The activity of inositol monophosphatase (IMPase), the lithium (Li)-inhibitable enzyme in the phosphatidylinositol (PI) signal transduction system, has recently been found significantly lower in lymphoblastoid cell lines from bipolar (BP) patients, particularly in Li-responders. To probe for possible quick detection of the disease and prediction of the therapeutic response we repeated our study in fresh lymphocytes. Since IMPase in fresh lymphocytes is inhibited in vivo by ongoing Li treatment and its pre-Li activity cannot be evaluated, IMPase mRNA levels were measured. Relative (to β-actin) mRNA levels were quantified by reverse transcriptase (RT)-PCR in 5 drug-free and 31 drug-treated BP patients compared with 36 control subjects in fresh lymphocytes. In agreement with our findings with IMPase activity, the small group of drug-free BP patients exhibited ∼2/3 reduction in IMPase relative mRNA levels compared to control subjects. Approximately 2-fold elevation of these levels toward control values was found for patients treated with Li and other mood stabilizers. The study further suggests the possible importance of IMPase in the aetiology of BP disorder and in the mediation of the therapeutic efficacy of Li. It may be that chronic inhibition of IMPase activity by Li results in up-regulation of its gene at the transcriptional level.