies have not been as conclusive, the majority of such studies do find deficits in this region. Likely, the reason for the negative findings includes the fact that the frontal lobe has often been measured as a whole, and small regional abnormalities in these cases might be missed. Importantly, when white matter and gray matter are examined differen - tially, studies have shown that each is reduced. Furthermore, when the frontal cortex is subdivided, differences do appear in dorsolateral regions, as well as in orbitofrontal (in females) and dorsomedial (in males) regions. Investigations into subdivisions of the fron - tal lobe have also revealed correlations with performance tests of verbal recall, visual memory, semantic fluency, and negative symptoms, consistent with theories of schizo - phrenia’s cognitive deficits residing in aberrations of frontal lobe structures. Increased neuronal packing density has been reported over the entire frontal lobe, particularly in the dorsolateral prefrontal cortex (DLPFC). Although negative findings have been reported on this measure in these regions, the importance of the DLPFC in schizophrenia is largely accepted, because many of the symptom- and cognition-related findings have been associated with alterations in DLPFC functioning. Of note, the abso - lute number of neurons in the DLPFC has not been found to be altered in patients with schizophrenia. 5. Neuropathology 47 The DLPFC has been shown to demonstrate a decrease in synaptophysin, a marker of postsynaptic density, and this finding is supplemented by a lower density of dendritic spines in this area in patients with schizophrenia. This may represent an excess of synap - tic pruning in this area, but it may also reflect the loss of dendrites, with resultant in - creases in synaptic density due to some other aberrant process that divests these neurons of trophic or sustaining factors. Magnetic resonance spectroscopic (MRS) investigations have demonstrated a reduction in N-acetylaspartate (NAA), a marker of neuronal integ - rity, in the DLPFC, which is present at first break and is consistent with a reduction in synaptic and dendritic density. Furthermore, several studies have demonstrated a state of relative hypofunctioning in the frontal cortex in patients with schizophrenia, consistent with the notion that there is both functional and structural aberration in this region. Temporal Lobe Like all investigations into brain pathology in schizophrenia, investigations into the tem - poral lobe have produced conflicting results. Although the majority of studies demon - strate reductions in total temporal lobe volume, almost 40% report negative findings. However, like so much of schizophrenia research, these conflicting findings are likely due in part to methodological differences that impact the accuracy of measurement, differ - ences in the definition of boundaries of the temporal lobe, and sample size limitations. As more studies have used more rigorous methods and better instruments, the number of positive studies in this area has been increasing. One might question whether the entire temporal lobe is a sufficiently specific region of interest to capture differences between patients with schizophrenia and controls. Subdividing the temporal lobe has revealed al- terations in three structures within the temporal lobe in schizophrenia: the medial tempo- ral lobe, the superior temporal gyrus, and the planum temporale. The medial temporal lobe includes the amygdala (responsible for emotional valence) and the parahippocampal gyrus (involved in aspects of memory), and has been found to be reduced in volume in the vast majority of imaging studies in schizophrenia, consistent with postmortem findings in this region and with the common finding of increased vol- ume of the temporal horn of the lateral ventricles, which surrounds the medial temporal lobe. Volume reductions in both substructures—amygdala–hippocampal complex and parahippocampal gyrus—are evident in chronic patients, but volume reductions in the amygdala–hippocampal complex are also present in first-episode patients. However, amygdala–hippocampal complex reductions are also present in mood disorders, some anxiety disorders, and as a function of aging, thus lacking specificity as an aspect of schizophrenia. And although the meaning of any lateralized differences remains un - known, it is common to find a left-greater-than-right separation between patients with schizophrenia and control subjects. Investigations into the hippocampus specifically, though, have yielded some intriguing results. In healthy subjects, there is an anatomical asymmetry in the hippocampus, with the right hippocampus being somewhat larger. Functionally, the hippocampus is involved in memory: The right hippocampus is preferentially involved in spatial memory, whereas the left is concerned with verbal memory. Reductions in hippocampal size and alterations in hippocampal shape have both been demonstrated in patients with schizophrenia. Volume reductions in the hippocampus have generally been found to be greater on the left, which coincides with parahippocampal reductions being greater on the left, as well as volume increases in the left temporal horn of the lateral ventricle. The cross-sectional area of py - ramidal neuron cell bodies has also been found to be reduced in patients with schizophre - nia. Again, negative reports have been published as well. Hippocampal neuronal shape 48 I. CORE SCIENCE AND BACKGROUND INFORMATION has been reported to be altered; pyramidal neurons of patients with schizophrenia are longer and thinner compared to those of controls. Conversely, the total number of hippocampal neurons appears to be unchanged in patients with schizophrenia. Smaller hippocampal volumes are present at first break, and twin studies suggest that this may be a genetic predisposition. These alterations may in fact represent an aberrant developmen - tal process that occurs in early life; however, delineating whether these changes reflect a primarily genetic or environmental pattern is still a task for the future. Neuronal packing density findings are inconsistent. Some findings show an increased packing density, others show a decreased packing density, and still others show no change in packing density. In contrast, there is some evidence that dendritic spines are decreased in density, with less apical arborization. Further support for these dendritic findings co - mes from spinophilin, a spine marker gene, which is also decreased in the hippocampus in patients with schizophrenia. These findings are consistent with and supported by the finding of decreased NAA—a biochemical marker of neuronal integrity—in the hippo - campus of patients with schizophrenia, which incidentally is present at first break and across all stages of the disease. Functional imaging shows metabolic activation patterns that are altered in relation to symptoms. Ionotropic glutamate receptors appear to be al - tered as well, along with gamma-aminobutyric acid (GABA), nicotinic, and serotonin re - ceptors, although the bulk of evidence exists for glutamatergic alteration. The expression of synaptic proteins (particularly synaptophysin, SNAP-25, and synapsin) has consistently been reported as decreased in patients with schizophrenia, sug- gesting that synapses in the hippocampus are themselves involved in the disorder, al- though whether these changes are casual or resultant remains elusive. Two other synaptic proteins, complexin I and II, are altered in expression in the hippocampus in patients with schizophrenia and are involved in inhibitory and excitatory processes, respectively. Although both are altered in expression, there is some evidence that complexin II is more affected, suggesting that excitatory pathways may be more affected. Further supporting the idea of excitatory neuron involvement, glutamatergic neurons appear to be affected as well in this region, as evidenced by a decrease in expression of the vesicular glutamate transporter (VGLUT1). Be that as it may, GABA neurons, which are inhibitory, are ap- parently involved in this region as well. And changes in these glutamatergic and GABA- ergic markers over the course of the disease lend support to the idea that schizophrenia is a progressive disease. The superior temporal gyrus (STG) contains primary auditory cortex within Heschl’s gyrus. On the left, the STG contains Wernicke’s area, which includes the planum temporale (PT). Investigations into the STG are some of the strongest findings in schizo - phrenia research, with volume reductions noted in upwards of 65% of studies. Interest - ingly, STG abnormalities have also been demonstrated in patients with schizophrenia spectrum disorders. Studies that compare schizophrenia and bipolar disorder are equivo - cal, with two studies showing decreased STG in patients with schizophrenia but not those with bipolar disorder, and one study showing the opposite. As discussed below, findings in the STG are associated with schizophrenia symptoms. The PT is within the boundary of the STG, but because of its role in language and speech processing has been a separate focus of investigation in schizophrenia. The usual left-greater-than-right PT asymmetry seen in control subjects is reduced and sometimes reversed in patients with schizophrenia, and because this asymmetry has been demonstrated in healthy subjects as early as the end of the second trimester of gestation, this loss of asymmetry has been hypothesized to re - flect abnormal lateralization in neurodevelopment. Although this chapter is not concerned with psychopathology per se, it is worth mentioning that some of the most robust associations between brain structure and schizo - 5. Neuropathology 49 phrenia symptoms have been with temporal lobe structures. Symptom severity has been associated with reductions in bilateral temporal lobe volume, along with decreased hippocampal and left STG volumes. The left anterior and left posterior STG have been strongly associated with the severity of both auditory hallucinations and thought disor - der. Schneiderian symptom severity has been associated with volumes of the right poste - rior cingulate gray matter and left anterior parahippocampal gyrus. Positive symptoms are not the only ones related to temporal lobe findings. Negative symptoms have been correlated with decreases in left medial temporal lobe volumes (as well as prefrontal white matter volume). Investigations specifically directed at white matter in patients with schizophrenia (discussed below) have noted an association between the organization and coherence of white matter tracts in temporal lobe regions and impulsivity. Recently, the integrity of white matter tracts in the medial temporal lobe has been determined to relate to the severity of positive, negative, and general psychopathology symptom domains. Parietal Lobe Relatively few investigations have been directed at the parietal lobe in patients with schizophrenia, and most of those that have do not subdivide the parietal lobe into subre - gions. Nonetheless, the majority of studies directed at parietal lobe structures have shown some volume reductions. More recently, subdivisions of the parietal lobe on imaging studies have revealed reductions in the inferior parietal lobe and supramarginal gyrus. Perhaps most strikingly, correlations have been demonstrated between the inferior pari- etal lobe, prefrontal cortex, and temporal cortex, supporting the idea that connected brain structures, and perhaps even the connecting tracts themselves, may be critical to our understanding of schizophrenia. Cerebellum Although the cerebellum historically was relegated to the role of coordinating movement, recent evidence has suggested that it may play a role in higher cognitive functions. The cerebellum is highly connected to cortical association areas and limbic regions, and the notion has been put forth that the cerebellum may be associated with schizophrenia. Un - fortunately, there have only been a handful of studies, and these studies have not yet con - sistently borne out any reliable findings. It should be noted, however, that these studies have varied widely in methodology, and little attempt has been made to subdivide the cer - ebellum into functionally discrete regions. SUBCORTICAL FINDINGS Thalamus The thalamus is a relay station modulating input from cortical, limbic, and reticular acti - vation areas, and it modulates sensory input and is involved in attention. The thalamus is also intimately connected to the prefrontal cortex, including the orbitofrontal and DLPFC with reciprocal connections. The size of the thalamus has been demonstrated to be smaller in patients with schizo - phrenia. Subdivision of the thalamus in cytoarchitectural investigations seems particu - larly appropriate given that the thalamus receives input and sends output to a variety of cortical structures, each with potentially independent functions. The dorsomedial nu - cleus, which sends projections to the prefrontal cortex, has been shown to have a signifi - cantly decreased number of axons. The coherence of this thalamocortical pathway has 50 I. CORE SCIENCE AND BACKGROUND INFORMATION also been demonstrated to be decreased in patients with schizophrenia, as measured by diffusion tensor imaging (DTI), a method by which the organization of white matter tracts can be determined (discussed below). The anteroventral nucleus, which projects largely to the prefrontal cortex, has also been found to have a decrease in the number of axons present. This is not to say that other areas of the thalamus do not have irregulari - ties; rather, the lack of information regarding other thalamic nuclei reflects a paucity of investigation into these areas. Importantly, a reduction in synaptic protein rab3a has also been found in studies utilizing a substantial sample of subjects with schizophrenia. Basal Ganglia An increase in the volume of the basal ganglia has repeatedly been demonstrated in pa - tients with schizophrenia. However, this increase has been determined to be largely a medication effect. Interestingly, it may be that typical neuroleptics are more responsible for this effect, because in one study, switching patients to an atypical neuroleptic for 1 year led to a decrease in caudate nucleus size. In contrast, medication-naive patients with schizophrenia have been shown to have reduced caudate size in several studies, although this finding is, of course, contradicted in a study that noted no significant size difference between basal ganglia volume in treated and never-treated patients. Finally, reduced vol - ume of the basal ganglia has been demonstrated in patients with depression as well, mak- ing the specificity of this finding to schizophrenia somewhat suspect. DYSCONNECTIVITY AND THE POSSIBLE ROLE OF WHITE MATTER IN SCHIZOPHRENIA The theory of dysconnectivity suggests that the inability of different brain regions to com- municate effectively with each other has a causal impact on the symptoms, course, and neuropathology of schizophrenia. Disorganized or poorly insulated neurotransmission may explain at least some of the observable psychophenomena of the disease. Proposed neuroanatomical consequences include the idea that areas that should receive ongoing, function-maintaining trophic signaling fall into disrepair when the tracts that connect these regions are not communicating optimally, and that this might explain some of the regional evidence we presented in earlier sections. In addition, if disconnectivity is part of the neuropathology of schizophrenia, then the components of these connections, particu - larly white matter, should be somehow aberrant in the brains of patients with schizophre - nia. Over the past several years, multiple lines of evidence have converged in support of the idea that, indeed, white matter—specifically oligodendrocytes and myelin—is involved in patients with schizophrenia. Increased cell density has been found in the deep white matter in patients withschizophrenia, along with maldistributionof neurons in whitematter of the prefrontal cortex (PFC), although both of these findings have not been universally demon - strated. Microarraystudies have found decreased expression of myelin-related genes in sev - eral brain regions, and quantification and qualification of oligodendrocytes in postmortem samples have found a deficit of close to 25% in the PFC of patients with schizophrenia, along with alteredspacing and distribution. Otherpostmortem examinations have revealed abnormal changes in both myelin and oligodendrocytes in the PFC and caudate nucleus of patients with schizophrenia.DTI (a special type ofMRI analysis that is wellsuited to the ex - amination of white matter) has found decreased organization and coherence of white mat - ter in widespread brain regions, including the PFC, temporoparietal and parieto-occipital regions, splenium, cingulum, posterior capsule, medial temporal cortex, and frontal white 5. Neuropathology 51 matter underlying the DLPFC and anterior cingulate. This evidence is buttressed by a find - ing of globally reduced fractional anisotropy (FA)—the output measure of the sum of vec - tors in a given brain region—in the brains of patients with schizophrenia. Relationships be - tween symptoms of schizophrenia and decreased FA have been demonstrated as well. For example, decreased FA in the medial temporal lobe has been associated with increasing symptom severity, as has a relationshipbetween decreasing FA in frontal white matterinpa - tients with schizophrenia and the ability to live independently. Other associations between decreased FA in the cingulum bundle and executive function have been recently demon - strated in patients with schizophrenia, whereas decreased FA in the uncinate fasciculus has been associated with deficits in declarative–episodic memory. Interestingly, increased FA has been demonstrated in the arcuate fasciculus in patients with auditory hallucinations. These findings, which continue to accumulate, strongly support the idea of white matter in - volvement and dysconnectivity inschizophrenia,although the exact nature of therolewhite matter plays in the disease is still under investigation. IS SCHIZOPHRENIA PROGRESSIVE? Although debate about whether schizophrenia is a progressive disease still continues, there appears to be increasing evidence that, at least in some populations and in some neuroanatomical measures, schizophrenia is progressive. For example, increase in ven- tricular size has been shown to progress over time as patients with schizophrenia further diverge from controls as time with the disease lengthens, and patients with the largest ventricles have been demonstrated to have both the worst premorbid levels of function- ing, and the worst prognoses and most severe symptoms. Temporal lobe and frontal lobe volume changes have been reported to progress with time as well. Further supporting the idea of schizophrenia as a progressive disease, in childhood-onset schizophrenia (COS), a rare but fairly well-characterized presentation, ventricles are enlarged and temporal vol- umes are decreased. But more importantly, patients with COS have a progression of brain pathology, with severe reductions in frontal and temporal lobes that by age 18 begin to resemble those of adult schizophrenia. Finally, patients with schizophrenia have been demonstrated to have a quickly progressing decline in cognitive function, beginning near age 65, despite years of stable cognitive performance over the course of their disease, highlighting the fact that cross-sectional evidence that argues for the static nature of the disease may require longitudinal confirmation. LIMITATIONS ON NEUROPATHOLOGICAL INVESTIGATIONS IN SCHIZOPHRENIA There are several problems with neuropathological investigations of schizophrenia (sum - marized in Table 5.2 on page 46). First, in postmortem investigations, the postmortem in - dex (PMI) is a profound determinant of tissue integrity and, consequently, of the validity and generalizability of findings. The PMI is essentially a measure of the integrity of brain tissue at the time of fixation, and it includes numerous variables, including the time from death to fixation, the pH of brain tissue at the time of death, the exact nature of death (i.e., suicide vs. “natural causes”), and the presence of agonal events that could alter brain tissue. Second, the variable attention to stereological methods in sampling or sec - tioning brain tissue is comparable to different methods of regional differentiation in im - aging studies. The lack of reliable methods in either instance can lead to inaccurate 52 I. CORE SCIENCE AND BACKGROUND INFORMATION results, especially given the subtleties of the findings in schizophrenia. Third, different groups of investigators apply different methodologies to the analysis of data, even when using 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 the field. The increasing specificity of investigation is partly the product of ongoing confirma - tion of more generalized findings, and partly the consequence of advances in investiga - tional technology. In any event, the result is that comparing results or performing meta- analyses over time become problematic, because these variations make datasets unique and difficult to pool. Finally, small sample sizes remain problematic in schizophrenia re - search, increasing the likelihood of both false-positive and false-negative results. FUTURE DIRECTIONS We began this chapter by stating that schizophrenia is likely an endophenotype. After this cursory review of the neuropathology of schizophrenia, one can readily see the disparate and piecemeal nature of the evidence at hand. Subtle findings are the rule rather than the exception, and although conflicting results may represent technological differences, they may also reveal different processes that lead to the same gross symptom picture in people with schizophrenia. Research in this devastating disease is fraught with difficulty, from the vast variation in the nature of the clinical presentation to the current impossibility of dividing schizophrenia into more homogenous subgroupings that further delineate differ- ent brain processes that may have gone awry in a particular patient. Treatment develop- ment remains hampered by this limitation as well, because etiology-driven treatments re- main on the horizon so long as the nature of the disease remains elusive. As technology advances in brain imaging, as well as in microscopic analysis, so will our understanding of how to partition schizophrenia in ways that propel our understanding forward, ulti- mately leading to advances in treatment and perhaps even prevention. KEY POINTS • Schizophrenia is likely an endophenotype, in which differences in disease presentation and course may reflect distinct but potentially interrelated neuropathological deficits. • There are undoubtedly genetic and environmental contributions to the etiology of schizo - phrenia. The neurodevelopmental model of schizophrenia should be given substantial weight, and it should be noted that insults that occur early in life may not have conse - quences until 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 defini - tively. • Increased ventricle size, reductions in temporal lobe and frontal lobe structures, along with thalamic abnormalities, reflect some of the most robust findings in schizophrenia research at this time. • White matter has a place in the study of schizophrenia. Alterations in connectivity that may result from alterations in myelin and oligodendrocytes seem to be worthy of serious consid - eration by the field. • At least portions of the neuroanatomical findings in schizophrenia research appear to be progressive. • Both white matter and gray matter aberrations may make separate but intimately reciprocal contributions to the schizophrenia syndrome. 5. Neuropathology 53 REFERENCES AND RECOMMENDED READINGS Davis K. L., Stewart D. G., Friedman, J. I., Buchsbaum, M., Harvey, P. D., Hof, P. R., et al. (2003). White, matter changes in schizophrenia: Evidence for myelin-related dysfunction. Archives of General Psychiatry, 60(5), 443–456. du Bois, T. M., Deng, C., & Huang, X. F. (2005). Membrane phospholipid composition, alterations in neurotransmitter systems and schizophrenia. Progress in Neuropsychopharmacology and Bio - logical Psychiatry, 29(6), 878–888. Frith, C. (2005). The neural basisofhallucinationsanddelusions. Comptes Rendus Biologies, 328(2), 169–175. Harrison, P. J. (1999). The neuropathology of schizophrenia: A critical review of the data and their in - terpretation. Brain, 122(4), 593–624. Hemsley, D. R. (2005). The development of a cognitive model of schizophrenia: Placing it in context. Neuroscience and Biobehavioral Reviews, 29(6), 977–988. Konradi, C. (2005). Gene expression microarray studies in polygenic psychiatric disorders: Applica - tions and data analysis. Brain Research Reviews, 50(1), 142–155. Kubicki, M., McCarley, R., Westin C. F., Park, H.J., Maier, S., Kikinis, R., et al. (2005). A review of diffusion tensor imaging studies in schizophrenia. Journal of Psychiatric Research, 41, 15–30. Shenton, M. E., Dickey, C. C., Frumin, M., & McCarley, R. W. (2001). A review of MRI findings in schizophrenia. Schizophrenia Research, 49(1–2), 1–52. Shoval, G., & Weizman, A. (2005). The possible role of neurotrophins in the pathogenesis and ther - apy of schizophrenia. European Neuropsychopharmacology, 15(3), 319–329. van den Buuse, M., Garner, B., Gogos, A., & Kusljic, S. (2005). Importance of animal models in schizophrenia research. Australian and New Zealand Journal of Psychiatry, 39(7), 550–557. 54 I. CORE SCIENCE AND BACKGROUND INFORMATION CHAPTER 6 GENETICS STEPHEN J. GLATT The goal of this text is to provide a concise, hands-on, up-to-date, authoritative book to assist clinicians in planning and delivering treatment for their clients with schizophrenia. As the title suggests, this chapter provides clinicians with an orientation to the subspec- ialty of psychiatry known as psychiatric genetics, and to the types of clinically relevant in- formation that psychiatric genetic research can yield for the early identification of—and intervention in—schizophrenia. Psychiatric genetics is an area of research in which hu- man behavior and mental phenomena are studied in relation to inherited factors, or genes. However, the term psychiatric genetics is actually shorthand for psychiatric genetic epidemiology, which more accurately reflects the discipline’s alignment with the larger field of genetic epidemiology. Genetic epidemiology has been defined as “a science that deals with etiology, distribution, and control of disease in groups of relatives and with in - herited causes of disease in populations” (Morton, 1982, Preface). Genetic epidemiolo - gists examine the distribution of illness within families with the goal of finding genetic and environmental causes of illness. Thus, psychiatric genetic epidemiology, or psychiat - ric genetics, considers both environmental and genetic factors—and their interactions—to be on an equal footing and to have an equal likelihood of influencing a given behavior, un - til data indicate otherwise. These assumptions are then tested empirically, of course, and the relative environmental and genetic contributions to a behavior can be determined. Psychiatric genetic research on a particular disorder such as schizophrenia (or any relevant “phenotype,” including subthreshold psychopathology, biological traits, etc.) tends to follow a series of questions in a logical progression (Table 6.1). This sequence, which has been referred to as “the chain of psychiatric genetic research” (Faraone, Tsuang, & Tsuang, 1999), proceeds as follows: First we ask, “Is the phenotype familial?” or “Does it run in families?” Second, “What is the relative magnitude of genetic and envi - ronmental contributions to the phenotype?” Third, “How is the phenotype transmitted from generation to generation?” Fourth, “If genes mediate this transmission, where are they located?” Fifth, “What specific genes influence risk for the phenotype?” These are difficult questions to answer for any trait, but particularly so for phenotypes as complex as human behavior and psychiatric disorders. Fortunately, a wide variety of methods are available to help psychiatric genetic researchers resolve these issues. Those listed in Table 55 [...]... polymorphisms found in schizophrenia populations may make certain individuals more susceptible to the negative effects of infection and inflammation TNF-a (promoter region A2) and IL-1 complex [IL-1-alpha (-8 89) allele 2, IL-1-beta (-5 11) allele 1, and IL-1RA allele 1] genetic polymorphisms have been associated with schizophrenia outcome These polymorphisms typically lead to both production of proinflammatory... Comparative birth weights of schizophrenics and their siblings Journal of Psychology, 64 (2) , 22 7 23 1 McGlashan, T H., & Hoffman, R E (20 00) Schizophrenia as a disorder of developmentally reduced synaptic connectivity Archives of General Psychiatry, 57, 637–647 Rapoport, J L., Addington, A M., Frangou, S., & Psych, M R (20 05) The neurodevelopmental model of schizophrenia: Update 20 05 Molecular Psychiatry,... Survey of Psychiatric Morbidity British Journal of Psychiatry, 185, 22 0 22 6 Birchwood, M., & Jackson, C (20 01) Schizophrenia Sussex, UK: Psychology Press Broome, M R., Wooley, J B., Tabraham, P., Johns, L C., Bramon, E., Murray, G K., et al (20 05) What causes the onset of psychosis? Schizophrenia Research, 79, 23 –34 Brown, G W., & Birley, J L T (1968) Crises and life changes and the onset of schizophrenia. .. interleukin–5 (IL-5), and interleukin–10 (IL-10), that are mainly involved in the stimulation of B cells and antibody responses The relative increase in Th2 cytokines during pregnancy has been associated with a down-regulation of Th1 cytokines, such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin 2 (IL -2 ) , which are involved in cell-mediated immunity and inflammation... lineage of ascertained target populations, the type and spacing of genotyped markers, and the various phenotypic definitions of schizophrenia applied to subjects To narrow down the search for genetic linkage with schizophrenia, Badner and Gershon (20 02) performed a meta-analysis of all previous genomewide linkage scans The results of this pooled analysis identified loci on chromosomes 8p, 13q, and 22 q as... 35–41 Feinberg, I (19 82) Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence? Journal of Psychiatric Research, 17(4), 319–334 Gilmore, J H., Jarskog, L F., Vadlamudi, S., & Lauder, J M (20 04) Prenatal infection and risk for schizophrenia: IL-1beta, IL-6, and TNFalpha inhibit cortical neuron dendrite development Neuropsychopharmacology, 29 (7), 122 1– 122 9 Lane, E A., & Albee,... the disorder Some of these include the genes coding for the serotonin 6 Genetics 63 2A receptor (HTR2A) and the dopamine D2 (DRD2) and D3 (DRD3) receptors Genes coding for disrupted-in -schizophrenia 1 (DISC1), dystrobrevin-binding protein 1 (DTNBP1), neuregulin 1 (NRG1), and regulator of G-protein signaling 4 (RGS4) have emerged as the strongest positional candidate risk genes for schizophrenia, but... first of many family studies of schizophrenia, the close relatives of an affected individual were found to have a sixfold increase in risk for developing the illness themselves Subsequent reports routinely replicated a pattern of higher schizophrenia prevalence among the relatives of patients with schizophrenia A quantitative review of 40 family studies of schizophrenia revealed a consistent pattern of. .. Behavior, and Immunity, 15(4), 411– 420 Cannon, M., Jones, P B., & Murray, R M (20 02) Obstetric complications and schizophrenia: Historical and meta-analytic review American Journal of Psychiatry, 159(7), 1080–10 92 Cannon, T D (1997) On the nature and mechanisms of obstetric influences in schizophrenia: A review and synthesis of epidemiologic studies International Review of Psychiatry, 9, 387–397 Cannon,... Rao, D C (1985) Resolving genetic models for the transmission of schizophrenia Genetic Epidemiology, 2, 99–110 Morton, N E (19 82) Outline of genetic epidemiology Basel: Karger O’Rourke, D H., Gottesman, I I., Suarez, B K., Rice, J., & Reich, T (19 82) Refutation of the general single-locus model for the etiology of schizophrenia American Journal of Human Genetics, 34, 630–649 Rüdin, E (1916) Zur Vererbung . is part of the neuropathology of schizophrenia, then the components of these connections, particu - larly white matter, should be somehow aberrant in the brains of patients with schizophre - nia. Over. Biologies, 328 (2) , 169–175. Harrison, P. J. (1999). The neuropathology of schizophrenia: A critical review of the data and their in - terpretation. Brain, 122 (4), 593– 624 . Hemsley, D. R. (20 05). The. find - ing of globally reduced fractional anisotropy (FA)—the output measure of the sum of vec - tors in a given brain region—in the brains of patients with schizophrenia. Relationships be - tween