Estradiol with Clomipramine Interaction Details

Brand Names Associated with Estradiol

Brand Names Associated with Clomipramine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 13, 2023

Interaction Effect

Possible attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)

Interaction Summary

In isolated cases, the pharmacologic effects of tricyclic antidepressants may be increased or decreased by estrogens, with paradoxical loss of antidepressant effect yet tricyclic toxicity being manifested simultaneously . The effects of the interaction appear to be estrogen dose-related  and may be of clinical importance primarily in patients previously stabilized on tricyclic therapy who are being started on estrogen therapy .

Severity

Minor

Onset

Delayed

Evidence

Established

How To Manage Interaction

If signs or symptoms of altered tricyclic response are noted, dose adjustment downward of either the estrogen or tricyclic component may be successful in restoring effectiveness or resolving toxicity. However, drug withdrawal may be required.

Mechanism Of Interaction

Possible inhibition of hepatic metabolism of the tricyclic antidepressant

Literature Reports

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 .

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 .

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 .

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 .

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 .

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 .

G) Estrogens may inhibit the oxidation of TCAs by affecting hepatic microsomal enzymes . 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 .

Estradiol Overview

• Estrogen is used to treat hot flushes ('hot flashes'; sudden strong feelings of heat and sweating) in women who are experiencing menopause ('change of life', the end of monthly menstrual periods). Some brands of estrogen are also used to treat vaginal dryness, itching, or burning, or to prevent osteoporosis (a condition in which the bones become thin and weak and break easily) in women who are experiencing or have experienced menopause. However, women who need a medication only to treat vaginal dryness or only to prevent osteoporosis should consider a different treatment. Some brands of estrogen are also to relieve symptoms of low estrogen in young women who do not produce enough estrogen naturally. Some brands of estrogen are also used to relieve the symptoms of certain types of breast and prostate (a male reproductive gland) cancer. Estrogen is in a class of medications called hormones. It works by replacing estrogen that is normally produced by the body.

Clomipramine Overview

• Clomipramine is used to treat people with obsessive-compulsive disorder (a condition that causes repeated unwanted thoughts and the need to perform certain behaviors over and over). Clomipramine is in a group of medications called tricyclic antidepressants. It works by increasing the amount of serotonin, a natural substance in the brain that is needed to maintain mental balance.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.