Two peptidase activities decrease in treated bipolar disorder not schizophrenic patients


  • Each author declares that they have no potential conflict of interest.

Robin SB Williams, Wolfson Institute for Biomedical Research, Cruciform Building, University College London, Gower St, London WC1 E6BT, UK.
Fax: 020 7916 5994;


Background:  Inhibition of prolyl oligopeptidase (PO) in primary neuronal cultures has been shown to reverse the effect of the common mood-stabilizers lithium, valproic acid and carbamazepine. In clinical studies, abnormal plasma PO activity has been associated with bipolar disorder (BD) and schizophrenia. However, this association is complicated by the discovery in bovine plasma of a Z-Pro-prolinal-insensitive peptidase (ZIP), a novel enzyme that cleaves the same substrate as PO.

Methods:  We developed an assay to distinguish between ZIP and PO and measured both activities in plasma from 48 BD and 50 schizophrenic patients undergoing treatment and compared them with 50 control subjects.

Results:  ZIP activity is restricted to blood plasma, whereas PO activity is present in the cytosol of lymphocytes, but can also be detected in blood plasma. Significant decreases in their plasma activities were found between treated BD (p = 0.007 and 0.03 respectively) but not schizophrenic (p > 0.05) patients and controls.

Conclusions:  We have found that the enzyme activity previously reported as plasma PO actually comprises two enzymes, PO and ZIP. This study shows a statistically significant decrease of both enzymes in BD patients undergoing lithium treatment. No statistically significant change in PO or ZIP activity is observed in schizophrenic patients.