Amitriptyline and Levonorgestrel: Interaction Details

a) A study evaluated the qualitative effects of concomitant administration of estrogen and tricyclic antidepressants (TCAs). In one trial, 30 depressed female prisoners were randomly assigned to 4 treatment groups. Ten patients received placebo, 10 received imipramine (150 milligrams/day) and placebo, 5 patients received imipramine (150 milligrams/day) and ethinyl estradiol (50 micrograms/day), while 5 patients received imipramine (150 milligrams/day) and ethinyl estradiol (25 micrograms/day). The 10 patients who received placebo did not improve over the 6 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 2 weeks, the 5 patients who 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 2 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, 5 women received imipramine 150 milligrams and ethinyl estradiol 50 micrograms 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 case report demonstrated an interaction in a 32-year-old female taking conjugated estrogens 2.5 milligrams and imipramine 100 milligrams. The patient developed lethargy, tremors, and signs of depersonalization. After 2 years of therapy, the patient increased her estrogen dose to 5 milligrams and then 7.5 milligrams 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 ². Some investigators have proposed that the side effects resulted from enhanced tricyclic antidepressant effects secondary to estrogen inhibition of hepatic microsomal enzymes ³.

c) A study evaluated women who 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) A study evaluated the effects of oral contraceptives on clomipramine in 42 women between the ages of 18 and 40 years. Twenty-three women took clomipramine 25 milligrams at bedtime while 19 took clomipramine 25 milligrams at bedtime with oral contraceptives. Over the 4-week study, 3 patients in the control group (2 due to side effects) and 5 in the experimental group (2 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) Three patients receiving conjugated estrogens and tricyclic antidepressants concurrently acquired akathisia. A 24-year-old patient receiving clomipramine 120 milligrams/day for anorexia nervosa and conjugated estrogens 1.25 milligrams/day for amenorrhea developed restless legs and a constant desire to move continuously. Estrogen was discontinued and benztropine 2 milligrams was administered, resulting in marked reduction and resolution within 48 hours. Akathisia and disorientation developed in a 55-year-old patient on conjugated estrogens 1.25 milligrams/day who was prescribed amitriptyline 50 milligrams/day for depression. Within hours of taking amitriptyline, the patient was confused, restless, and possessed an inner desire to move continuously. Symptoms disappeared after discontinuing amitriptyline. Positive rechallenge at one week with doxepin 100 milligrams, with resolution following discontinuation of doxepin. A third case of akathisia was reported in a 35-year-old patient who received conjugated estrogens 1.25 milligrams/day and amitriptyline 50 milligrams/day. 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 micrograms or less of ethinyl estradiol) from 27% to 44% (p less than 0.05) as evident by an increase in the AUC ⁷.

g) Estrogens may inhibit the oxidation of tricyclic antidepressants (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.