Chronic lithium (Li) therapy, used extensively in the treatment of bipolar affective disorders, is one of psychiatry's most effective treatments. The data on the effects of Li on baseline PTH and calcium (Ca) levels are conflicting. A clear resetting of the PTH set-point to the right was documented in vitro; however, the effect of Li on the Ca-PTH axis has not been rigorously studied in vivo. In this study, we used a Ca and citrate infusion protocol to fully characterize PTH dynamics in seven female patients, 40 +/- 11 yr old, on chronic Li therapy for 5.23 +/- 4.0 yr, compared with seven controls, 41 +/- 16 yr old (mean +/- SD). Baseline ionized Ca (Cai) and intact PTH levels were 5.2 +/- 0.06 mg/dL and 38.4 +/- 5.7 pg/mL in the Li group and 4.9 +/- 0.06 mg/dL and 21.2 +/- 5.0 pg/mL in the controls, (mean +/- SEM) P = 0.008 and 0.042, respectively. We defined an inverse sigmoidal curve between Cai and the intact biologically active PTH molecule (iPTH) for the two study groups and demonstrated a significant shift in the iPTH set-point to the right in the Li-treated patients, compared with controls. The set-point was 5.08 +/- 0.04 for the former group and 4.88 +/- 0.04 mg/dL for the latter, P = 0.004. Patients on Li had significantly higher Cai levels during citrate and Ca infusions, P = 0.0008 and 0.012, respectively; however, iPTH levels were not significantly different between the two study groups during either infusion. The shift in the iPTH set-point to the right in the Li-treated patients and the similar iPTH levels, despite higher serum Cai levels during both infusions, establish the presence of a clear alteration in PTH dynamics in patients on chronic Li therapy.