Clomipramine: Dosage, Presentations, Side Effects, Precautions, Interactions, Overdose and Mechanism of Action

It is a tricyclic antidepressant used in obsessive compulsive disorder therapy.

Clomipramine can cause transient and serum elevations in serum enzymes and is a rare cause of clinically apparent acute liver injury.

Clomipramine is a dibenzazepine-derived tricyclic antidepressant that works by inhibiting the reuptake of serotonin in the synaptic clefts of the central nervous system, increasing serotonin levels in the brain .

Clomipramine also has some blocking activity at postsynaptic dopamine receptors. Clomipramine, the 3-chloro analog of imipramine, is a tricyclic antidepressant derived from dibenzazepine. Tricyclic antidepressants are structurally similar to phenothiazines.

They contain a tricyclic ring system with an alkylamine substituent on the central ring. In non-depressed individuals, clomipramine does not affect mood or arousal, but it can cause sedation.

In depressed people, clomipramine has a positive effect on mood. Tricyclic antidepressants are strong serotonin and norepinephrine reuptake inhibitors.

Tertiary amine tricyclic antidepressants, such as clomipramine, are more potent inhibitors of serotonin reuptake than secondary amine tricyclic antidepressants, such as nortriptyline and desipramine.

Tricyclic antidepressants also down-regulate brain β-adrenergic receptors and sensitize postsynaptic serotonergic receptors with chronic use.

The antidepressant effects of tricyclic antidepressants are believed to be due to the general increase in serotonergic neurotransmission.

Tricyclic antidepressants also block histamine-H1 receptors, α1-adrenergic receptors, and muscarinic receptors, accounting for their sedative, hypotensive, and anticholinergic effects, respectively.

Clomipramine is used in the therapy of obsessive-compulsive disorder and was approved for this indication in the United States in 1989. And disorders with an obsessive-compulsive component (eg, depression , schizophrenia, Tourette syndrome).

Non-labeled indications include panic disorder, chronic pain (eg, central pain, idiopathic pain, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy, autistic disorder, trichotillomania, oncophagia, stuttering, premature ejaculation, and syndrome. premenstrual.

Clomipramine is rapidly absorbed from the gastrointestinal tract and is demethylated in the liver to its main active metabolite, desmethylclomipramine.

Dosage and presentations

Clomipramine is available in generic form and under the Anafranil brand names in 25, 50 and 75 mg capsules.

Clomipramine treatment should be started at the lowest recommended dose and increased slowly according to the patient’s response to minimize the risk of side effects. Clomipramine tablets are best tolerated when taken with food.

The typical recommended dose for obsessive compulsive disorder is 25 mg per day, increasing to at least 100 mg per day with a maximum dose of 250 mg per day for adults and 200 milligrams for children and adolescents.


Well absorbed from the gastrointestinal tract after oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food.

Peak plasma concentrations occurred 2-6 hours after oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng / ml to 154 mg / ml (mean, 92 ng / ml).

Your condition will not improve any faster, and your risk of side effects such as seizures may increase. Keep taking it even if you feel fine. To help you remember, use it at the same time every day. Some conditions can get worse when the medicine is stopped abruptly.

You may experience sweating, dizziness, nausea, vomiting, headache, or irritability if you suddenly stop taking this medicine. Your dose may need to be decreased gradually. It may take 2 to 3 weeks or more before the full effects of this medicine are noticed.


Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N-demethylation of clomipramine through CYP2C19, 3A4 and 1A2.

Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed by 8-hydroxylation, 2-hydroxyclomipramine formed by 2-hydroxylation, and clomipramine N-oxide formed by N-oxidation.

Side effects

Common side effects include dizziness, headache, insomnia, drowsiness, gastrointestinal upset, increased appetite, weight gain, blurred vision, dry mouth, and urinary retention.

To decrease side effects such as an upset stomach, clomipramine can be started in low doses, given in several doses throughout the day with meals, and slowly increased as the body adjusts.

Anxiety symptoms may temporarily worsen when you start taking clomipramine.

Some people may be more likely to have eye problems with clomipramine. Your doctor may want you to have an eye exam to see if you are more likely to have these eye problems.

Call your doctor right away if you have eye pain, vision changes, or swelling or redness in or around the eye.

Rare but potentially serious adverse events include suicidal ideation and behavior, worsening of depression or mania, glaucoma, serotonin syndrome, hypersensitivity reactions, and seizures.

Tell your doctor right away if you have any serious side effects, including mental / mood changes (such as confusion, depression, memory problems), enlarged / painful breasts, unwanted breast milk production, painful / irregular menstrual periods, stiffness. muscular, buzzing.

Sexual problems (such as decreased sexual ability, changes in desire), tremors, numbness / tingling of the hands / feet, difficulty urinating.

Easy bruising / bleeding, unusual / uncontrollable movements (especially of the tongue / face / lips), dark urine, yellowing of the eyes / skin.

Avoid eating grapefruit or drinking grapefruit juice while being treated with this medicine unless your doctor tells you otherwise.

This medicine can increase the chances of seizures in some people, including people who have had seizures in the past. Talk to your doctor to see if you are more likely to have seizures while taking clomipramine.

Low platelet counts have rarely happened with clomipramine. This can lead to an increased chance of bleeding. Call your doctor right away if you have unexplained bruising or bleeding.

Low white blood cell counts have rarely happened with clomipramine. This can lead to an increased chance of getting an infection. Call your doctor right away if you have signs of infection such as fever, chills, or a sore throat.

A very bad and sometimes fatal reaction has happened to clomipramine. Most of the time, this reaction has signs such as fever, rash, or swollen glands with problems in the body’s organs such as the liver, kidney, blood, heart, muscles, and joints or lungs.

Some side effects of clomipramine can occur and generally do not require medical attention.


Before taking clomipramine, tell your doctor. This product may contain inactive ingredients, which can cause allergic reactions or other problems.

Heart problems (for example, arrhythmias, coronary artery disease, recent heart attack), intestinal problems (for example, chronic constipation, ileus), liver problems.

Kidney problems, personal or family history of other mental disorders / mood conditions eg bipolar disorder, schizophrenia), history of hospitalization for a very serious reaction to certain medications (neuroleptic malignant syndrome).

Heartburn / stomach acid in the esophagus (for example, due to hiatal hernia), seizures, overactive thyroid (hyperthyroidism), difficulty urinating (urinary retention, prostate enlargement).

Caution is advised when using this drug in children who participate in active sports because it may increase the risk of heart problems.

Newborns exposed to clomipramine during pregnancy may experience withdrawal symptoms or side effects. Tell your doctor right away if you notice tremors, feeding problems, fast breathing, or seizures in your newborn.


Patients starting treatment with clomipramine should consult with their doctor or pharmacist to find out if any of their current medications or supplements have interactions with other medications with clomipramine.

Additionally, patients receiving clomipramine treatment should always consult with their physician before starting treatment with any new medications.

Interactions with other medications can change how your medications work or increase the risk of serious side effects. Some products that may interact with clomipramine include:

Medications that can cause bleeding / bruising (for example, ‘blood thinners’ such as warfarin / heparin, antiplatelet medications, including aspirin, or non-steroidal anti-inflammatory medications, such as ibuprofen).

Many drugs (besides clomipramine) can affect the heart rate, including amiodarone, dofetilide, quinidine, sotalol, pimozide, procainamide, macrolide antibiotics (such as erythromycin), among others.

Check all prescription and non-prescription drug labels carefully, as many medications contain pain relievers / fever reducers (non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, naproxen) which, if taken together with this drug, can increase your risk of bleeding.

You should continue to take a low dose of aspirin, as prescribed by your doctor for specific medical reasons, such as heart attack or stroke prevention (usually in doses of 81-325 milligrams per day).

Clomipramine is generally not recommended for use with other tricyclic antidepressants or related cyclic antidepressants. Co-administration with drugs that share similar properties increases the risk of side effects.

Examples of similar antidepressants are amoxapine, imipramine (Tofranil), and desipramine (Norpramin).

Clomipramine shares pharmacological properties with Class IA and Class III antiarrhythmic drugs. Concomitant administration increases the risk of QT prolongation and life-threatening arrhythmias.

For this reason, the use of clomipramine with bretylium, dofetilide (Tikosyn), dronedarone (Multaq), flecainide (Tambocor), sotalol (Betapace), quinidine (Quinidex), procainamide (Pronestyl), propafenone (Rythmol), ranolazine should be avoided. (Ranexa), ibutilida (Corvert) and others.

Clomipramine should be avoided when possible or used with caution with medications known to prolong the QTc interval. Examples of such drugs are thioridazine (Mellaril), ziprasidone (Geodon), pimozide (Orap), and others.

Clomipramine increases serotonin levels in the brain. Co-administration with other drugs that also increase serotonin levels increases the risk of serotonin syndrome.

Symptoms of serotonin syndrome include the rapid development of hyperthermia (high body temperature), high blood pressure, muscle stiffness, confusion, and delirium.

Some medications that increase serotonin levels are monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and linezolid (Zyvox). For a complete list, ask your doctor or pharmacist.

Ask your pharmacist about the safe use of these products. Smoking cigarettes lowers the blood levels of this drug. Tell your doctor if you smoke or if you have recently stopped smoking.

Is it safe to take oral clomipramine if I am pregnant or breastfeeding?

Clomipramine has not been adequately evaluated in pregnant women. Due to the lack of conclusive safety data, clomipramine should be used in pregnancy only if the benefit justifies the potential risk to the fetus.

Clomipramine is classified as pregnancy risk category C by food and drug administration. Clomipramine is excreted in human milk. Due to the lack of safety data, the use of clomipramine is not recommended in women who are breastfeeding.

Clomipramine overdose

Symptoms of an overdose may include: fast / irregular heartbeat, severe dizziness, fainting, delirium, seizures, loss of consciousness. If you miss a dose, take it as soon as you remember.

Laboratory and / or medical tests (eg, EKG, liver function tests, blood counts) may be done to monitor your progress or check for side effects.


Signs and symptoms vary in severity depending on factors such as the amount of drug absorbed, the age of the patient, and the time since ingestion of the drug.

Critical manifestations of an overdose include cardiac arrhythmias, severe hypotension, seizures, and central nervous system definition depression, including coma.

Changes in the electrocardiogram, particularly in the QRS axis or width, are clinically significant indicators of tricyclic toxicity.

In US clinical trials, 2 deaths occurred in 12 reported cases of acute overdose with Anafranil, either alone or in combination with other medications.

One death involved a patient suspected of ingesting a 7000 mg dose. The second death involved a patient suspected of ingesting a 5750 mg dose.


Liver test abnormalities have been reported in up to 16% of patients treated with tricyclic antidepressants, but elevations are exceptionally greater than 3 times the upper limit of normal.

Elevations in serum aminotransferase during clomipramine therapy are reported in 1% to 3% of patients, and abnormalities were generally mild, asymptomatic, and transient, reversing even with continuation of medication.

As with many tricyclic antidepressants, rare cases of clinically apparent acute liver damage have been reported in patients taking clomipramine.

The clinical features of clomipramine drug-induced liver disease cases have not been well defined.

Acute liver injury caused by tricyclic antidepressants usually occurs 1 to 4 weeks after starting the drug and presents with fatigue followed by dark urine and jaundice.

Both hepatocellular and cholestatic injury patterns have been described. The injury is generally mild to moderate in severity and recovery is rapid when the tricyclic is interrupted.

Immunoallergic features such as rash, fever, and eosinophilia are uncommon, and autoantibodies are generally not detected. Fatal cases are extremely rare. Likelihood score: D (possible rare cause of clinically apparent liver injury).

Mechanism of injury

The mechanism by which clomipramine causes elevated serum aminotransferase is not known. It undergoes extensive liver metabolism, and a possible cause of liver injury is the production of a toxic intermediate of metabolism that may be directly toxic or may induce a hypersensitivity reaction.

Result and management

The elevations in serum aminotransferase that occur with clomipramine therapy are generally self-limited and do not require dose modification or treatment interruption. Acute liver injury caused by clomipramine is usually self-limited and benign.

The results of re-exposure after acute clomipramine liver injury have not been reported, but re-exposure with tricyclic antidepressants usually causes early recurrence of liver injury which can be severe and therefore should be avoided.

Patients with clinically apparent clomipramine-induced liver injury may be cross-sensitive to other tricyclic antidepressants, but must be able to tolerate other antidepressants, phenothiazines, and atypical antipsychotics.


Tricyclic antidepressants were thought to work exclusively by inhibiting the reuptake of neurotransmitters norepinephrine and serotonin by nerve cells.

However, this response occurs immediately, but the mood does not rise for about two weeks.

Changes in receptor sensitivity are now thought to occur in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions.

Presynaptic receptors are affected: α1 and β1 receptors are sensitized, α2 receptors are desensitized (leading to increased norepinephrine production).

Tricyclics are also known as effective pain relievers for different types of pain, especially neuropathic or neuralgic pain.

Mechanism of action

Clomipramine is a strong serotonin reuptake inhibitor (SRI), but not completely selective, since the main active metabolite desmethylclomipramine preferably acts as a norepinephrine reuptake inhibitor.

Α1 receptor blockade and down-regulation have been observed and most likely play a role in the short-term effects of clomipramine.

A blockage of sodium channels and the N-methyl-D-aspartate (NMDA) receptor could, as occurs with other tricyclics, explain its effect on chronic pain, particularly the neuropathic type.