Influence of imipramine on the hypothalamic/pituitary/thyroid axis of the rat

The effects of the tricyclic antidepressant drug imipramine at different levels of the hypothalamic/pituitary/thyroid axis were investigated in the rat. Intraperitoneal (IP) treatment for 14 days with imipramine at 10 mg/kg, but not 2 mg/kg, reduced serum total thyroxine (T4) and triiodothyronine (T3). A similar decrease in serum total T4 was observed in thyroidectomized T4-treated rats, suggesting that imipramine treatment enhances T4 clearance instead of reducing T4 secretion. There were no parallel decreases in serum free T4 and T3 concentrations, due to the simultaneous increase in the free fractions of both T4 and T3 following imipramine treatment. In vitro experiments using equilibrium dialysis indicated that neither imipramine nor its metabolite desipramine directly influenced the binding of T4 or T3 to their transport proteins following addition to normal serum, suggesting an indirect effect of imipramine or desipramine on free hormone concentrations in vivo. Concentrations of T4 and T3 in the brain, liver, and heart were unaffected by imipramine treatment, suggesting that the drug did not affect cellular uptake and metabolism of T4 and T3. Serum concentrations of thyrotropin (TSH) were unaffected by imipramine pretreatment at either dose level, compatible with the fact that serum free T4 and T3 concentrations were not reduced. Moreover, there was no difference in thyrotrope responsiveness to stimulation by TSH-releasing hormone (TRH) and to inhibition by T4 and T3 in rat anterior pituitary cells cultured ex vivo for 18 hours from control and imipramine-treated rats. Furthermore, in vitro exposure of cultured rat anterior pituitary cells to imipramine and desipramine indicated that both agents decreased TSH secretion only at concentrations greater than 10(-6) mol/L. These concentrations of imipramine and desipramine in the culture medium would exceed the free concentrations of these drugs seen in vivo therapeutically. In addition, no direct effects of 10(-6) mol/L imipramine or desipramine on the TSH response to TRH or to T3 were observed in vitro in cultured pituitary cells. A potential indirect effect of imipramine or desipramine on TSH secretion via altered hypothalamic control of thyrotropes does not seem likely, due to the lack of effect of imipramine treatment on serum TSH concentrations in imipramine-treated rats. In conclusion, imipramine treatment reduces serum total T4 and T3 in the rat, with enhanced clearance being the most likely explanation for the effect on T4. There was no evidence for altered tissue T4 or T3 concentrations or for altered thyrotrope function. The enhanced T4 clearance may explain the reduction in total T4 reported for imipramine-treated depressed patients. However, the effects of imipramine treatment on the transport of thyroid hormones in plasma need to be examined in more detail in patients, since interspecies differences in the nature of the transport proteins preclude extrapolation of the present results from the rat.