- Background: Inositol monophosphatase (IMPase) is a key enzyme in the regulation of the activity of the phosphatidyl inositol (PI) signaling pathway. This enzyme is also found in the cerebrospinal fluid (CSF), where it may prove useful as a marker of dysfunctional PI signal transduction. Methods: IMPase activity was measured in lumbar CSF of depressed and neuroleptic-treated schizophrenic patients. In addition, and to gain an insight into the factors that influence the levels of CSF IMPase, enzyme activity was measured in subgroups of schizophrenic patients treated for 3–7 days with lithium or 7 days with inositol. Results: CSF IMPase activity was significantly increased by 88% in depressed and by 172% in schizophrenic patients relative to control subjects. Lithium produced a marked increase in CSF IMPase activity in the group as a whole, and this group effect could be more specifically attributed to 3 of the 8 individuals in whom enzyme activity increased by over 300%. On the other hand, inositol had no effect on CSF IMPase activity. Conclusions: In the absence of a clear relationship between CSF IMPase activity and neuronal PI signaling pathways it is not possible to correlate these changes with altered neuronal function. Nevertheless, increased CSF IMPase activity in depression and schizophrenia may be a marker of the pathophysiological processes underlying these disorders. Moreover, the large lithium-induced increase in IMPase activity seen in a subgroup of schizophrenic subjects suggests a differential regulation of CSF enzyme activity in these patients.