Clomipramine

Clomipramine (brand-name Anafranil®) is a tricyclic antidepressant. It was developed in the 1960s by the Swiss drug manufacturer Geigy (now known as Novartis) and has been in clinical use worldwide for decades.

Indications

 * Depression with lack of energy or mild agitation
 * Obsessive compulsive disorder (OCD)
 * Panic attacks with or without agoraphobia
 * Narcolepsy
 * Chronic pain with or without organic disease, particular headache of the tension type
 * enuresis (involuntary nightly urinating in sleep) in children and adolescents
 * Off label: sometimes antidepressants of this type have been found helpful in reducing relapses in cocaine addicts and to help repair cocaine-caused neurotransmitter imbalances and early brain damage. Further studies are needed for clomipramine in this regard.

It may take 2 to 3 weeks before the full effects of this medication are noticed in all indications.

Along with SSRIs, clomipramine is a frequently prescribed drug for the treatment of OCD. As is typical with the older tricyclic antidepressants, it has more side effects than SSRIs, so some authorities regard it as a second-line treatment to be used if treatment with SSRIs fails. However, disregarding side effects, it may be slightly more effective in combatting the symptoms of OCD. It is not commonly used for treating depression, and usually another tricyclic (or drug from a different class) would be used. Clomipramine and the SSRIs (specifically Paroxetine) have also been used to treat premature ejaculation.

Contraindications

 * Concomitant therapy with an (irreversible) MAO inhibitor (e.g. tranylcypromine, phenelzine)
 * Acute intoxication with central depressants (alcohol, psychoactive drugs, narcotics)
 * States of confusion (caution), absolutely contraindicated in patients with coma and delirium tremens
 * Patients with severe agitation or anxiety (give sedative drugs concomitantly)
 * Hypersensitivity/allergy against clomipramine or other related tricyclic compounds
 * Hypertrophy of the prostate with urine retention (=difficulty in urinating)
 * Caution: hypertrophy of the prostate without urine retention
 * Preexisting closed angle glaucoma
 * Epilepsy and other conditions which lower the seizure threshold (alcohol-withdrawal, active brain tumors)
 * Serious liver disease (elimination is decreased), if clomipramine is given consider dose reduction
 * Serious kidney disease (elimination is decreased), if clomipramine is given consider dose reduction
 * Severe hypotension, shock, serious cardiovascular dysfunction (postinfarctous states, heart insufficience, arrhythmias), avoid high oral doses or injections/infusions
 * Preexisting bone marrow depression (leukopenia, thrombocytopenia, anemia, pancytopenia), can be worsened by clomipramine
 * Hyperthyroidism (overfunction of the thyroid gland) makes the patient more sensitive to side effects of clomipramine. Cautious doses should be used and the overfunction should be treated.
 * Caution should be exerted when treating pediatric patients under 18 years of age

Pharmacology
Clomipramine is the 3-chloro derivative of imipramine. Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SSRI), as the primary active metabolite desmethylclomipramine acts preferably as norepinephrine reuptake inhibitor. Other hydroxy-metabolites are also active. α1 receptor blockage and beta receptor downregulation as well as postsynaptic antagonism on H1 receptors have been noted.

As with other tricyclics, downregulation of NMDA receptors may also account for its effects.

Clomipramine has the disadvantage of a higher incidence of seizures than seen with other tricyclic antidepressants (up to a dose of 250mg daily in 0,5%, more than 300 mg in 2%).

Some studies have indicated that clomipramine is slightly more effective in the treatment of depression than other tricyclics.

Side effects
Clomipramine may have a broad range of side effects:
 * central nervous system: Often, fatigue, dizziness, lightheadedness, headaches, confusion, agitation, insomnia, nightmares, increased anxiety, seizures (0,5% to 2%, see above), rarely hypomania or induction of schizophrenia (immediate termination of therapy required), and extrapyramidal side-effects (pseudoparkinsonism, dyskinesia, rarely tardive dyskinesia) are noted.
 * Anticholinergic side effects in different grades of severity are quite common: dry mouth, constipation, rarely ileus (paralysis of the large intestine, life-threatening), difficulties in urinating, sweating, precipitation of glaucoma (may lead to permanent eye-damage or even blindness, if untreated). The incidence of dental caries may be increased due to dry mouth.
 * antiadrenergic side effects occur very frequently due to strong central and peripheral blockage of alpha receptors: hypotension, postural collapse (when patient is rising too fast from lying or sitting position to standing), arrhythmias (sinus tachycardia, bradycardia, AV block, rarely other forms of cardiac problems). Preexisting heart insufficiency can be worsened.

Most of these side-effects are dose related and/or tolerance will develop with continued use.


 * Allergic/toxic: skin reactions and photosensitivity with increased frequency of sunburns are seen in a few percentage of cases. Rarely liver damage of the cholostatic type, hepatitis, and leukopenia or other forms of blood dyskrasia are seen, also severe acute allergy including difficulties in breathing, skin reaction, chest pain etc.
 * Other side effects may include heartburn, weight gain, but also nausea and bruxism - teeth-grinding while asleep - (the latter due to the strong inhibition of reuptake of serotonin).
 * The drug often causes sexual problems in men (e.g. impotence, ejaculation difficulties). In about 5% of patients, it can instead cause inadvertent orgasms when yawning.

Drug abuse and dependence
Clomipramine has no known potential for abuse and dependence. It is not a controlled substance.

Withdrawal symptoms occurring when clomipramine is stopped abruptly (agitation, fatigue, nausea, headaches, insomnia, sometimes activation of mania and rebound of depression or anxiety) is not indicative of dependence and can be avoided, if clomipramine is gradually withdrawn by reducing the daily dose by approximately 25% weekly. If medical reasons dictate an immediate termination of treatment, a short-term course of benzodiazepines (up to four weeks as needed) will usually suppress the unpleasant withdrawal symptoms.

Other reasons for caution
Depression itself can lead to thoughts or attempts of suicide. Emotionally unstable patients or those with suicidal thoughts should receive the smallest amount of the drug feasible. Often cotreatment with a sedative drug (e.g. a benzodiazepine or chlorprothixene) is necessary until remission of depression is evident.

Caution is advised when using clomipramine in the elderly, because they may be more sensitive to the effects of the drug (e.g., confusion may occur or worsen). Clomipramine should be used during pregnancy only if clearly needed. It is excreted into breast milk. The effects on the infant are not known at this time.

Drug interactions
Clomipramine shows a number of clinical significant interactions, either due to central depressant or stimulant activity of the other drug or due to interference of the other drug with the metabolization and elimination of clomipramine or vice versa. Some examples are:
 * MAO inhibitors (e.g., furazolidone, linezolid, phenelzine, selegiline, tranylcypromine): severe reactions including central excitation, hypertensive crisis, bizarre behaviour, psychosis, seizures, coma and death are possible. Serotonin syndrome is likely.
 * Central stimulants: Potentially dangerous central excitation with agitation and anxiety may be encountered.
 * SSRI type antidepressants (eg. fluoxetine): Side effects of clomipramine are increased.
 * Drugs with central depressant activity (tranquilizers, alcohol, narcotics): Increased central depression (dizziness, drowsiness etc.) is frequently noted.
 * Antihypertensive drugs: The risk of hypotension, collapse, and tachycardia is increased.
 * Interactions with OTC medications against colds and sleeping aids with diphenhydramine, doxylamine and St. John's wort may occur.

Dosage
Initial doses are usually 25 mg 2 or 3 times daily or 75 mg once daily in slow released form. The dose may be increased in regular intervals (the usual dose per day is 100 to 225 mg). Doses up to 300 mg may be used, but these are associated with an increased risk of seizures. This medication may be taken with food to prevent stomach upset.

In hospitalized patients initial intramuscular injections and very slow intravenous infusions can be used, but the risk of hypotension and seizures may be increased with parental drug use. The advantage is that the onset of action may be faster.

Usually, clomipramine needs some weeks to reach its maximum effects and needs to be given as longterm treatment, sometimes for life (narcolepsy). Sometimes, in patients with narcolepsy the full effect of clomipramine is not sufficient. In these cases treatment with clomipramine should be terminated gradually and a commonly used central stimulant (e.g. modafinil, methylphenidate or methamphetamine) tried instead.

Clomipramine is not able to elevate the mood of non-depressive persons and any unindicated use may be dangerous.

Overdose
If overdose is suspected, contact your local poison control center or emergency room immediately. United States residents can call the US national poison hotline at 1-800-222-1222. Other worldwide poison centers can be found at the World directory of poisons centers

Ten out of 12 patients presenting with manifest clomipramine overdose survived with appropriate treatment. These 10 patients took clomipramine doses of up to 5 grams. The 2 patients who died ingested 5.75 and 7 grams, respectively. Outside the US one patient died who took only 0.75 grams. Lethal doses may be lower, if other drugs have been taken in an overdose, too, particular central nervous depressants.

The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.

Veterinary uses
Clomipramine is widely used for the treatment of disturbed behaviour of dogs, cats, and horses. Marketed by Novartis for veterinary use under the name 'Clomicalm', clomipramine is given orally and is indicated for:

"Treatment of stereotypic behaviours (obsessive-compulsive disorders) in dogs such as acral lick dermatitis, excessive grooming and tail chasing. An aid in the treatment of anxiety disorders in dogs such as destructiveness, excessive vocalisation, loss of toilet control, associated with separation anxiety. An aid in the treatment of urine spraying in desexed and female cats." (Product Information for Clomicalm, Novartis Animal Health Australasia Pty Limited).

Brands

 * Anafranil® registered TM of Mallinckrodt in the United States
 * Anafranil® registered TM of Novartis, sold worldwide
 * generics