Diseases of white matter and schizophrenia-like psychosis Mark Walterfang, Stephen J. Wood, Dennis Velakoulis, David Copolov, Christos Pantelis Objective: To analyse the available data regarding the presentation of psychosis in dis- eases of central nervous system (CNS) white matter. Method: The available neurological and psychiatric literature on developmental, neoplas- tic, infective, immunological and other white matter diseases was reviewed. Results: A number of diseases of the white matter can present as schizophrenia-like psychoses, including leukodystrophies, neoplasms, velocardiofacial syndrome, callosal anomalies and inflammatory diseases. Conclusions: Production of psychotic symptoms may result from functional asynchrony of interdependent regions, due to alterations in critical circuits as a result of pathology. The nature, location and timing of white matter pathology seem to be the key factors in the development of psychosis, especially during the critical adolescent period of association area myelination. Diseases that disrupt the normal formation of myelin appear to cause psychosis at higher rates than those that disrupt mature myelinated structures. Diffuse rather than discrete lesions, in particular those affecting frontotemporal zones, are also more strongly associated with schizophrenia-like psychosis. These illnesses point to the central role that white matter plays in maintaining CNS connectivity and to how pathology of the white matter may contribute to the neurobiology of psychosis. Key words: connectivity, frontotemporal, myelin, psychosis, schizophrenia, white matter. Australian and New Zealand Journal of Psychiatry 2005; 39:746–756 Mark Walterfang, Consultant Psychiatrist and Senior Research Fellow (Cor- respondence) Melbourne Neuropsychiatry Centre, Level 2, John Cade Building, Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia. Email: mark.walterfang@mh.org.au Mental Health Research Institute, Melbourne, Australia. Stephen J. Wood, Research Fellow Melbourne Neuropsychiatry Centre, University of Melbourne, Melbourne, Australia Brain Research Institute, Austin Health, Heidelberg West, Australia Dennis Velakoulis, Clinical Director Melbourne Neuropsychiatry Centre, University of Melbourne, Melbourne, Australia David Copolov, Research Group Leader Mental Health Research Institute, Melbourne, Australia Christos Pantelis, Research Director Melbourne Neuropsychiatry Centre, University of Melbourne, Melbourne, Australia Received 3 October 2004; revised 13 January 2005; accepted 24 January 2005. The term psychosis has been refined over the last 40 years from a loose definition of functional impairment due to gross psychiatric illness [1] to a more restric- tive definition emphasizing delusions and hallucinations, or disorganized thought and behaviour. Although these symptoms are the hallmark of schizophrenia, they can also be present in a range of medical and neurological conditions which have long been described as ‘organic psychosis’ [2]. However, the definition of organic as ‘identifiable structural brain disease or toxic-metabolic brain dysfunction’ is problematic as the ‘non-organic’ psychoses also have demonstrable brain pathology, and the alternative classification of primary and secondary schizophrenia has been suggested to more appropriately capture the aetiologies of psychosis [3]. Furthermore, a broad definition of the term organic psychosis is often additionally used in the literature and clinical medical practice to refer to the presence of psychotic symptoms