We are approaching the challenge of elucidating novel mechanisms in neuropsychiatric disease by using high-throughput global profiling methods, with an emphasis on pathway and functional changes. Previous studies from our laboratory have suggested a role for abnormal brain metabolism in the pathophysiology of schizophrenia. Applying these methods across disorders allows us to pinpoint unique molecular disease signatures as distinct from general indicators of compromised brain function. 2D-DIGE was used to investigate the protein profile of tissue from dorsolateral prefrontal cortex (gray and white matter) from patients with bipolar disorder, Down's syndrome, Alzheimer's disease, and control subjects. Differentially expressed proteins were sequence identified and organised according to functional category and compared to our previous findings from schizophrenia samples. Down's syndrome and Alzheimer's samples gave highly similar results to each other, with all differentially expressed proteins being upregulated, especially synaptic and cytoskeletal proteins. In the schizophrenia group, the majority of proteins were downregulated, with a substantial number involved in glucose and other metabolism, and similar results were seen in both gray and white matter. In contrast, bipolar disorder gray and white matter gave strikingly different patterns of protein expression. These data show that the protein profile of brain tissue from schizophrenic patients has distinct molecular characteristics compared to bipolar disorder and to neurodegenerative disorders. Furthermore, the changes identified by global profiling methods can be used to identify both unique and common mechanisms in major psychiatric and neurological disorders.