Systematic (IUPAC) name
Clinical data
Trade names Anafranil
AHFS/ monograph
MedlinePlus a697002
Pregnancy cat. C (U.S.)[1]
May cause withdrawal symptoms in newborn.
Legal status Prescription only
Routes Oral, IM, IV
Pharmacokinetic data
Bioavailability Oral ~50%
Metabolism Hepatic
Half-life Clomipramine ~35 hours
Desmethylclomipramine (main active metabolite) ~50 hours
Excretion Renal
CAS number 303-49-1 YesY
ATC code N06AA04
PubChem CID 2801
IUPHAR ligand 2398
DrugBank APRD00253
ChemSpider 2699 YesY
KEGG D07727 YesY
ChEBI CHEBI:47780 YesY
Chemical data
Formula C19H23ClN2 
Mol. mass 314.9 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Clomipramine (Anafranil) is a tricyclic antidepressant (TCA). It was developed in the 1960s by the Swiss drug manufacturer Geigy (now known as Novartis) and has been in clinical use worldwide ever since.



Clomipramine had been used experimentally to reduce relapses in cocaine addicts, and to repair neurotransmitter damage caused by cocaine; however, further studies are needed in this area. Clomipramine has also been used experimentally to treat dogs with severe anxiety disorders (separation anxiety, etc.), OCD, or cognitive dysfunction syndrome.[citation needed]

It may take two to three weeks before the full effects of this medication are noticed in most indications and two months or more in OCD.

Along with SSRIs, clomipramine is a frequently prescribed drug for the treatment of OCD. As is typical with the older tricyclic antidepressants (the tertiary amines), 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 combating 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.


  • 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
  • Pre-existing 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
  • Pre-existing 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


Clomipramine is the 3-chlorinated derivative of imipramine.


Clomipramine is a blocker of the following transporters:[4]

As well as an antagonist/inverse agonist at the following receptors:[4][5][6][7]

All affinities listed were assayed using human materials except those for 5-HT3, 5-HT6, and 5-HT7 which are for mouse/rat tissues due to human values being unavailable.[4][5][6][7] Though it is unclear whether it has ever been screened, clomipramine may also act on sigma receptors and calcium, potassium, and sodium channels similarly to other TCAs.

Clomipramine possesses the highest in vitro affinity for the SERT of any of the TCAs. While its affinities for sites other than SERT are almost all over 100-fold lower in comparison, clomipramine is used at relatively high doses (25–300 mg) similar to those employed with other TCAs; hence, at clinical doses clomipramine is not a selective serotonin reuptake inhibitor (SSRI) but instead a very, very strong serotonin reuptake inhibitor with additional norepinephrine reuptake inhibitor, antiserotonergic, antiadrenergic, antidopaminergic, antihistamine, and anticholinergic properties and associated side effects. Clomipramine's affinity for the DAT is very low/negligible and it therefore lacks any significant dopamine reuptake inhibitor actions.

It should also be noted that clomipramine's active metabolite desmethylclomipramine is a much more potent norepinephrine reuptake inhibitor than clomipramine itself. As a result, in vivo clomipramine is more balanced of a serotonin-norepinephrine reuptake inhibitor, though with preferential serotonergic actions nonetheless.

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 below), 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). Pre-existing 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 loss, 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.[8]

Clomipramine has the disadvantage of a higher incidence of seizures than seen with other TCAs (up to a dose of 250 mg daily in 0.5%, more than 300 mg in 2%).[citation needed]

Drug abuse and addiction

Clomipramine has no known potential for addiction or abuse; it is not known to be a controlled substance in any jurisdiction where it is available.

Although clomipramine is not an abusable or controlled substance, physical dependence can develop. Upon abrupt termination of treatment, this may lead to what is known either as discontinuation syndrome of the TCA type or as tricyclic antidepressant withdrawal. Signs of this occurring may include agitation, fatigue, nausea, headaches, insomnia, activation of mania and rebound of depression or anxiety. This unpleasant, but temporary and nonlethal, condition can be successfully averted if the daily dose of clomipramine is gradually reduced by approximately 25 per cent. each week. If immediate discontinuation is required for medical reasons, a short-term (up to four weeks, pro re nata) course of any minor tranquiliser will generally minimise any withdrawal symptoms, although only the benzodiazepines are in common clinical use in the United Kingdom for this indication.

Minor tranquilisers sold today
  • Benzodiazepines, such as chlordiazepoxide — most widely used since 1960s for this and similar indications
  • Aldehydes (limited to paraldehyde and trichloroacetaldehyde monohydrate) — usually for paediatric and geriatric patients
  • Z-drugs, such as zaleplon, zopiclone, and zolpidem — briefly popular in the late 1990s and early 2000s
  • Barbiturates, such as Amytal — used somewhat less than formerly due to danger in overdose, but still on shelves
  • Chlormethiazole (Heminevrin)
  • Ethanol (drinking alcohol) — almost never used, but is equivalent in action profile to benzodiazepines and barbiturates so can be used theoretically in their stead
  • Typical antihistamines, such as diphenhydramine and hydroxyzine

It may be noted that, because of either a) addiction and dependence or b) toxicity issues, certain classes of minor tranquilisers no longer remain on the market in the United Kingdom or in Canada, and so can not be used for any indication, including the management of antidepressant discontinuation syndrome. One of the most prolific classes of drugs so banned are the quinazolinone sedatives (the former gold standard being methaqualone); similarly, the drug methylpentynol was also taken off the shelves.

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 (e.g. 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.


Initial doses are usually 25 mg two or three 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 parenteral 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 long-term treatment, sometimes for life (narcolepsy). In cases of narcolepsy, antidepressant compounds like clomipramine are used to manage symptoms of cataplexy, which usually manifests as sleep paralysis (the inability to move skeletal muscles upon waking from REM sleep). In most patients with narcolepsy, clomipramine monotherapy is not sufficient to control non-cataleptic symptoms, such as excessive daytime fatigue and sleep attacks. In these cases, a commonly used CNS stimulant medication (e.g. modafinil, dextroamphetamine or methylphenidate) is used in lieu of, or in addition to, a tricyclic antidepressant like clomipramine. Concomitant use of a psychostimulant medication and an antidepressant is common in narcolepsy. Other antidepressants used to help control cataplexy include desipramine, protriptyline and venlafaxine.

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


If overdose is suspected, medical authorities recommend contacting the local poison control center or emergency room/A&E immediately. Other worldwide poison centers can be found at the World directory of poison 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 two 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, particularly central nervous system depressants.[citation needed]

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

Augmenting Clomipramine with Fluvoxamine

Clomipramine is typically metabolized to desmethyl-clomipramine by CYP450 1A2. Desmethyl-clomipramine is an NRI. While combining SSRIs and tricyclic antidepressants is risky, fluvoxamine, an inhibitor of CYP450 1A2, could be added to clomipramine to preserve more of the molecule in the original state, which is more serotonergic, thus creating a powerful synergy.[9]

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 has different licensed uses in different countries.

In the US, clomipramine is currently only licensed to treat separation anxiety in dogs.[10] However it is often prescribed in off-label use for many other conditions including other anxiety disorders, phobias (noise phobia in dogs, et al.), obsessive-compulsive disorders (tail chasing, excessive grooming, et al.), and "mood" problems. It has also been used in older dogs suffering from canine cognitive dysfunction (CCD) or canine cognitive dysfunction syndrome (CDS or CCDS), though it is important to note that unlike Anipryl clomipramine is not thought to reverse the condition by increasing dopamine levels in the brain to improve function; it only "treats the symptoms" so to speak and only those related to anxiety to make the dog feel more relaxed and calmer.

The UK license is restricted to the drug being used:

"As an aid in the treatment of separation-related disorders in dogs manifested by destruction and inappropriate elimination (defecation and urination) and only in combination with behavioural modification techniques."

In Australia the license is broader:

"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


Off-label use: If a drug is used outside of its license in a given country, this constitutes "off-label" use. For example, use of clomipramine in urine spraying cats would be off-label in the UK, but within the Australian license. This is important because legal restrictions on the off-label use of drugs apply nationally, and must be considered when using such drugs in a given problem in a particular species. Clomipramine has been used for cognitive dysfunction syndrome to alleviate anxiety associated with the disease; however it is not believed to manage the underlying cause of the problem.

See also


  1. ^ DailyMed: About DailyMed
  2. ^ Albert U, Aguglia E, Maina G, Bogetto F (November 2002). "Venlafaxine versus clomipramine in the treatment of obsessive-compulsive disorder: a preliminary single-blind, 12-week, controlled study". J Clin Psychiatry 63 (11): 1004–9. PMID 12444814. 
  3. ^ a b Stahl, S. Stahl's Essential Psychopharmacology: The Prescriber's Guide. Cambridge University Press. New York, NY. 2009. pp.89
  4. ^ a b c Millan MJ, Gobert A, Lejeune F, et al. (August 2001). "S33005, a novel ligand at both serotonin and norepinephrine transporters: I. Receptor binding, electrophysiological, and neurochemical profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine". The Journal of Pharmacology and Experimental Therapeutics 298 (2): 565–80. PMID 11454918. 
  5. ^ a b Monsma FJ, Shen Y, Ward RP, Hamblin MW, Sibley DR (March 1993). "Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs". Molecular Pharmacology 43 (3): 320–7. PMID 7680751. 
  6. ^ a b Ruat M, Traiffort E, Leurs R, et al. (September 1993). "Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation". Proceedings of the National Academy of Sciences of the United States of America 90 (18): 8547–51. doi:10.1073/pnas.90.18.8547. PMC 47394. PMID 8397408. 
  7. ^ a b Toll L, Berzetei-Gurske IP, Polgar WE, et al. (March 1998). "Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications". NIDA Research Monograph 178: 440–66. PMID 9686407. 
  8. ^ "Yin, Yang and Yawn" - Snopes article on Clomipramine
  9. ^ Stahl, S. Stahl's Essential Psychopharmacology: The Prescriber's Guide. Cambridge University Press. New York, NY, 2009. pp.94
  10. ^