Experimental and clinical studies suggest an involvement of the opioid neuropeptide system in psychiatric disorders. Notably, opioid peptide immunoreactivity is altered in the cerebrospinal fluid of chronic schizophrenics and manic-depressive subjects. 1–3 Despite these clinical findings, few postmortem investigations 4, 5 have examined the association of endogenous opioid neuropeptides with schizophrenia and suicide. Anatomically, a tight interaction exists within the neostriatum between the opioid peptide (dynorphin and enkephalin) system and classical neurotransmitters such as dopamine 6 which has been implicated in both the psychotic symptoms and the cognitive deficits that characterize schizophrenia (see review). 7 The neostriatum is differentially organized into patch and matrix neurochemical mosaic compartments anatomically connected to limbic-and sensorimotor-related brain regions, respectively. 6, 8 Moreover, the human neostriatum is characterized by a heterogenous expression of the prodynorphin opioid gene: high in the patch, but low in the matrix compartment. 9, 10 The present results show for the first time a differential alteration of prodynorphin within distinct striatal compartments in postmortem tissue from nonschizophrenic suicide subjects. The prodynorphin patch/matrix mRNA expression was elevated in the caudate nucleus of suicide subjects as compared to normal controls and schizophrenics in which no alterations in opioid peptides or D 1 and D 2 mRNA expression were apparent. Altogether the findings suggest that discrete dysfunction of the endogenous opioid dynorphin system might contribute to depression and the risk of suicide in nonschizophrenic subjects.