Affiliations: The Clinical Neuroscience Division, Laboratory of Neuroscience, Department of Psychiatry, Brockton VA Medical Centre and Harvard Medical School, Boston, MA, USA
Note: [] Corresponding author: Dr. Martha E. Shenton,
Department of Psychiatry - 116A, VAMC-Brockton/West Roxbury, Harvard Medical
School, 940 Belmont Street, Brockton, MA 02401, USA. Tel.: +1 508 583 4500 1371;
Fax: +1 508 580 0059; E-mail: [email protected]
Abstract: Schizophrenia is a disorder characterized by multiple symptoms, with
a varied course and outcome. The etiology is yet unknown, but multiple
pathological processes or, equally likely, a unique pathophysiological process,
may be involved. Here, we review evidence for progressive changes in
schizophrenia in order to understand further the pathophysiology of this
disorder. We first present evidence for clinical and psycho-social changes over
time, followed by evidence from structural brain studies that suggests that
schizophrenia is a brain disorder. We then review findings from the small
number of longitudinal studies that have evaluated structural brain changes in
schizophrenia, followed by a review of the evidence for neurophysiological
changes, both cross-sectional and longitudinal. This is followed by a
discussion of possible cellular mechanisms, including NMDA receptor
abnormalities, that might account for structural and functional brain changes (temporal and frontal),
and we discuss how these abnormalities might be related to not only the specific signs and symptoms of
schizophrenia but also to the onset and course of the illness. Finally, we
discuss neurodevelopment (static and perhaps non-static alterations) and
neurodegenerative theories of schizophrenia. We propose that the two are not
mutually exclusive, but instead likely reflect a "two-hit" model for some
subtypes of schizophrenia.
