Clomipramine

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Definition

Clomipramine is an antidepressant drug used primarily to alleviate obsessions and compulsions in patients with obsessive-compulsive disorder . Clomipramine is also used in the treatment of depressive disorders and in a number of other psychiatric and medical conditions. In the United States, the drug has also been known by the brand name Anafranil.

Purpose

Clomipramine is principally used in the treatment of the obsessions and compulsions of obsessive-compulsive disorder (OCD), when these symptoms greatly disrupt the patient's daily activities. Obsessions are repetitive thoughts and impulses, and compulsions are repetitive behaviors. Patients with OCD find these experiences inappropriate, distressing, and time-consuming.

Clomipramine may also be used in the treatment of depressive disorders, especially when associated with obsessions and compulsions, in panic disorder , pain management, sleep attacks ( narcolepsy and cataplexy), and anorexia nervosa . The drug may help to reduce compulsive behaviors in a variety of disorders with such symptoms, including trichotillomania (hair-pulling), onychophagia (nail-biting), Tourette's disorder (tics and vocalizations), and childhood autism .

Description

Clomipramine is one of the tricyclic antidepressants, so-called because of the three-ring chemical structure common to these drugs. In the 1940s and 1950s, pharmaceutical researchers synthesized a number of new compounds for possible medical use as antihistamines and sedatives. After testing in animal experiments, a few of these substances were selected for human study. One potential drug, a tricyclic compound called imipramine , was not useful in calming agitation, but it had a striking effect in improving the mood of certain patients with depression.

Since the discovery of imipramine, many other tricyclic antidepressants have been developed with somewhat differing pharmacological activities and side effect profiles. Within this group of drugs, clomipramine is exceptionally potent in affecting levels of serotonin in the brain . In this action, it is similar to serotonin-selective antidepressant drugs, like fluoxetine (Prozac), which act specifically on serotonin levels and are effective in OCD. Serotonin is a messenger chemical (neurotransmitter) involved in transmitting signals between nerve cells. Clomipramine reduces the effects on serotonin neurotransmission in depression and OCD symptoms.

Recommended dosage

For adults, clomipramine is administered in dosages up to a maximum of 250 mg per day. Starting with a dose of 25 mg, the dosage is increased during the first two weeks to 100 mg per day. If needed, it is further increased gradually over the next several weeks. The initial dose is low to avoid side effects, and it is increased slowly to permit the patient to develop tolerance or adapt to side effects that may occur.

Older patients (over age 65), children, and adolescents are more sensitive to the side effects and toxicities of tricyclic antidepressants such as clomipramine. The maximum daily dose is usually lower for elderly patients than younger adults. For children and adolescents, the maximum recommended daily dose is the lesser of 100 mg or 3 mg per kg of body weight.

Precautions

Epileptic seizures are the most important risk associated with clomipramine. Among patients taking the drug for six months or more, more than 1% may experience seizures. The risk of seizure increases with larger doses, and seizures have been reported to occur following abrupt discontinuation of the medication. Caution and physician supervision is required if the patient has a history of epilepsy or some other condition associated with seizures, such as brain damage or alcoholism.

Clomipramine and other tricyclic antidepressants often cause drowsiness. Activities requiring alertness, such as driving, should be avoided until patients understand how the drug affects them. Dizziness or light-headedness may occur on arising from a seated position, due to sudden decreases in blood pressure. Fainting may also occur. Some patients, especially men with prostate enlargement, may experience difficulty urinating. Glaucoma may be worsened. Sensitivity to ultraviolet light may increase, and sunburns may occur more easily.

Tricyclic antidepressants, including clomipramine, should be used with caution and physician supervision in patients with heart disease, because of the possibility of adverse effects on heart rhythm. Adverse effects on the heart occur frequently when tricyclics are taken in overdose. Only small quantities of these drugs should be given to patients who may be suicidal.

Tricyclic antidepressants may cause dry mouth, due to decreased saliva, possibly contributing to the development of tooth decay, gum disease, and mouth infections. Patients should avoid sweets, sugary beverages, and chewing gum containing sugar.

It has not been determined whether clomipramine is safe to take during pregnancy, and the patient's need for this medicine should be balanced against the possibility of harm to the fetus. Tricyclic antidepressants may be secreted in breast milk and may cause sedation and depress breathing of a nursing infant.

Side effects

Clomipramine may cause many side effects. Initially, the side effects of tricyclic drugs may be more pronounced, but sensitivity often decreases with continued treatment.

The following more common side effects are grouped by the body system affected:

Cardiovascular: decreases of blood pressure on arising, which may cause dizziness or fainting, increases of blood pressure, rapid heart rate, pounding heart, altered heart rhythm.
Nervous system: sedation, dizziness, headache, confusion, nervousness, restlessness, sleep difficulties, numbness, tingling sensations, tremors, twitches, increased seizure tendency.
Digestive system: dry mouth, nausea, loss of appetite, indigestion, and constipation.
Autonomic: blurred vision, increased sweating.
Genital/urinary: difficulty urinating, menstrual pain, ejaculatory difficulty, impotence, decreased sex drive.
Skin: rashes, sensitivity to sunlight.
Body as a whole: fatigue , weight gain, flushing.

Less commonly, tricyclic drugs may cause adverse effects on almost any organ or system of the body, particularly the blood, hormones, kidney, and liver. Patients should consult their physicians if symptoms develop or bodily changes appear.

Interactions

Tricyclic antidepressants, such as clomipramine, may interact with many other drugs. Patients should inform their physicians about all other drugs they are taking before starting treatment.

Clomipramine may intensify the effects of other drugs that act on serotonin levels, possibly producing serotonin syndrome, a rare but dangerous condition with fever, sweating, tremors, and changes in mental state. Drugs that may interact this way include other antidepressants, especially selective serotonin re-uptake inhibitor (SSRI) drugs and monoamine oxidase (MAO) inhibitors. These drugs should not be taken within two weeks of taking clomipramine. Other drugs to avoid include lithium, alprazolam (Xanax), fenfluramine (Pondimin), amphetamine, dextromethorphan (used in cough suppressants), meperidine (Demerol), and tramadol (Ultram).

Tricyclic drugs may intensify the effects of other drugs causing sedation, including alcohol, barbiturates , narcotic pain medications, minor tranquilizers, and antihistamines. Tricyclics may cause excessive reductions of blood pressure in patients taking blood pressure medicine, especially on arising or standing up. Conversely, these drugs may interfere with the pressure-reducing effects of certain other blood pressure medicines and may necessitate an adjustment in dosage. Tricyclics may interact with thyroid medications to produce abnormalities of heart rhythm. Concurrent use of tricyclic antidepressants with other psychiatric medicines may result in intensification of certain side effects.

Certain drugs may interfere with the elimination of tricyclic antidepressants from the body, causing higher blood levels and increased side effects. This effect may occur with cimetidine (Tagamet), other antidepressants, methylphenidate (Ritalin, Concerta), and some antipsychotic medications.

Resources

BOOKS

American Society of Health-System Pharmacists, Inc. AHFS Drug Information, edited by Gerald K. McEvoy, Pharm.D. Bethesda, MD: American Society of Health-System Pharmacists, Inc., 2001.

Hardman, Joel G., Alfred Goodman Gilman, Lee E. Limbird, editors. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill, 1996.

Medical Economics staff. Physicians' Desk Reference. 53rd ed. Montvale, NJ: Medical Economics Company, Inc., 1999.

Nissen, David, ed. Mosby's GenRx. 11th ed. St. Louis: Mosby, Inc., 2001.

The United States Pharmacopeial Convention, Inc. USP DI(r) Volume I– Drug Information for the Health Care Professional. 21st ed. Englewood, CO: Micromedex, Inc., 2001.

The United States Pharmacopeial Convention, Inc. USP DI(r) Volume II– Advice for the Patient. 21st ed. Englewood, CO: Micromedex, Inc., 2001.

Richard Kapit, M.D.