Skip to main content Accessibility help
×
Hostname: page-component-586b7cd67f-gb8f7 Total loading time: 0 Render date: 2024-11-28T05:25:00.746Z Has data issue: false hasContentIssue false

20 - Neurodegenerative models of schizophrenia

Published online by Cambridge University Press:  04 August 2010

L. Fredrik Jarskog
Affiliation:
University of North Carolina School of Medicine, Chapel Hill, USA
John H. Gilmore
Affiliation:
University of North Carolina School of Medicine, Chapel Hill, USA
Jeffrey A. Lieberman
Affiliation:
University of North Carolina School of Medicine, Chapel Hill, USA
Matcheri S. Keshavan
Affiliation:
University of Pittsburgh
James L. Kennedy
Affiliation:
Clarke Institute of Psychiatry, Toronto
Robin M. Murray
Affiliation:
Institute of Psychiatry, London
Get access

Summary

The concept of schizophrenia as a neurodegenerative disorder has a long and somewhat controversial past. The absence of a histopathological phenotype in schizophrenia has been cited as evidence against a neurodegenerative hypothesis. However, studies of schizophrenia increasingly demonstrate subtle yet consistent histopathological deficits in addition to evidence of progressive clinical and neuroimaging findings. It is believed that schizophrenia can be considered as a limited neurodegenerative disorder with neurodevelopmental antecedents. Studies from clinical, neurocognitive, neuroimaging, and neuropathological domains are reviewed in critical analysis of this hypothesis. The conclusion is increasingly supported by neuroimaging studies that find progressive neurostructural changes, especially in gray matter content and ventricle size, and studies that report limited progression of clinical symptoms and neurocognitive function. Future studies utilizing high-resolution neuroimaging and sophisticated neuropsychological testing techniques will undoubtedly provide greater insight on the timing, regionality, and degree of progression in the early stages of schizophrenia.
Type
Chapter
Information
Publisher: Cambridge University Press
Print publication year: 2004

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abrahamson, D. (1983). Schizophrenia deterioration. Br J Psychiatry 143: 82–83Google Scholar
Addington, J., Addington, D. (2002). Cognitive functioning in first-episode schizophrenia. J Psychiatry Neurosci 27: 188–192Google ScholarPubMed
Akbarian, S., Kim, J. J., Potkin, S. G.et al. (1995). Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 52: 258–266CrossRefGoogle ScholarPubMed
Andreasen, N. C., O'Leary, D. S., Flaum, M.et al. (1997). Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients. Lancet 349: 1730–1734CrossRefGoogle ScholarPubMed
Arango, C., Kirkpatrick, B., Koenig, J. (2001). At issue: stress, hippocampal neuronal turnover, and neuropsychiatric disorders. Schizophr Bull 27: 477–480CrossRefGoogle ScholarPubMed
Arnold, S. E., Trojanowski, J. Q., Gur, R. E.et al. (1998). Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 55: 225–232CrossRefGoogle Scholar
Benes, F. M. (1995). Is there a neuroanatomic basis for schizophrenia? An old question revisited. Neuroscientist 1: 104–115CrossRefGoogle Scholar
Benes, F. M., McSparren, J., Bird, E. D., SanGiovanni, J. P., Vincent, S. L. (1991). Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 48: 996–1001CrossRefGoogle ScholarPubMed
Benes, F. M., Vincent, S. L., Todtenkopf, M. (2001). The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects. Biol Psychiatry 50: 395–406CrossRefGoogle ScholarPubMed
Benes, F. M., Walsh, J., Bhattacharyya, S., Sheth, A., Berretta, S. (2003). DNA fragmentation is decreased in schizophrenia but not in bipolar disorder. Arch Gen Psychiatry 60: 359–364CrossRefGoogle ScholarPubMed
Bertolino, A., Callicott, J. H., Nawroz, S.et al. (1998). Reproducibility of proton magnetic resonance spectroscopic imaging in patients with schizophrenia. Neuropsychopharmacology 18: 1–9CrossRefGoogle ScholarPubMed
Bilder, R. M., Lipschutz-Broch, R. G., Geisler, S. H., Mayerhoff, D. I., Lieberman, J. A. (1992). Intellectual deficits in first-episode schizophrenia: evidence for progressive deterioration. Schizophr Bull 18: 437–488CrossRefGoogle ScholarPubMed
Black, J. E., Klintsova, A. Y., Kodish, I. M., Greenough, W. T., Uranova, N. A. (2002). What is missing in the reduced neuropil of schizophrenic prefrontal cortex? A combined golgi and electron microscopy study. Biol Psychiatry 51: S54Google Scholar
Cahn, W., Hulshoff Pol, H. E., Lems, E. B. T. E.et al. (2002). Brain volume changes in first-episode schizophrenia. Arch Gen Psychiatry 59: 1002–1010CrossRefGoogle ScholarPubMed
Cannon, M., Jones, P., Huttunen, M. O.et al. (1999). School performance in Finnish children and later development of schizophrenia. Arch Gen Psychiatry 56: 457–463CrossRefGoogle ScholarPubMed
Cannon, M., Caspi, A., Moffitt, T. E.et al. (2002). Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder. Results from a longitudinal birth cohort. Arch Gen Psychiatry 59: 449–456CrossRefGoogle ScholarPubMed
Cecil, K. M., Lenkinski, R. E., Gur, R. E., Gur, R. C. (1999). Proton magnetic resonance spectroscopy in the frontal and temporal lobes of neuroleptic naive patients with schizophrenia. Neuropsychopharmacology 20: 131–140CrossRefGoogle ScholarPubMed
Church, S. M., Cotter, D., Bramon, E., Murray, R. M. (2002). Does schizophrenia result from developmental or degenerative processes?J Neural Transm Suppl 63: 129–147Google Scholar
Cotter, D. R., Pariante, C. M., Everall, I. P. (2001). Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull 55: 585–595CrossRefGoogle ScholarPubMed
Coyle, J. T., Puttfarcken, P. (1993). Oxidative stress, glutamate, and neurodegenerative disorders. Science 262: 689–695CrossRefGoogle ScholarPubMed
Davis, K. L., Buchsbaum, M. S., Shihabuddin, L.et al. (1998). Ventricular enlargement in poor-outcome schizophrenia. Biol Psychiatry 43: 783–793CrossRefGoogle ScholarPubMed
DeLisi, L. E., Sakuma, M., Tew, W.et al. (1997). Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res Neuroimaging 74: 129–140CrossRefGoogle ScholarPubMed
Done, D. J., Crow, T. J., Johnstone, E. C., Sacker, A. (1994). Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11. Br Med J 309: 699–703CrossRefGoogle ScholarPubMed
Eastwood, S. L., Harrison, P. J. (1995). Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography. Neuroscience 69: 339–343CrossRefGoogle ScholarPubMed
Eaton, W. W., Thara, R., Federman, B., Melton, B., Liang, K.-Y. (1995). Structure and course of positive and negative symptoms in schizophrenia, Arch Gen Psychiatry 52: 127–134CrossRefGoogle Scholar
Fannon, D., Chitnis, X., Doku, V.et al. (2000). Features of structural brain abnormality in first-episode psychosis. Am J Psychiatry 157: 1829–1834CrossRefGoogle ScholarPubMed
Fenton, W. S., McGlashan, T. H. (1994). Antecedents, symptom progression, and long-term outcome of the deficit syndrome in schizophrenia. Am J Psychiatry 151: 351–356Google Scholar
Friedman, J. I., Harvey, P. D., McGurk, S. R.et al. (2002). Correlates of change in functional status of institutionalized geriatric schizophrenic patients: focus on medical comorbidity. Am J Psychiatry 159: 1388–1394CrossRefGoogle ScholarPubMed
Fuller, R., Nopoulos, P., Arndt, S.et al. (2002). Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastic test performance. Am J Psychiatry 159: 1183–1189CrossRefGoogle ScholarPubMed
Garey, L. J., Ong, W. Y., Patel, T. S., Kanani, M., Davis, A., Mortimer, A. M., Barnes, T. R. E., Hirsch, S. R. (1998). Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry 65: 446–453CrossRefGoogle Scholar
Glantz, L. A., Lewis, D. A. (1997). Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia: regional and diagnostic specificity. Arch Gen Psychiatry 54: 943–952CrossRefGoogle ScholarPubMed
Glantz, L. A., Lewis, D. A. (2000). Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 57: 65–73CrossRefGoogle Scholar
Gur, R. E., Cowell, P., Turetsky, B. I.et al. (1998). A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 55: 145–152CrossRefGoogle ScholarPubMed
Hambrecht, M., Lammertink, M., Klosterkötter, J., Matuschek, E., Pukrop, R. (2002). Subjective and objective neuropsychological abnormalities in a psychosis prodrome clinic. Br J Psychiatry 181(Suppl. 43): S30–S37CrossRefGoogle Scholar
Hardy, J., Gwinn-Hardy, K. (1998). Genetic classification of primary neurodegenerative disease. Science 282: 1075–1079CrossRefGoogle ScholarPubMed
Harrison, P. J. (1999). The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain 122: 593–624CrossRefGoogle ScholarPubMed
Harrison, P. J., Eastwood, S. L. (2001). Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus 11: 508–519CrossRefGoogle Scholar
Harvey, P. D., Silverman, J. M., Mohs, R. C.et al. (1999). Cognitive decline in late-life schizophrenia: a longitudinal study of geriatric chronically hospitalized patients. Biol Psychiatry 45: 32–40CrossRefGoogle ScholarPubMed
Heaton, R. K., Gladsjo, J. A., Palmer, B. W.et al. (2001). Stability and course of neuropsychological deficits in schizophrenia. Am J Psychiatry 58: 24–32Google Scholar
Hinsberger, A. D., Williamson, P. C., Carr, T. J., Stanley, J. A., Drost, D. J., Densmore, M., MacFabe, G. C., Montemurro, D. G. (1997). Magnetic resonance imaging volumetric and phosphorus 31 magnetic resonance spectroscopy measurements in schizophrenia. J Psychiatry Neurosci 22: 111–117Google Scholar
Ho, B.-C., Alicata, D., Ward, J.et al. (2003). Untreated initial psychosis: relation to cognitive deficits and brain morphology in first-episode schizophrenia. Am J Psychiatry 160: 142–148CrossRefGoogle ScholarPubMed
Hoff, A. L., Sakuma, M., Wieneke, M.et al. (1999). Longitudinal neuropsychological follow-up study of patients with first-episode schizophrenia. Am J Psychiatry 156: 1336–1341Google ScholarPubMed
Hoff, A. L., Sakuma, M., Razi, K.et al. (2000). Lack of association between duration of untreated illness and severity of cognitive and structural brain deficits at the first episode of schizophrenia. Am J Psychiatry 157: 1824–1828CrossRefGoogle ScholarPubMed
Huber, G., Gross, G., Shuttler, R., Linz, M. (1980). Longitudinal studies of schizophrenic patients. Schizophr Bull 6: 592–605CrossRefGoogle ScholarPubMed
Hulshoff Pol, H. E., Schnack, H. G., Bertens, M. G. B. C.et al. (2002). Volume changes in gray matter in patients with schizophrenia. Am J Psychiatry 159: 244–250CrossRefGoogle ScholarPubMed
Jacobsen, L. K., Giedd, J., Castellanos, F. X.et al. (1998). Progressive reduction of temporal lobe structures in childhood-onset schizophrenia. Am J Psychiatry 155: 678–685CrossRefGoogle ScholarPubMed
Jarskog, L. F., Gilmore, J. H., Selinger, E. S., Lieberman, J. A. (2000). Cortical Bcl-2 protein expression and apoptotic regulation in schizophrenia. Biol Psychiatry 48: 641–650CrossRefGoogle Scholar
Jarskog, L. F., Selinger, E. S., Lieberman, J. A., Gilmore, J. H. (2001). Apoptotic regulatory proteins afford reduced neuroprotection in schizophrenia. Schizophr Res 49: 53SGoogle Scholar
Jones, P., Rodgers, B., Murray, R., Marmot, M. (1994). Child development risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 344: 1398–1402CrossRefGoogle ScholarPubMed
Karson, C. N., Mrak, R. E., Schluterman, K. O.et al. (1999). Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for “hypofrontality”. Mol Psychiatry 4: 39–45CrossRefGoogle ScholarPubMed
Kasai, K., Shenton, M. E., Salisbury, D. F.et al. (2003). Progressive decrease of left superior temporal gyrus gray matter volume in patients with first-episode schizophrenia. Am J Psychiatry 160: 156–164CrossRefGoogle ScholarPubMed
Keller, A., Castellanos, F. X., Vaituzis, A. C.et al. (2003). Progressive loss of cerebellar volume in childhood-onset schizophrenia. Am J Psychiatry 160: 128–133CrossRefGoogle ScholarPubMed
Kraeplin E. (1919). Dementia Praecox and Paraphrenia, Edinburgh, E and S Livingstone
Kremen, W. S., Seidman, L. J., Pepple, J. R.et al. (1994). Neuropsychological risk indicators for schizophrenia: a review of family studies. Schizophr Bull 20: 103–119CrossRefGoogle ScholarPubMed
Lewis, D. A., Lieberman, J. A. (2000). Catching up on schizophrenia: natural history and neurobiology. Neuron 28: 325–334CrossRefGoogle ScholarPubMed
Lieberman, J. A., Sheitman, B. B., Kinon, B. J. (1997). Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity. Neuropsychopharmacology 17: 205–229CrossRefGoogle ScholarPubMed
Lieberman, J. A., Chakos, M., Wu, H.et al. (2001a). Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry 49: 487–499CrossRefGoogle Scholar
Lieberman, J. A., Perkins, D., Belger, A.et al. (2001b). The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry 50: 884–897CrossRefGoogle Scholar
Loebel, A. D., Lieberman, J. A., Alvir, J. M. J.et al. (1992). Duration of psychosis and outcome in first-episode schizophrenia. Am J Psychiatry 149: 1183–1188Google ScholarPubMed
Margolis, R. L., Chuang, D. M., Post, R. M. (1994). Programmed cell death: implications for neuropsychiatric disorders. Biol Psychiatry 35: 946–956CrossRefGoogle ScholarPubMed
Mason, P., Harrison, G., Glazebrook, C., Medley, I., Croudance, T. (1996). The course of schizophrenia over 13 years. A report from the International Study on Schizophrenia (IsoS) coordinated by the World Health Organization. Br J Psychiatry 169: 580–586CrossRefGoogle Scholar
Mathalon, D. H., Sullivan, E. V., Lim, K. O., Pfefferbaum, A. (2001). Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 58: 148–157CrossRefGoogle ScholarPubMed
Mattson, M. P., Keller, J. N., Begley, J. G. (1998). Evidence for synaptic apoptosis. Exp Neurol 153: 35–48CrossRefGoogle ScholarPubMed
Mayerhoff, D. I., Loebel, A. D., Alvir, J. M. J.et al. (1994). The deficit state in first-episode schizophrenia. Am J Psychiatry 151: 1417–1422Google Scholar
McGlashan, T. H. (1988). A selective review of recent North American long-term follow-up studies of schizophrenia. Schizophr Bull 14: 515–542CrossRefGoogle ScholarPubMed
Moritz, S., Andresen, B., Perro, C., for the PERSIST Study Group (2002). Neurocognitive performance in first-episode and chronic schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 252: 33–37CrossRefGoogle ScholarPubMed
Murray, R. M., Lewis, S. W. (1987). Is schizophrenia a neurodevelopmental disorder?Br Med J 296: 681–682CrossRefGoogle Scholar
Nair, T. R., Christensen, J. D., Kingsbury, S. J.et al. (1997). Progression of cerebroventricular enlargement and the subtyping of schizophrenia. Psychiatry Res Neuroimaging 74: 141–150CrossRefGoogle ScholarPubMed
Nopoulos, P., Flashman, L., Flaum, M., Arndt, S., Andreasen, N. (1994). Stability of cognitive functioning early in the course of schizophrenia. Schizophr Res 14: 29–37CrossRefGoogle ScholarPubMed
Ona, V. O., Li, M., Vonsattel, J. P. G.et al. (1999). Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399: 263–267CrossRefGoogle Scholar
Onley, J. W., Farber, N. B. (1995). Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52: 998–1007Google Scholar
Pakkenberg, B. (1990). Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch Gen Psychiatry 47: 1023–1028CrossRefGoogle ScholarPubMed
Pakkenberg, B. (1993). Total nerve cell number in neocortex in chronic schizophrenics and controls estimated using optical disectors. Biol Psychiatry 34: 768–772CrossRefGoogle ScholarPubMed
Pantelis, C., Velakoulis, D., McGorry, P. D.et al. (2002). Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet Accessed 10 December 2002: http://image.thelancet.com/extras/01art9092web.pdfGoogle Scholar
Pettegrew, J. W., Keshavan, M. S., Panchalingam, K.et al. (1991). Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics: a pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry 48: 563–568CrossRefGoogle ScholarPubMed
Pettegrew, J. W., Keshavan, M. S., Minshew, N. J. (1993). 31P Nuclear magnetic resonance spectroscopy: neurodevelopment and schizophrenia. Schizophr Bull 19: 35–53CrossRefGoogle Scholar
Pfohl, B., Winokur, G. (1982). The evolution of symptoms in institutionialized hebephrenic/catatonic schizophrenics. Br J Psychiatry 141: 567–572CrossRefGoogle ScholarPubMed
Pierri, J. N., Volk, C. L., Auh, S., Sampson, A., Lewis, D. A. (2001). Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia. Arch Gen Psychiatry 58: 466–473CrossRefGoogle ScholarPubMed
Pinals, D. A., Breier, A. (1997). Schizophrenia. In Psychiatry, ed. A. Tasman, J. Kay, J. A. Lieberman. Philadelphia, PA: W. B. Saunders, pp. 927–965
Purohit, D. P., Perl, D. P., Haroutunian, V.et al. (1998). Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia. Arch Gen Psychiatry 55: 205–211CrossRefGoogle ScholarPubMed
Rajkowska, G., Selemon, L. D., Goldman-Rakic, P. S. (1998). Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 55: 215–224CrossRefGoogle ScholarPubMed
Rapoport, J. L., Giedd, J., Kumra, S.et al. (1997). Childhood-onset schizophrenia: progressive ventricular change during adolescence. Arch Gen Psychiatry 54: 897–903CrossRefGoogle ScholarPubMed
Rapoport, J. L., Giedd, J. N., Blumenthal, J.et al. (1999). Progressive cortical change during adolescence in childhood-onset schizophrenia: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 56: 649–654CrossRefGoogle ScholarPubMed
Roberts, G. W., Colter, N., Lofthouse, R.et al. (1986). Gliosis in schizophrenia: a survey. Biol Psychiatry 21: 1043–1050CrossRefGoogle ScholarPubMed
Roberts, G. W., Colter, N., Lofthouse, R., Johnstone, E. C., Crow, T. J. (1987). Is there gliosis in schizophrenia? Investigation of the temporal lobe. Biol Psychiatry 22: 1459–1468CrossRefGoogle ScholarPubMed
Rund, B. R. (1998). A review of the longitudinal studies of cognitive decline in schizophrenia patients. Schizophr Bull 24: 425–435CrossRefGoogle ScholarPubMed
Saykin, A. J., Shtasel, D. L., Gur, R. E.et al. (1994). Neuropsychological deficits in neuroleptic naive patients with first episode schizophrenia. Arch Gen Psychiatry 51: 124–131CrossRefGoogle ScholarPubMed
Schlaepfer, T. E., Harris, G. J., Tien, A. Y.et al. (1994). Decreased regional cortical gray matter volume in schizophrenia. Am J Psychiatry 151: 842–848Google Scholar
Selemon, L. D., Rajkowska, G., Goldman-Rakic, P. S. (1995). Abnormally high neuronal density in the schizophrenic cortex: a morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 52: 805–818CrossRefGoogle ScholarPubMed
Selemon, L. D., Rajkowska, G., Goldman-Rakic, P. S. (1998). Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional, stereologic counting method. J Comp Neurol 392: 402–4123.0.CO;2-5>CrossRefGoogle ScholarPubMed
Smith, A. (1964). Mental deterioration in chronic schizophrenia. J Nerv Ment Dis 139: 479–487CrossRefGoogle ScholarPubMed
Stanley, J. A., Williamson, P. C., Drost, D. J.et al. (1995). An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy. Arch Gen Psychiatry 52: 399–406CrossRefGoogle Scholar
Stevens, J. R. (1982). Neuropathology of schizophrenia. Arch Gen Psychiatry 39: 1131–1139CrossRefGoogle ScholarPubMed
Thompson, P. M., Sower, A. C., Perrone-Bizzozero, N. I. (1998). Altered levels of the synaptosomal associated protein SNAP-25 in schizophrenia. Biol Psychiatry 43: 239–243CrossRefGoogle Scholar
Weinberger, D. R. (1987). Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44: 660–669CrossRefGoogle ScholarPubMed
Weinberger, D. R., McClure, R. K. (2002). Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain?Arch Gen Psychiatry 59: 553–558CrossRefGoogle ScholarPubMed
Weinberger, D. R., Berman, K. F., Zec, R. F. (1986). Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch Gen Psychiatry 43: 114–124CrossRefGoogle ScholarPubMed
Woods, B. T. (1998). Is schizophrenia a progressive neurodevelopmental disorder? Toward a unitary pathogenetic mechanism. Am J Psychiatry 155: 1661–1670CrossRefGoogle Scholar
Wyatt, R. J. (1991). Neuroleptics and the natural course of schizophrenia. Schizophr Bull 17: 325–351CrossRefGoogle ScholarPubMed
Wyatt, R. J. (1995). Early intervention for schizophrenia: can the course of the illness be altered?Biol Psychiatry 38: 1–3CrossRefGoogle ScholarPubMed
Young, K. A., Manaye, K. F., Liang, C. H., Hicks, P. B., German, D. C. (2000). Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia. Biol Psychiatry 47: 944–953CrossRefGoogle Scholar
Zipursky, R. B., Lim, K. O., Sullivan, E. V., Brown, B. W., Pfefferbaum, A. (1992). Widespread cerebral gray matter volume deficits in schizophrenia. Arch Gen Psychiatry 49: 195–205CrossRefGoogle Scholar
Zorrilla, L. T. E., Heaton, R. Ket al. (2000). Cross-sectional study of older outpatients with schizophrenia and health comparison subjects: no differences in age-related decline. Am J Psychiatry 157: 1324–1326CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×