Long-term treatment with
lithium salts has been established as an effective prophylactic
therapy in manic-depressive (bipolar) illness. Many patients, however, display a lack of (or partial) treatment response. We recently proposed that pharmacogenetic factors may influence and determine the therapeutic efficacy of
lithium in
bipolar disorder. The
lithium-blockable
enzyme inositol polyphosphate 1-phosphatase in the
phospholipase C signaling pathway is a putative target for the mood-stabilizing effects of
lithium. In the present study, we searched for
DNA variations in the human INPP1 gene encoding the
inositol polyphosphate 1-phosphatase enzyme. We report the existence of four common polymorphisms in the coding region of the gene. The
DNA alterations were all single base substitutions, of which one (A682G) predicted an
amino acid change (Thr228Ala), whereas the remaining three (G153T, G348A and C973A) were silent, In a Norwegian pilot sample the frequencies of the four single base substitutions were not significantly different between
lithium-treated bipolar patients and healthy control individuals. When subdivided with respect to
drug response, however, the C973A transversion was present in six out of nine
lithium responders (67%) versus one out of nine non-responders (11%) In contrast, the C973A polymorphism was equally common among
lithium responders and non-responders in an independent sample of bipolar patients from Israel. Future studies are therefore need to determine whether allelic variants of the INPP1 gene are associated with a favourable efficacy of
lithium in
manic-depressive illness.