Ovarian Hormones and Antidepressants

Depression is more prevalent among women than men. Yet, very little is known about the potential influence of female hormones, such as estrogen and progesterone, on the action of antidepressant (AD) drugs that are commonly prescribed to both, men and women. Therefore, we conducted a preclinical study to address this. We focused our study on a classical AD drug called Desipramine (sold as Norpramin) and widely prescribed to people of all genders.

Desipramine blocks the reuptake of a neurochemical messenger, norepinephrine, back into neurons by binding to the norepinephrine transporter present on neuronal ends. To test the influence of female hormones on this drug’s action, we compared how effective the drug was at inducing an antidepressant-like effect in ovariectomized female rats in the absence and presence of female hormones, using a well-established behavioral assay for measuring antidepressant effects of treatments. We showed that, on a short timescale, female hormones blocked the antidepressant-like effects of desipramine altogether. Further analysis showed that the hormone treatment itself did not alter norepinephrine reuptake nor did it interfere with the binding of desipramine to its target, the transporter.

Next, we tested if long-term hormone treatment would interfere with the AD drug’s action. First, we conducted a pilot study to determine the appropriate dose of estrogen that the animals should be treated with in order to achieve serum estrogen levels comparable to those seen during the proestrus stage of the estrous cycle in normally cycling female rats. Ovariectomized female rats were given three different doses of estrogen in the form of pellets that were implanted under their skin. Serum estrogen levels were measured on Day 18. These data helped us pick an appropriate dose for our long-term study and were included in the publication for the benefit of other researchers in the field. On a longer timescale, the female hormones did not interfere with the drug’s action at the two doses of the drug that were tested. Interestingly, the hormone treatment regimen itself had a pro-depressive effect. In addition to the behavioral studies, we checked if the hormones altered circulating levels of the AD drug. Despite receiving identical doses of desipramine, drug levels were up to two-fold higher in animals who also received hormone treatment compared to those that did not, possibly due to an influence of the hormones on the metabolism of the drug. Taken together, these studies suggest that female hormones may not interfere with desipramine treatment in women. However, one has to be careful about the dose prescribed as serum levels of the drug were much higher in the presence of female hormones. These studies also emphasize the importance of treatment duration when designing studies to determine possible interactions between hormones (or other drugs) and AD drugs.