Estradiol and Amitriptyline: Interaction Details

a) Some studies evaluated the qualitative effects of concomitant administration of estrogen and TCAs. In one trial, 30 depressed female prisoners were randomly assigned to four treatment groups. Ten patients received placebo, 10 received imipramine (150 mg daily) and placebo, five patients received imipramine (150 mg daily) and ethinyl estradiol (50 mcg daily), while five patients received imipramine (150 mg daily) and ethinyl estradiol (25 mcg daily). The 10 patients that received placebo did not improve over the six weeks of the study. The 10 patients taking estrogen and imipramine demonstrated a significantly greater improvement in symptoms than did the 10 patients taking imipramine alone. However, after two weeks, the five patients that received imipramine and high-dose estrogen had not improved as much as the patients receiving imipramine and low-dose estrogen. The only side-effect reported was drowsiness, which only affected the patients taking imipramine. Following the discontinuation of ethinyl estradiol, a time period of two weeks was required for the high-dose estrogen group to do as well as the low-dose group. This effect was attributed to the presence of residual estrogen in the high-dose group. In another group, five women received imipramine 150 mg and ethinyl estradiol 50 mrg daily did not improve as much as 10 patients receiving only imipramine. Also, the patients on the combination had severe side-effects including lethargy, coarse tremor and systolic hypotension ¹.

b) A 32-year-old female taking conjugated estrogens 2.5 mg and imipramine 100 mg developed lethargy, tremors, and signs of depersonalization. After two years of therapy, the patient increased her estrogen dose to 5 mg and then 7.5 mg daily. The patient became nauseated, had constant headaches, and low normal blood pressure. All lab work was normal. Upon discontinuing the estrogen, the side effects abated. Some investigators have proposed that the side effects resulted from enhanced TCA effects secondary to estrogen inhibition of hepatic microsomal enzymes ²³.

c) In a study women received clomipramine and oral contraceptives or clomipramine alone. At the beginning of the study there were 30 women taking the combination, but 12 subsequently dropped out. The 18 patients on the combination were matched with 18 patients taking clomipramine alone. No significant difference was noted in the patients' responses to clomipramine. It was proposed that there was no significant difference in side-effects between the groups; however, the groups were matched after patients had dropped out of the study. Had the patients been matched prior to the study, different conclusions may have been drawn ⁴.

d) The effects of oral contraceptives on clomipramine was studied in 42 women between the ages of 18 and 40. Twenty-three women took clomipramine 25 mg at bedtime while 19 took clomipramine 25 mg at bedtime with oral contraceptives. Over the four-week study, three control patients (two due to side-effects) and five in the experimental group (two due to side-effects) dropped out. Venous blood samples were drawn at weekly intervals for measurement of serum clomipramine concentrations. No difference in serum concentrations was noted between the groups. However, this result may be partially due to the low dose of clomipramine given ⁵.

e) The onset of akathisia was reported in 3 patients receiving conjugated estrogens and tricyclic antidepressants concurrently. A 24-year-old patient receiving clomipramine 120 mg daily for anorexia nervosa and conjugated estrogens 1.25 mg daily for amenorrhea developed restless legs and a constant desire to move continuously. Estrogen was discontinued and benztropine 2 mg was administered, resulting in marked reduction and resolution within 48 hours. Akathisia and disorientation developed in a 55-year-old patient on conjugated estrogen 1.25 mg daily who was prescribed amitriptyline 50 mg daily for depression. Within hours of amitriptyline, the patient was confused, restless, and possessed an inner desire to move continuously. Symptoms disappeared after discontinuing amitriptyline. A third case of akathisia was reported in a 35-year-old patient who received conjugated estrogen 1.25 mg daily and amitriptyline 50 mg daily. Akathisia developed within a few hours after taking the first dose of amitriptyline and resolved within 48 hours following discontinuation of the antidepressant ⁶.

f) The absolute bioavailability of imipramine increased in women who received low-dose oral contraceptives (50 mcg or less of ethinyl estradiol) from 27% to 44% (p less than 0.05) as evident by an increase in the area under the plasma concentration time curve ⁷.

g) Estrogens may inhibit the oxidation of TCAs by affecting hepatic microsomal enzymes ⁸. Many TCAs are metabolized via oxidation and conjugation pathways. Inhibition of the oxidation of TCAs could result in accumulation and toxicity due to decreased clearance. Estrogens are suspected of possessing other effects on the central nervous system resulting in an antidepressant effect ⁹.