Clomipramine
Encyclopedia
Clomipramine 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.
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.
.
of the following transporters:
As well as an antagonist
/inverse agonist
at the following receptors
:
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. Though it is unclear whether it has ever been screened, clomipramine may also act on sigma receptor
s 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 effect
s. 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.
Most of these side effects are dose related and/or tolerance will develop with continued use.
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%).
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.
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.
) 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.
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 and any unindicated use may be dangerous.
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.
The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.
. 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.
In the US, clomipramine is currently only licensed to treat separation anxiety in dogs. 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:
In Australia the license is broader:
.
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.
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
(TCA). It was developed in the 1960s by the Swiss drug manufacturer Geigy (now known as Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
) and has been in clinical use worldwide ever since.
Indications
- Obsessive compulsive disorder (OCD) approved by the U.S. Food and Drug AdministrationFood and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) - Major depression
- Panic disorderPanic disorderPanic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
with or without agoraphobiaAgoraphobiaAgoraphobia is an anxiety disorder defined as a morbid fear of having a panic attack or panic-like symptoms in a situation from which it is perceived to be difficult to escape. These situations can include, but are not limited to, wide-open spaces, crowds, or uncontrolled social conditions... - NarcolepsyNarcolepsyNarcolepsy is a chronic sleep disorder, or dyssomnia, characterized by excessive sleepiness and sleep attacks at inappropriate times, such as while at work. People with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern, which often is confused with insomnia...
- Premature ejaculationPremature ejaculationPremature ejaculation is a condition in which a man ejaculates earlier than he or his partner would like him to. Premature ejaculation is also known as rapid ejaculation, rapid climax, premature climax, or early ejaculation....
- Depersonalization disorderDepersonalization disorderDepersonalization disorder is a dissociative disorder in which the sufferer is affected by persistent or recurrent feelings of depersonalization and/or derealization. Diagnostic criteria include persistent or recurrent experiences of feeling detached from one's mental processes or body...
- Chronic painChronic painChronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
with or without organic disease, particular headache of the tension type - EnuresisBedwettingNocturnal enuresis, commonly called bedwetting, is involuntary urination while asleep after the age at which bladder control usually occurs. Nocturnal enuresis is considered primary when a child has not yet had a prolonged period of being dry...
(involuntary nightly urinating in sleep) in children and adolescents - CataplexyCataplexyCataplexy is a sudden and transient episode of loss of muscle tone, often triggered by emotions. It is a rare disease , but affects roughly 70% of people who have narcolepsy...
Clomipramine had been used experimentally to reduce relapses in cocaine addicts, and to repair neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
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.
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
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
) have also been used to treat premature ejaculation.
Contraindications
- Concomitant therapy with an (irreversible) MAO inhibitorMonoamine oxidase inhibitorMonoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
(e.g. tranylcypromineTranylcypromineTranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase...
, phenelzinePhenelzinePhenelzine is a non-selective and irreversible monoamine oxidase inhibitor of the hydrazine class which is used as an antidepressant and anxiolytic...
) - Acute intoxication with central depressants (alcohol, psychoactive drugs, narcotics)
- States of confusion (caution), absolutely contraindicated in patients with coma and delirium tremensDelirium tremensDelirium tremens is an acute episode of delirium that is usually caused by withdrawal from alcohol, first described in 1813...
- 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 retentionUrinary retentionUrinary retention, also known as ischuria, is a lack of ability to urinate. It is a common complication of benign prostatic hyperplasia , although it can also be caused by nerve dysfunction, constipation, infection, or medications...
(difficulty in urinating) - Caution: hypertrophy of the prostate without urine retention
- Pre-existing closed angle glaucomaGlaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
- 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 hypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, shock, serious cardiovascular dysfunction (postinfarctous states, heart insufficience, arrhythmias), avoid high oral doses or injections/infusions - Pre-existing bone marrow depression (leukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, thrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
, anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, pancytopeniaPancytopeniaPancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
), can be worsened by clomipramine - HyperthyroidismHyperthyroidismHyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
(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
Chemistry
Clomipramine is the 3-chlorinated derivative of imipramineImipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
.
Pharmacology
Clomipramine is a blockerReuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
of the following transporters:
- Serotonin transporterSerotonin transporterThe serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
(SERT) (Ki = 0.14 nM) - Norepinephrine transporterNorepinephrine transporterThe norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
(NET) (Ki = 54 nM) - Dopamine transporterDopamine transporterThe dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
(DAT) (Ki = 3,020 nM)
As well as an antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
/inverse agonist
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
at the following receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
:
- 5-HT2A receptor5-HT2A receptorThe mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
(Ki = 36 nM) - 5-HT2C receptor5-HT2C receptorThe 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
(Ki = 65 nM) - 5-HT3 receptor5-HT3 receptorThe 5-HT3 receptor is a member of the superfamily of ligand-gated ion channels, a superfamily that also includes the neuronal nicotinic acetylcholine receptors , and the inhibitory neurotransmitter receptors for GABA and glycine...
(Ki = 85 nM) - 5-HT6 receptor5-HT6 receptorThe 5-HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gs/Go and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.-Distribution:The 5-HT6 receptor is...
(Ki = 54 nM) - 5-HT7 receptor5-HT7 receptorThe 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin The 5-HT7 receptor is coupled to Gs and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various...
(Ki = 127 nM) - D1 receptor (Ki = 219 nM)
- D2 receptor (Ki = 162 nM)
- D3 receptor (Ki = 30 nM)
- α1-adrenergic receptor (Ki = 3.2 nM)
- α2-adrenergic receptor (Ki = 525 nM)
- H1 receptor (Ki = 31 nM)
- mACh receptorMuscarinic acetylcholine receptorMuscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s (Ki = 37 nM)
All affinities listed were assayed using human
Human
Humans are the only living species in the Homo genus...
materials except those for 5-HT3, 5-HT6, and 5-HT7 which are for mouse/rat tissues due to human values being unavailable. Though it is unclear whether it has ever been screened, clomipramine may also act on sigma receptor
Sigma receptor
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...
s and calcium
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
, potassium
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
, and sodium channels similarly to other TCAs.
Clomipramine possesses the highest in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
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
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
(SSRI) but instead a very, very strong serotonin reuptake inhibitor with additional norepinephrine reuptake inhibitor
Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
, antiserotonergic, antiadrenergic, antidopaminergic, antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
, and anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
properties and associated side effect
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...
s. Clomipramine's affinity for the DAT is very low/negligible and it therefore lacks any significant dopamine reuptake inhibitor
Dopamine reuptake inhibitor
A dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
actions.
It should also be noted that clomipramine's active metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
desmethylclomipramine is a much more potent norepinephrine reuptake inhibitor than clomipramine itself. As a result, in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
clomipramine is more balanced of a serotonin-norepinephrine reuptake inhibitor
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
, 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, insomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, nightmares, increased anxiety, seizures (0.5% to 2%, see below), rarely hypomaniaHypomaniaHypomania is a mood state characterized by persistent and pervasive elevated or irritable mood, as well as thoughts and behaviors that are consistent with such a mood state...
or induction of schizophreniaSchizophreniaSchizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
(immediate termination of therapy required), and extrapyramidalExtrapyramidal systemIn human anatomy, the extrapyramidal system is a neural network located in the brain that is part of the motor system involved in the coordination of movement. The system is called "extrapyramidal" to distinguish it from the tracts of the motor cortex that reach their targets by traveling through...
side effects (pseudoparkinsonism, dyskinesiaDyskinesiaDyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
, rarely tardive dyskinesiaTardive dyskinesiaTardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
) are noted. - AnticholinergicAnticholinergicAn anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
side effects in different grades of severity are quite common: dry mouth, constipation, rarely ileusIleusIleus is a disruption of the normal propulsive ability of the gastrointestinal tract.Ileus is commonly defined simply as bowel obstruction. However, authoritative sources define it as decreased motor activity of the GI tract due to non-mechanical causes...
(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 cariesCariesCaries is a progressive destruction of any kind of bone structure, including the skull, ribs and other bones, or the teeth. Caries can be caused by osteomyelitis, which is a microorganism disease. A disease that involves caries is mastoiditis, an inflammation of the mastoid process, in which the...
may be increased due to dry mouth. - AntiadrenergicAdrenergicAn adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine . Thus, it is a kind of sympathomimetic agent...
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 tachycardiaSinus tachycardiaSinus tachycardia is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult. The normal heart rate in the average adult ranges from 60–100 beats/min...
, bradycardiaBradycardiaBradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
, 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 photosensitivityPhotosensitivityPhotosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
with increased frequency of sunburns are seen in a few percentage of cases. Rarely liver damage of the cholostatic type, hepatitisHepatitisHepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, 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 heartburnHeartburnHeartburn, also known as pyrosis or acid indigestion is a burning sensation in the chest, just behind the breastbone or in the epigastrium...
, weight loss, but also nausea and bruxismBruxismBruxism is characterized by the grinding of the teeth and typically includes the clenching of the jaw. It is an oral parafunctional activity that occurs in most humans at some time in their lives. In most people, bruxism is mild enough not to be a health problem...
–teeth-grinding while asleep–(the latter due to the strong inhibition of reuptake of serotoninSerotoninSerotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
). - 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.
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%).
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 chlordiazepoxideChlordiazepoxideChlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
— most widely used since 1960s for this and similar indications - Aldehydes (limited to paraldehydeParaldehydeParaldehyde is the cyclic trimer of acetaldehyde molecules. Formally, it is a derivative of 1,3,5-trioxane. The corresponding tetramer is metaldehyde. A colourless liquid, it is sparingly soluble in water and highly soluble in alcohol. Paraldehyde slowly oxidizes in air, turning brown and producing...
and trichloroacetaldehyde monohydrate) — usually for paediatric and geriatric patients - Z-drugs, such as zaleplonZaleplonZaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...
, zopicloneZopicloneZopiclone is a non-benzodiazepine hypnotic agent used in the treatment of insomnia. In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone, is sold under the name Lunesta...
, and zolpidemZolpidemZolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
— 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)
- EthanolEthanolEthanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
(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 diphenhydramineDiphenhydramineDiphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
and hydroxyzineHydroxyzineHydroxyzine is a first-generation antihistamine of the diphenylmethane and piperazine classes. It was first synthesized by Union Chimique Belge in 1956 and was marketed by Pfizer in the United States later the same year, and is still in widespread use today....
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
Quinazolinone
Quinazolinone is a heterocyclic chemical compound. There are two structural isomers, 2-quinazolinone and 4-quinazolinone, with the 4-isomer being the more common.-Derivatives:...
sedatives (the former gold standard being methaqualone
Methaqualone
Methaqualone is a sedative-hypnotic drug that is similar in effect to barbiturates, a general central nervous system depressant. The sedative-hypnotic activity was first noted by Indian researchers in the 1950s and in 1962 methaqualone itself was patented in the US by Wallace and Tiernan...
); similarly, the drug methylpentynol
Methylpentynol
Methylpentynol is a hypnotic/sedative with anticonvulsant effects. It was discovered by Bayer in 1928 and was previously used for the treatment of insomnia but has been replaced by newer drugs with better safety profiles....
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 chlorprothixeneChlorprothixene
Chlorprothixene is a typical antipsychotic drug of the thioxanthene class and was the first of the series to be synthesized...
) 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., furazolidoneFurazolidoneFurazolidone is a nitrofuran antibacterial. It is marketed by Roberts Laboratories under the brand name Furoxone and by GlaxoSmithKline as Dependal-M.-Uses:It is used to treat diarrhoea and enteritis caused by bacteria or protozoan infections....
, linezolidLinezolidLinezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics...
, phenelzinePhenelzinePhenelzine is a non-selective and irreversible monoamine oxidase inhibitor of the hydrazine class which is used as an antidepressant and anxiolytic...
, selegilineSelegilineSelegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...
, tranylcypromineTranylcypromineTranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase...
): severe reactions including central excitation, hypertensive crisis, bizarre behaviour, psychosis, seizures, coma and death are possible. Serotonin syndromeSerotonin syndromeSerotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
is likely. - Central stimulants: Potentially dangerous central excitation with agitation and anxiety may be encountered.
- SSRI type antidepressants (e.g. fluoxetineFluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
): 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 OTCOver-the-counter drugOver-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
medications against colds and sleeping aids with diphenhydramineDiphenhydramineDiphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
, doxylamineDoxylamineDoxylamine is one of the many sedating antihistamines used by itself as a short-term sedative, and in combination with other drugs as a night-time cold and allergy relief drug...
and St. John's wort may occur.
Dosage
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
Sleep paralysis
Sleep paralysis is paralysis associated with sleep that may occur in healthy persons or may be associated with narcolepsy, cataplexy, and hypnagogic hallucinations. The pathophysiology of this condition is closely related to the normal hypotonia that occurs during REM sleep. When considered to be a...
(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
Modafinil
Modafinil is an analeptic drug manufactured by Cephalon, and is approved by the U.S. Food and Drug Administration for the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea...
, dextroamphetamine
Dextroamphetamine
Dextroamphetamine is a psychostimulant drug which is known to produce increased wakefulness and focus as well as decreased fatigue and decreased appetite....
or methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
) 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
Desipramine
Desipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
, protriptyline
Protriptyline
Protriptyline is a tricyclic antidepressant , specifically a secondary amine, indicated for the treatment of depression and ADHD...
and venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
.
Clomipramine is not able to elevate the mood of non-depressive persons and any unindicated use may be dangerous.
Overdose
If overdose is suspected, medical authorities recommend contacting the local poison control centerPoison control center
A poison control center is a medical facility that is able to provide immediate, free, and expert treatment advice and assistance over the telephone in case of exposure to poisonous or hazardous substances...
or emergency room/A&E
Emergency department
An emergency department , also known as accident & emergency , emergency room , emergency ward , or casualty department is a medical treatment facility specialising in acute care of patients who present without prior appointment, either by their own means or by ambulance...
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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
depressants.
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 NRINorepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
. While combining SSRIs and tricyclic antidepressants is risky, fluvoxamine
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
, 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.
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. However it is often prescribed in off-label use for many other conditions including other anxiety disorders, phobias (noise phobia in dogs
Noise phobia in dogs
Dog Noise Phobia, along with Dog Noise Anxiety, are terms sometimes used by dog owners and veterinarians to describe canine fear of and the corresponding stress responses to loud noises....
, 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:
In Australia the license is broader:
.
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.