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Clomipramine - Uses, Mechanism of Action, Precautions, and Side Effects

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Clomipramine is a class of drugs that is used to treat obsessive-compulsive disorder. The article explains the drug in detail.

Medically reviewed by

Dr. Muntaqa Butt

Published At November 15, 2022
Reviewed AtJuly 17, 2023

Overview:

Clomipramine is a type of tricyclic antidepressant that is used in treating obsessive-compulsive disorder (OCD), such as repeated thoughts, actions, and disorders with an obsessive-compulsive component, such as depression, schizophrenia and Tourette's disorder. Clomipramine is used in adults and children more than ten years old.

How Does Clomipramine Work?

Clomipramine belongs to a group of drugs known as antidepressants and works as an anti-obsessive agent. Clomipramine works by decreasing obsessions and compulsions. The mode of action could be more explicit. However, it is thought to work by increasing the activity of some chemical substances in the brain known as norepinephrine and serotonin. These chemical substances help in regulating mood and behavior.

Uses of Clomipramine:

Clomipramine is indicated in -

  • Treating obsessive-compulsive disorder (OCD).

  • Depression.

  • Panic disorder.

  • Chronic pain.

  • Cataplexy - Cataplexy is a sudden weakness of muscles occurring while the individual is awake.

  • Narcolepsy - Narcolepsy is a sleep disorder causing drowsiness in the daytime.

  • Autistic disorder.

  • Trichotillomania - This condition in which the patient tends to pull one's hair.

  • Premenstrual syndrome.

Limitations:

Clomipramine toxicity occurs with doses over 300 mg per day. It can also occur if the patient takes the drug with MAOI, S-RI, or drugs inhibiting CYP450 2D6.

Dosage Restrictions:

1. Route of Administration - Oral.

2. Dosage Strengths -

  • 25 mg.

  • 50 mg.

  • 75 mg

3. Dosage Forms -

Capsules with an ivory body printed with "M" in black.

Special Considerations:

  • Pregnancy - Clomipramine should be used during pregnancy only if the advantage justifies the risk to the fetus. Withdrawal symptoms such as nervousness, tremor, and seizures have been reported in infants whose mothers took Clomipramine until delivery.

  • Breastfeeding - Clomipramine has been found in the milk of nursing mothers. It might cause side effects in the infant. The decision to discontinue the drug or discontinue breastfeeding should be made while considering the importance of the medicine to the mother.

  • Pediatric - The effectiveness of Clomipramine in kids younger than ten years of age has not been established.

  • Geriatric - The dose selection for the elderly should be carefully made, usually beginning at the lower end of the dosage. Clomipramine is associated with significant hyponatremia in elderly patients.

Warnings and Contraindications:

Clomipramine has been contraindicated in -

  • Patients with a history of hypersensitivity to the drug or other tricyclic antidepressants.

  • Monoamine Oxidase Inhibitors (MAOIs) - The use of monoamine oxidase inhibitors to treat psychiatric disorders with Clomipramine or within 14 days of stopping treatment with Clomipramine is contraindication because of the risk of serotonin syndrome. Beginning Clomipramine in patients treated with Linezolid or intravenous Methylene blue is also not indicated because of the increased risk of developing serotonin syndrome.

  • Myocardial Infarction - Clomipramine is contraindicated during the recovery phase after myocardial infarction.

Warnings and Precautions:

1) Black Box Warnings -

Antidepressants have been found to increase the risk of suicidal behavior in kids, adolescents, and young adults who take antidepressants for major depressive disorders and other psychiatric conditions. Therefore, in children and young adults, the risks should be assessed against the benefits of taking antidepressants.

The patients should be closely monitored during the initial one to two months of antidepressant therapy for any changes in their behavior, such as suicidal tendencies.

The patient's family should tell them about the patient's behavior changes to the doctor.

An increase in suicidal tendencies or behavior that are not a part of the existing symptoms might require discontinuation of the antidepressant therapy.

2) Serotonin Syndrome - The development of serotonin syndrome has been found with Clomipramine alone but with concomitant use of other serotonergic drugs. Serotonin syndrome symptoms include agitation, hallucinations, delirium, coma, tachycardia, dizziness, diaphoresis, hyperthermia, tremor, rigidity, incoordination, nausea, vomiting, and diarrhea.

3) Angle-closure Glaucoma - Clomipramine can cause pupillary dilation and might trigger an angle closure attack in a patient with narrow eye angles.

4) Seizures - Seizures are the most critical risk of Clomipramine use.

5) Drug Rash With Eosinophilia and Systemic Symptoms (DRESS) - DRESS has been reported using Clomipramine. The drug should be discontinued immediately in case of a severe reaction to DRESS.

Precautions:

  • Suicide - Suicidal tendencies should be considered while prescribing Clomipramine. The smallest drug quantity should be prescribed to decrease the risk of overdose.

  • Cardiovascular Effects - Precaution should be taken in treating patients with cardiovascular diseases, and the dose can be gradually changed.

  • Psychosis and Other Neuropsychiatric Phenomenon - Patients treated with Clomipramine have shown various neuropsychiatric changes such as delusions, hallucinations, paranoia, and the like.

  • Mania or Hypomania - Mania or hypomania has been reported in patients with affective disorders treated with tricyclic antidepressants such as Clomipramine.

  • Hepatic Changes - Clomipramine has been found to increase SGOT and SGPT levels.

  • Hematological Changes - Leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia are associated with the use of Clomipramine.

  • Central Nervous System - Most central nervous system involvement is seen when Clomipramine is used with other drugs.

  • Sexual Dysfunction - The rate of sexual dysfunction in patients treated with Clomipramine has been found to increase manifold.

For Patients:

What Is Obsessive Compulsive Disorder (OCD)?

Obsessive-compulsive disorder is a chronic, long-lasting pattern of thoughts and obsessions that lead one to do repetitive behaviors. Individuals with OCD might have symptoms of obsessions, compulsions, or both. These obsessions and compulsions can interfere with day-to-day activities, causing stress.

Why Is Clomipramine Prescribed for Obsessive Compulsive Disorder?

Clomipramine is prescribed to treat people with obsessive-compulsive disorders. Clomipramine belongs to a group of medications called tricyclic antidepressants that increase the amount of a substance in the brain required to maintain mental stability, known as serotonin.

Facts One Should Know About Clomipramine:

Clomipramine comes in capsules of 25 mg, 50 mg, and 75 mg strength. It is used to treat excessively repeated thoughts and impulses of obsessive-compulsive disorder.

How Should One Take Clomipramine?

Clomipramine is taken orally with or without food. To reduce the side effects like stomach upset, the drug might be started at a lower dose, in several meals, and gradually increased as the body gets adjusted. After a few weeks, Clomipramine can be taken once a day during bedtime. The medication should be taken exactly as prescribed by the doctor.

What Should One Discuss With the Doctor Before Beginning Clomipramine?

Before starting Clomipramine, the doctor should be informed about -

  • Any allergy to Clomipramine or any other tricyclic antidepressants.

  • If one takes monoamine oxidase inhibitors (MAO) such as Isocarboxazid, Linezolid, Methylene Blue, Phenelzine, and the like or has stopped taking MAO within the past 14 days.

  • The prescription or non-prescription medications, vitamins, nutritional supplements, and herbal medicines one takes. Specifically mention blood thinners like Warfarin, Benztropine, Cimetidine, Clonidine, Dicyclomine, oral contraceptives, and the like.

  • Any recent episode of a heart attack.

  • In case one is getting treated with electroshock therapy, drinks or has drunk a large quantity of alcohol, has had seizures, has brain damage, has problems with the urinary system or prostate, irregular heartbeat, blood pressure problems, thyroid problems, or heart, liver, or kidney disease.

  • If one is pregnant, plans to conceive, or is breastfeeding.

  • If one is over 65 years of age, the risk and benefits of using Clomipramine should be discussed with the doctor.

  • In case of any surgery, including dental surgery, the doctor should be informed about the intake of Clomipramine.

  • One should understand that the medication can make one drowsy, that might increase the risk of getting a seizure. Therefore, do not drive a car or operate machines while on medication.

  • In the case of the use of tobacco products, the doctor should be informed. This is because smoking can decrease the effectiveness of the drug.

  • The doctor should be contacted if one has nausea, eye pain, vision changes, swelling, or redness.

Is Clomipramine Safe?

Clomipramine might affect the heart rhythm, which can cause severe, faster, irregular heartbeats and symptoms like dizziness and fainting. Therefore, the elderly should take the medication with caution.

Is Clomipramine Effective?

Clomipramine is more effective in treating obsessive-compulsive disorder than other medications like Sertraline, Fluoxetine, and Fluvoxamine.

What Side Effects Can One Expect With Clomipramine?

The common side effects include -

  • Drowsiness.

  • Dry mouth.

  • Vomiting.

  • Nausea.

  • Diarrhea.

  • Constipation.

  • Nervousness.

  • Sexual dysfunction.

  • A decrease in memory or concentration.

  • Headache.

  • Blocked nose.

  • Weight and appetite change.

Some serious side effects include -

  • Uncontrolled shaking of a body part.

  • Seizures.

  • An irregular, fast heartbeat.

  • Difficulty in urination.

  • Hallucinations.

  • Tremors.

  • Difficulty in breathing.

  • Severe muscle stiffness.

  • Unusual fatigue.

  • Signs of infection such as sore throat and fever.

Can One Stop Taking Clomipramine Without the Doctor's Approval?

Clomipramine should not be stopped without the doctor's consent. On sudden stoppage of the drug, one might experience withdrawal symptoms such as dizziness, nausea, vomiting, headache, fatigue, problems with sleep, fever, and irritability.

Are There Any Dietary Restrictions to Consider When Taking Clomipramine?

One should avoid grapefruit or drinking grapefruit juice while on the drug unless the doctor advises otherwise.

How Should One Store Clomipramine?

Clomipramine capsules should be stored at 20 to 25 degrees Celsius temperature. It should be dispensed in properly closed containers with child-resistant packaging. In addition, Clomipramine should be protected from moisture.

How Should One Dispose of Clomipramine?

Clomipramine should not be thrown in the toilet or drain. Instead, the medication should be properly discarded by consulting the pharmacist or the local waste disposal company once it expires.

What To Do in Case of Overdose?

In case of an overdose, the poison control helpline should be immediately called. If the person has collapsed, had a seizure, troubled breathing, or is unconscious, the emergency services should be informed as soon as possible.

For Doctors:

Indications - Clomipramine is primarily used in treating obsessive-compulsive disorder in ten years and above. Other indications include the following -

  • Depression.

  • Anxiety.

  • Treatment-resistant depression.

  • Cataplexy syndrome.

  • Insomnia.

  • Neuropathic pain.

  • Chronic pain.

  • Body dysmorphic disorder.

  • Panic disorder.

  • Premature ejaculation.

  • Pediatric nocturnal enuresis.

  • Trichotillomania.

What Is the Pharmacology of Clomipramine?

Description

Clomipramine, or the 3-chloro analog of Imipramine, is a dibenzazepine-derivative tricyclic antidepressant (TCA). Tricyclic antidepressants are structurally the same as Phenothiazines. They also have a tricyclic ring with an alkyl amine substituent on the central ring. The average weight of Clomipramine is 314.852.

Components

1. Active Ingredients- Clomipramine hydrochloride.

2. Inactive Ingredients -

  • D and C red number 33 (25 mg capsules).
  • D and C are yellow numbers 10.
  • FD and C blue number 1 (50 mg capsules).
  • FD and C yellow number 6.
  • Gelatin.
  • Magnesium stearate.
  • Methylparaben.
  • Propylparaben.
  • Scratch (corn).
  • Titanium dioxide.

Clinical Pharmacology:

Mechanism of Action -

Clomipramine is a tertiary amine that belongs to a group of medications known as tricyclic antidepressants. It is a dibenzazepine tricyclic antidepressant. Clomipramine is a serotonin-reuptake inhibitor with a stronger liking for the serotonin transporter than the other tricyclic antidepressants and serotonin-reuptake inhibitors. Clomipramine increased serotonergic and noradrenergic transmissions.

Pharmacodynamics -

Clomipramine is thought to influence obsessive-compulsive traits through its effects on serotonergic neuronal transmission. The exact neurochemical mechanism is not known. However, Clomipramine's capacity to inhibit serotonin reuptake (5-HT) is considered significant. Recently it has been found that the changes occur in the cerebral cortex and hippocampus. Presynaptic receptors, alpha 1, and beta one receptors are sensitized, whereas alpha two receptors are desensitized, thus increasing the production of noradrenaline.

Pharmacokinetics-

  • Mean Cmax - 16 to 310 ng/mL.

  • Median Tmax - 0.73 to 3.1 hours.

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose]

[Tmax- Time taken for a drug to reach maximum concentration after administration of a dose]

  • Pharmacokinetic Changes - Clomipramine is bioavailable in the capsules and is not affected by the presence of food.

A. Distribution-

  • Steady-state Plasma Levels - 100 to 250 ng/mL (parent drug) and 230 to 550 ng/mL (metabolite).

  • Time to Approach Steady-state Levels - One to two weeks following multiple-dose oral administration.

  • Binding to Plasma Proteins - 97 to 98 %.

B. Metabolism -

The metabolism of Clomipramine takes place in the liver via oxidation by CTP450 2D6. The half-life of Clomipramine is 17 to 28 hours. Clomipramine is then metabolized to the steady-state active metabolite desmethyl Clomipramine by CYP450 1A2.

C. Excretion -

  • Recovery of Clomipramine - 60 % recovered in urine, and 32 % recovered in the feces.

D. Elimination - After administration of a single dose of 150 mg of Clomipramine, the elimination half-life was 32 hours, and desmethylclomipramine was 69 hours. Elimination half-life might change with different doses because of the metabolism.

Special Considerations:

  • Pregnancy: Clomipramine is a category C pregnancy drug, meaning it has been found to cause adverse effects to the fetus if the mother takes the medication.

  • Breastfeeding - Clomipramine tends to pass into the breastmilk, causing side effects to the breastfed infant.

  • Geriatric Use - Careful dose selection for elderly patients is needed as their kidneys might not work as they used to, causing the body to process the drugs very slowly. Due to this, the medication remains in the body of the elderly patient for a longer time, thereby increasing the risk of side effects.

  • Pediatric - Clomipramine should not be administered to kids younger than ten.

Drug Interactions:

  • 1,2 - Benzodiazepine - The risk of side effects has been found to increase when Clomipramine is combined with 1,2 - Benzodiazepine.

  • Aceclofenac - There is an increased risk of gastrointestinal bleeding when Clomipramine is combined with Aceclofenac.

  • Acebutolol - A decrease in the metabolism of Clomipramine has been reported when taken with Acebutolol.

What Have Clinical Trials Shown About Clomipramine?

A randomized, double-blind, placebo-controlled trial of intravenous versus oral use of Clomipramine was conducted in individuals with obsessive-compulsive disorder to test the following hypothesis -

  • Intravenous use will cause more significant and immediate improvement than oral use.

  • Individuals responding well to pulse loading will continue to improve in the eight weeks of orally administered Clomipramine treatment.

Results

The first hypothesis was confirmed 4.5 days after administering the sec and pulse-loaded dose. Six out of seven individuals were given intravenous Clomipramine, but only one out of eight patients who were given the medication orally responded to the drug.

After eight weeks of orally administered Clomipramine therapy, the results supported the second hypothesis. However, four out of six patients who responded to the pulse loading did not show much improvement than those who had not.

Patient Counseling Information:

The patient and their families should be informed about the benefits and risks of Clomipramine use and counseled on its proper usage. The healthcare provider should advise the patient and their caretakers to go through the patient medication guide about, 'antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions. The patients should clarify any doubt regarding the guide with the doctor. The patients should be asked to report to their healthcare provider in case of any side effects after taking Clomipramine.

Administration Instructions:

  • Clomipramine should be taken orally as per the doctor's instructions. It is available in capsule form, with 25 mg, 50 mg, and 75 mg.

  • The starting dose is 25 mg per day which is gradually increased. Clomipramine can be given in single or split doses. However, the patients should be advised to take the medication with food as it can lead to gastrointestinal irritation.

  • Clomipramine begins to show effect between six to twelve weeks.

  • It should not be stopped without the doctor's consent, as it can lead to withdrawal symptoms.

Complications or Side Effects:

The common side effects include

  • Nausea.

  • Weight gain.

  • Increased appetite.

  • Sedation.

  • Low blood pressure.

  • Anxiety.

  • Restlessness.

  • Sexual dysfunction.

  • Sweating.

  • Bluish-green urine.

  • Arrhythmia.

  • Tachycardia.

  • Orthostasis.

  • Seizures.

  • Paralysis.

  • Liver failure.

  • Increased eye pressure.

  • Mania.

  • Suicidal tendency.

Frequently Asked Questions

1.

What Is Clomipramine Used For, and Is It a Sleeping Pill?

Clomipramine is a medicine used in treating a clinical condition called obsessive-compulsive disorder (OCD), where the patient shows symptoms of nervousness that causes people to calm down, causing drowsiness. 

2.

Is Clomipramine a Potent Antidepressant And a Sedative?

Clomipramine is a highly efficient antidepressant to drugs like Sertraline, Fluvoxamine, and Fluoxetine. It is a tricyclic antidepressant that causes sedation.

3.

Can Clomipramine Stabilize Mood and Calm Anxiety?

Clomipramine, when tested on patients with anxiety, is known to calm the mind and cause mood stabilization. It works by causing stability by restoring a balance in the brain enzymes like serotonin.

4.

What Are the Effects of Clomipramine on the Brain?

The effects of Clomipramine on the brain are:
- Calms the mind.
- Balances the brain hormones.
- Increases the efficacy of serotonin.
- Brings a sedative effect.

5.

Do Clomipramine Have Side Effects on Memory?

On long-term use of Clomipramine drug, the body does tend to show certain side effects on memory, and they are:
- Disorder in the sleep cycle.
- Clouded memory.
- Anxiety.
- Tinnitus.

6.

Does Clomipramine Have a Better Effect Than Ssri?

Yes, Clomipramine is more efficient than SSRI groups of drugs. Still, however, the adverse drug reactions of Clomipramine are comparatively more frequent, like dry mouth, dizziness, etc., when taken at higher doses.

7.

How Should You Avoid Taking Clomipramine?

Patients with the following health conditions should avoid Clomipramine, and they are:
- Neuroblastoma.
- Major depressive disorder.
- Alcoholic patients.
- Serotonin syndrome
- Patients are having suicidal thoughts etc.

8.

Can Clomipramine Cause Addiction?

No Clomipramine is a drug that is not considered an addictive drug, but sudden discontinuation may cause potential withdrawal symptoms, so abrupt discontinuation of the drug should be avoided.

9.

Why Is It Important To Take Clomipramine at Night?

As Clomipramine causes prominent drowsiness making the patient feel more sleepy, disoriented, and cloudy-minded, it is more advisable to take this at night than in the daytime.

10.

What Are the Symptoms of Clomipramine?

The clinical symptoms of Clomipramine are:
- Nausea.
- Dry mouth.
- Vomiting.
- Drowsiness.
- Constipation.
- Decreased sexual drive.

11.

What Are the Drugs That Function Similar to Clomipramine?

The drugs that are similar in function to that Clomipramine are:
- Fluoxetine.
- Fluvoxamine.
- Citalopram.
- Sertraline. 
- Paroxetine.
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Dr. Muntaqa Butt
Dr. Muntaqa Butt

General Practitioner

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