Clomipramine, sold under the brand name Anafranil among others, is a

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

(TCA). It is used in the treatment of various conditions, most notably

obsessive–compulsive disorder Obsessive–compulsive disorder (OCD) is a mental disorder in which an individual has intrusive thoughts (an ''obsession'') and feels the need to perform certain routines (''Compulsive behavior, compulsions'') repeatedly to relieve the dis ...

but also many other disorders, including

hyperacusis Hyperacusis is an increased Hearing, sensitivity to sound and a low tolerance for environmental noise. Definitions of hyperacusis can vary significantly; it often revolves around damage to or dysfunction of the Stapes, ''stapes'' bone, stapedius ...

panic disorder Panic disorder is a mental disorder, specifically an anxiety disorder, characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath ...

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

trichotillomania Trichotillomania (TTM), also known as hair-pulling disorder or compulsive hair pulling, is a mental disorder characterized by a long-term urge that results in the pulling out of one's own hair. A brief positive feeling may occur as hair is rem ...

body dysmorphic disorder Body dysmorphic disorder (BDD), also known in some contexts as dysmorphophobia, is a mental disorder defined by an overwhelming preoccupation with a perceived flaw in one's physical appearance. In BDD's delusional variant, the flaw is imagined ...

and

chronic pain Chronic pain is pain that persists or recurs for longer than 3 months.https://icd.who.int/browse/2025-01/mms/en#1581976053 It is also known as gradual burning pain, electrical pain, throbbing pain, and nauseating pain. This type of pain is in cont ...

. It has also been notably used to treat

premature ejaculation Premature ejaculation (PE) is a male sexual dysfunction that occurs when a male Ejaculation, expels semen (and most likely experiences orgasm) soon after beginning sexual activity, and with minimal penile stimulation. It has also been called ''e ...

and the cataplexy associated with

narcolepsy Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...

. It may also address certain fundamental features surrounding

besides cataplexy (especially hypnagogic and hypnopompic hallucinations). The evidence behind this, however, is less robust. As with other antidepressants (notably including

selective serotonin reuptake inhibitors Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

), it may paradoxically increase the risk of

suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...

in those under the age of 25, at least in the first few weeks of treatment. It is typically taken by mouth, although intravenous preparations are sometimes used. Common side effects include dry mouth, constipation, loss of appetite, sleepiness, weight gain, sexual dysfunction, and trouble urinating. Serious side effects include an increased risk of

suicidal behavior Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or acad ...

in those under the age of 25,

seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

mania Mania, also known as manic syndrome, is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome defined as a state of Abnormality (behavior), abnormally elevated arousal, affect (psychology), affect, and energy level. During a mani ...

, and liver problems. If stopped suddenly, a withdrawal syndrome may occur with headaches, sweating, and

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

. It is unclear if it is safe for use in pregnancy. Its mechanism of action is not entirely clear but is believed to involve increased levels of

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

. Clomipramine was discovered in 1964 by the Swiss drug manufacturer Ciba-Geigy. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

Medical uses

Clomipramine has a number of uses in medicine, including in the treatment of: *

Obsessive–compulsive disorder Obsessive–compulsive disorder (OCD) is a mental disorder in which an individual has intrusive thoughts (an ''obsession'') and feels the need to perform certain routines (''Compulsive behavior, compulsions'') repeatedly to relieve the dis ...

(OCD), which happens to be its only US -labeled indication. Other regulatory agencies (such as the TGA of Australia and the MHRA of the UK) have also approved clomipramine for this indication. *

Major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

(MDD), a popular off-label use in the US. It is approved by the

Australian Australian(s) may refer to: Australia * Australia, a country * Australians, citizens of the Commonwealth of Australia ** European Australians ** Anglo-Celtic Australians, Australians descended principally from British colonists ** Aboriginal Aus ...

TGA and the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...

MHRA for this indication. In Japan it is also approved for depression. Some have suggested the possible superior efficacy of clomipramine compared to other antidepressants in the treatment of MDD, especially the more severe, although at the current time the evidence may be insufficient to more fully substantiate this claim. As-with other tricyclic antidepressants, the antidepressant response specifically may be augmented, including in treatment-resistant cases, with

triiodothyronine Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. Production of T3 and its prohormone thyroxi ...

, at a dosage of 50 mcg. In the case of clomipramine specifically, this may also be the case with obsessive-compulsive disorder. *

Panic disorder Panic disorder is a mental disorder, specifically an anxiety disorder, characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath ...

with or without

agoraphobia Agoraphobia is an anxiety disorder characterized by symptoms of anxiety in situations where the person perceives their environment to be unsafe with no way to escape. These situations can include public transit, shopping centers, crowds and q ...

. *

Body dysmorphic disorder Body dysmorphic disorder (BDD), also known in some contexts as dysmorphophobia, is a mental disorder defined by an overwhelming preoccupation with a perceived flaw in one's physical appearance. In BDD's delusional variant, the flaw is imagined ...

* Repetitive self-injurious/self-harming behaviours in those with

intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

specifically. * The subtype of systemised paranoia characterised by somatic phenomena. * Compulsive nail-biting (onychophagia). * Cataplexy associated with

. This is a TGA and MHRA-labeled indication for clomipramine. * Self-bloodletting *

Premature ejaculation Premature ejaculation (PE) is a male sexual dysfunction that occurs when a male Ejaculation, expels semen (and most likely experiences orgasm) soon after beginning sexual activity, and with minimal penile stimulation. It has also been called ''e ...

, where it may be more effective than

paroxetine Paroxetine ( ), sold under the brand name Paxil among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, obsessive-compulsive disorder, o ...

Depersonalization-derealization disorder Depersonalization-derealization disorder (DPDR, DDD) is a mental disorder in which the person has persistent or recurrent feelings of depersonalization and/or derealization. Depersonalization is described as feeling disconnected or detached fro ...

Chronic pain Chronic pain is pain that persists or recurs for longer than 3 months.https://icd.who.int/browse/2025-01/mms/en#1581976053 It is also known as gradual burning pain, electrical pain, throbbing pain, and nauseating pain. This type of pain is in cont ...

with or without organic disease, particularly headache of the tension type. * Developmental stuttering *

Sleep paralysis Sleep paralysis is a state, during waking up or falling asleep, in which a person is conscious but in a complete state of full-body paralysis. During an episode, the person may hallucinate (hear, feel, or see things that are not there), wh ...

, with or without

Enuresis Enuresis is a repeated inability to control urination. Use of the term is usually limited to describing people age-appropriateness, old enough to be expected to exercise such control. Involuntary urination is also known as urinary incontinence. Th ...

(involuntary urinating in sleep) in children. The effect may not be sustained following treatment, and alarm therapy may be more effective in both the short-term and the long-term. Combining a tricyclic (such as clomipramine) with

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

medication may be more effective for treating enuresis than the tricyclic alone. *

Trichotillomania Trichotillomania (TTM), also known as hair-pulling disorder or compulsive hair pulling, is a mental disorder characterized by a long-term urge that results in the pulling out of one's own hair. A brief positive feeling may occur as hair is rem ...

* In combination with

lithium Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...

and tryptophan for severe, particularly treatment-resistant depression. This combination, in a similar vein, has also been used for clomipramine-resistant obsessive-compulsive disorder. When electro-convulsive therapy is performed alongside this treatment-regime (as may be the case in severe depression and accompanied with thyroxine,) however, great care must be taken with lithium. The overall risk of seizures may have to be weighted against the refractory severity of the current illness and necessity of the amalgamation of treatment(s). * Isolated cataplexy unto itself (i.e., in the absence of characteristically associated narcolepsy), admittedly a rare condition * There is anecdotal and tentative, as-yet-undocumented information suggesting that clomipramine may address certain core features of

, and possibly

misophonia Misophonia (or selective sound sensitivity syndrome) is a disorder of decreased Distress tolerance, tolerance to specific sounds or their associated Stimulus (psychology), stimuli, or cues. These cues, known as "triggers", are experienced as Dis ...

. In the case of

, this appears to be especially the case at doses > 150 mg/d. As-with obsessive-compulsive disorder, a full response to any one dose may not be experienced for up to 12–16 weeks. Although lithium is most-associated with the treatment of

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

(where it is known for its general mood-stabilising features and to be especially useful in treating and preventing

), it may have a certain place in the management of treatment-resistant depression (which is often of higher severity than other depressions which have not been addressed with ECT). In these cases is often prescribed alongside SSRIs (e.g.,

fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...

venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...

and various of the tricyclics (e.g., clomipramine, amitriptyline, nortriptyline, maprotiline), which is why it may feature sometimes in the discussion of depression being managed with clomipramine. Lithium also significantly reduces the long-term risk of

in general. In any case, it is not necessary to have a diagnosis of bipolar affective disorder (manic-depressive illness), or even to be considered to have subtle elements of it (“soft bipolarity”), to benefit from lithium in the context of treatment with clomipramine. In a

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

of various trials involving

(Prozac),

fluvoxamine Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and, perhaps more-especially, obsessive–compu ...

(Faverin/Luvox), and

sertraline Sertraline, sold under the brand name Zoloft among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, generalized anxiety disorder, socia ...

(Zoloft) to test their relative efficacies in treating OCD, clomipramine was found to be significantly more effective. Other studies have borne similar results even when risk of bias is eliminated. A potentially significantly greater inherent side-effect profile, however, makes it a second-line choice in the treatment of OCD. SSRIs are generally better-tolerated but appear to be inferior in terms of actual clinical efficacy.

Contraindications

Contraindications include: * Known hypersensitivity to clomipramine, or any of the excipients or cross-sensitivity to tricyclic antidepressants of the dibenzazepine group * Recent

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

* Any degree of heart block or other cardiac arrhythmias *

Mania Mania, also known as manic syndrome, is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome defined as a state of Abnormality (behavior), abnormally elevated arousal, affect (psychology), affect, and energy level. During a mani ...

* Severe liver disease * Narrow angle glaucoma * Untreated

urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include urinary incont ...

* It must not be given in combination or within 3 weeks before or after treatment with a

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

. (

Moclobemide Moclobemide, sold under the brand names Amira, Aurorix, Clobemix, Depnil and Manerix among others, is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat Clinical depression, depression and social anxiety. It is not ...

-included; however, clomipramine may be initiated sooner at 48 hours following discontinuation of moclobemide.)

Pregnancy and lactation

Clomipramine use during pregnancy is associated with congenital heart defects in the newborn. It is also associated with reversible withdrawal effects in the newborn. Clomipramine is also distributed in breast milk and hence nursing while taking clomipramine is advised against.

Side effects

Clomipramine has been associated with the

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s listed below: Very common (>10% frequency): * Accommodation defect * Blurred vision * Nausea * Dry mouth (Xerostomia) * Constipation * Fatigue * Dizziness *

Tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

* Headache * Myoclonus * Drowsiness *

Somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

* Restlessness * Micturition disorder * Sexual dysfunction (

erectile dysfunction Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...

and loss of libido) *

Hyperhidrosis Hyperhidrosis is a medical condition in which a person exhibits excessive perspiration, sweating, more than is required for the Thermoregulation, regulation of body temperature. Although it is primarily a physical burden, hyperhidrosis can deterio ...

(profuse sweating) Common (1–10% frequency): * Weight loss * Dystonia * Cognitive impairment *

Orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...

Sinus tachycardia Sinus tachycardia is a sinus rhythm of the heart, with an increased rate of electrical discharge from the sinoatrial node, resulting in a tachycardia, a heart rate that is higher than the upper limit of normal (90–100 beats per minute for adu ...

* Clinically irrelevant ECG changes (e.g. T- and ST-wave changes) in patients of normal cardiac status * Palpitations *

Tinnitus Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...

(hearing ringing in one's ears) *

Mydriasis Mydriasis is the Pupillary dilation, dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, Physical trauma, trauma, or the use of c ...

(dilated pupils) * Vomiting * Abdominal disorders * Diarrhoea * Decreased appetite * Increased transaminases * Increased

Alkaline phosphatase The enzyme alkaline phosphatase (ALP, alkaline phenyl phosphatase, also abbreviated PhoA) is a phosphatase with the physiological role of dephosphorylating compounds. The enzyme is found across a multitude of organisms, prokaryotes and eukaryo ...

Speech disorders Speech disorders, impairments, or impediments, are a type of communication disorder in which normal manner of articulation, speech is disrupted. This can mean fluency disorders like stuttering and cluttering. Someone who is unable to speak due to ...

Paraesthesia Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or chronic and has many possible underlying causes. Paresthesia is usually painless and can oc ...

* Muscle hypertonia * Dysgeusia *

Memory impairment Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

* Muscular weakness * Disturbance in attention * Confusional state * Disorientation * Hallucinations (particularly in elderly patients and patients with Parkinson's disease) * Anxiety * Agitation * Sleep disorders *

Hypomania Hypomania (literally "under mania" or "less than mania") is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome characterized essentially by an apparently non-contextual elevation of Mood (psychology), mood (i.e., euphoria) th ...

* Aggression *

Depersonalization Depersonalization is a dissociative phenomenon characterized by a subjective feeling of detachment from oneself, manifesting as a sense of disconnection from one's thoughts, emotions, sensations, or actions, and often accompanied by a feeling of ...

Insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

* Nightmares * Aggravation of depression *

Delirium Delirium (formerly acute confusional state, an ambiguous term that is now discouraged) is a specific state of acute confusion attributable to the direct physiological consequence of a medical condition, effects of a psychoactive substance, or ...

* Galactorrhoea (lactation that is not associated with pregnancy or breastfeeding) * Orgasms triggered by yawning * Hot flush * Dermatitis allergic (skin rash, urticaria) * Photosensitivity reaction * Pruritus (itching) Uncommon (0.1–1% frequency): * Convulsions *

Ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

Arrhythmias Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beats ...

* Elevated blood pressure * Activation of psychotic symptoms Very rare (<0.01% frequency): * Pancytopaenia — an abnormally low amount of all the different types of blood cells in the blood (including platelets, white blood cells and red blood cells). *

Leukopenia Leukopenia () is a decrease in the number of white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections. Signs and symptoms Symptoms may include: * s ...

— a low white blood cell count. *

Agranulocytosis Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing neutropenia in the circulating blood. I ...

— a more severe form of leukopenia; a dangerously low

neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

count which leaves one open to life-threatening infections due to the role of the white blood cells in defending the body from invaders. *

Thrombocytopenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...

— an abnormally low amount of

platelets Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...

in the blood which are essential to clotting and hence this leads to an increased tendency to bruise and bleed, including, potentially, internally. * Eosinophilia — an abnormally high number of eosinophils — the cells that fight off parasitic infections — in the blood. * Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) — a potentially fatal reaction to certain medications that is due to an excessive release of

antidiuretic hormone Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...

— a hormone that prevents the production of urine by increasing the reabsorption of fluids in the kidney — this results in the development of various electrolyte abnormalities (e.g. hyponatraemia ow blood sodium hypokalaemia ow blood potassium hypocalcaemia ow blood calcium. *

Glaucoma Glaucoma is a group of eye diseases that can lead to damage of the optic nerve. The optic nerve transmits visual information from the eye to the brain. Glaucoma may cause vision loss if left untreated. It has been called the "silent thief of ...

Oedema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may inclu ...

(local or generalised) *

Alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...

(hair loss) * Hyperpyrexia (a high fever that is above 41.5 °C) *

Hepatitis Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...

(liver swelling) with or without

jaundice Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...

— the yellowing of the eyes, the skin, and mucous membranes due to impaired liver function. * Abnormal ECG * Anaphylactic and anaphylactoid reactions including hypotension *

Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to antipsychotics (neuroleptic) or other drugs that block the effects of dopamine. Symptoms include high fever, confusion, rigid muscles, va ...

(NMS) — a potentially fatal side effect of antidopaminergic agents such as antipsychotics, tricyclic antidepressants and antiemetics (drugs that relieve nausea and vomiting). NMS develops over a period of days or weeks and is characterised by the following symptoms: **

** Muscle rigidity ** Mental status change (such as confusion, delirium, mania, hypomania, agitation, coma, etc.) **

Hyperthermia Hyperthermia, also known as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme te ...

(high body temperature) **

Tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

(high heart rate) ** Blood pressure changes ** Diaphoresis (sweating profusely) ** Diarrhoea * Alveolitis allergic (

pneumonitis Pneumonitis describes general inflammation of lung tissue. Possible causative agents include radiation therapy of the chest, exposure to medications used during chemo-therapy, the inhalation of debris (e.g., animal dander), aspiration, herbicide ...

) with or without eosinophilia * Purpura * Conduction disorder (e.g. widening of

QRS complex The QRS complex is the combination of three of the graphical deflections seen on a typical electrocardiogram (ECG or EKG). It is usually the central and most visually obvious part of the tracing. It corresponds to the depolarization of the ri ...

, prolonged QT interval, PR/PQ interval changes, bundle-branch block, torsade de pointes, particularly in patients with

hypokalaemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an ...

) Individual side-effects may or may not be amendable to treatment. As noted below, bethanechol may alleviate anti-muscarinic/anti-cholinergic side-effects. It may also treat sexual side-effects common to the likes of clomipramine, SSRIs and

phenelzine Phenelzine, sold under the brand name Nardil among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine family which is primarily used as an antidepressant and anxiolytic to treat depression and a ...

. Topiramate has been used to off-set the weight-gain induced from various antidepressants and antipsychotics, and more broadly for general weight-loss (likewise with bupropion). This option may be especially attractive in patients either overweight prior to clomipramine treatment or who have gained an undesirable amount of weight on it. Another potential advantage of topiramate in the adjunctive treatment of people taking clomipramine is engendered in its status as an anti-convulsant medication, thereby theoretically increasing the seizure-threshold in patients (which clomipramine decreases to an extent which precludes its dosage ranging above 250 m.g./d. in normal circumstances, likewise with maprotiline and its 225 m.g./d. upper-ceiling). It may, thus, be useful and of increased importance in any case for patients with a familial or personal history of

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

of some other kind to concurrently take a daily dose of an anti-convulsant drug ( topiramate, gabapentin, etc.) should they require or opt for treatment with an antidepressant which reduces the seizure-threshold significantly ( bupropion, clomipramine, amoxapine, maprotiline,

). In the case of seizures occurring due to overdose of tricyclic antidepressants, intravenous

lorazepam Lorazepam, sold under the brand name Ativan, Tavor among others, is a benzodiazepine medication. It is used to treat anxiety (including anxiety disorders), insomnia, severe agitation, active seizures including status epilepticus, alcoh ...

may successfully terminate them. Phenytoin may or may not prevent them in the first instance but its status as an appropriate acute treatment for these seizures is somewhat controversial. Tremor may be relieved with a beta-blocker (e.g., pindolol,

propranolol Propranolol is a medication of the beta blocker class. It is used to treat hypertension, high blood pressure, some types of cardiac dysrhythmia, irregular heart rate, thyrotoxicosis, capillary hemangiomas, akathisia, performance anxiety, and ...

atenolol Atenolol is a beta blocker medication primarily used to treat high blood pressure and angina, heart-associated chest pain. Although used to treat high blood pressure, it does not seem to improve mortality rate, mortality in those with the condi ...

). In certain cases of tremor, pindolol may be an especially sensible option for serious consideration, as there is substantial evidence that its utilisation is an effective augmentation-strategy for obsessive-compulsive disorder, an important indication for clomipramine.

Withdrawal

Withdrawal symptoms may occur during gradual or particularly abrupt withdrawal of tricyclic antidepressant drugs. Possible symptoms include: nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, nervousness, anxiety, dizziness and worsening of psychiatric status. Differentiating between the return of the original psychiatric disorder and clomipramine withdrawal symptoms is important. Clomipramine withdrawal can be severe. Withdrawal symptoms can also occur in neonates when clomipramine is used during pregnancy. A major mechanism of withdrawal from tricyclic antidepressants is believed to be due to a rebound effect of excessive cholinergic activity due to neuroadaptations as a result of chronic inhibition of cholinergic receptors by tricyclic antidepressants. Restarting the antidepressant and slow tapering is the treatment of choice for tricyclic antidepressant withdrawal. Some withdrawal symptoms may respond to anticholinergics, such as

atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically give ...

or benztropine mesylate.

Overdose

Clomipramine overdose usually presents with the following symptoms: * Signs of

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

depression such as: ** stupor ** coma ** drowsiness ** restlessness ** ataxia * Mydriasis * Convulsions * Enhanced reflexes * Muscle rigidity * Athetoid and choreoathetoid movements *

Serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...

- a condition with many of the same symptoms as neuroleptic malignant syndrome but has a significantly more rapid onset * Cardiovascular effects including: ** arrhythmias (including Torsades de pointes) ** tachycardia ** QTc interval prolongation ** conduction disorders ** hypotension ** shock **

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

** cardiac arrest * Apnoea *

Cyanosis Cyanosis is the change of Tissue (biology), tissue color to a bluish-purple hue, as a result of decrease in the amount of oxygen bound to the hemoglobin in the red blood cells of the capillary bed. Cyanosis is apparent usually in the Tissue (bi ...

* Respiratory depression * Vomiting * Fever * Sweating *

Oliguria Oliguria or hypouresis is the low output of urine specifically more than 80 ml/day but less than 400ml/day. The decreased output of urine may be a sign of dehydration, kidney failure, hypovolemic shock, hyperosmolar Hyperglycemic Nonketotic Syndro ...

Anuria Anuria is nonpassage of urine, in practice is defined as passage of less than 100 milliliters of urine in a day. Anuria is often caused by failure in the function of kidneys. It may also occur because of some severe obstruction like kidney stone ...

There is no specific antidote for overdose and all treatment is purely supportive and symptomatic. Treatment with

activated charcoal "Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016). Background In an inter ...

may be used to limit absorption in cases of oral overdose. Anyone suspected of overdosing on clomipramine should be hospitalised and kept under close surveillance for at least 72 hours. Clomipramine has been reported as being less toxic in overdose than most other TCAs in one meta-analysis but this may well be due to the circumstances surrounding most overdoses as clomipramine is more frequently used to treat conditions for which the rate of suicide is not particularly high such as OCD. In another meta-analysis, however, clomipramine was associated with a significant degree of toxicity in overdose.

Interactions

Clomipramine may interact with a number of different medications, including the

monoamine oxidase inhibitors Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espe ...

which include isocarboxazid,

moclobemide Moclobemide, sold under the brand names Amira, Aurorix, Clobemix, Depnil and Manerix among others, is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat Clinical depression, depression and social anxiety. It is not ...

selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

and

tranylcypromine Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used a ...

antiarrhythmic agents Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia. ...

(due to the effects of TCAs like clomipramine on cardiac conduction. There is also a potential pharmacokinetic interaction with

quinidine Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...

due to the fact that clomipramine is metabolised by

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

''in vivo''), diuretics (due to the potential for

(low blood potassium) to develop which increases the risk for QT interval prolongation and torsades de pointes), the

SRIs; due to both potential additive serotonergic effects leading to serotonin syndrome and the potential for a pharmacokinetic interaction with the SSRIs that inhibit

(e.g.,

)] and serotonergic agents such as triptans, other tricyclic antidepressants, tramadol, etc. (due to the potential for serotonin-toxicity ,

serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...

). Its use is also advised against in those concurrently on

inhibitors, due to the potential for increased plasma levels of clomipramine and the resulting potential for CNS and cardiotoxicity.

Fluvoxamine Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and, perhaps more-especially, obsessive–compu ...

increases the serotoninergic effects of clomipramine and, likewise, clomipramine increases fluvoxamine levels.

Pharmacology

Pharmacodynamics

Clomipramine is a reuptake inhibitor of

and

, or a

serotonin–norepinephrine reuptake inhibitor Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopaus ...

(SNRI); that is, it blocks the reuptake of these

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

s back into

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s by preventing them from interacting with their transporters, thereby increasing their

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

concentrations in the

synaptic cleft Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in neuromuscular junction, muscles or glands. Chemical synapses allow neurons to form biological neural ...

and resulting in increased serotonergic and noradrenergic neurotransmission. In addition, clomipramine also has

antiadrenergic An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors. There are five adrenergic receptors, which are divided into two groups. The first group of receptors are the beta (β) adrenergic receptors. There are Beta-1 ad ...

antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides ...

, antiserotonergic, antidopaminergic, and

activities. It is specifically an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.α₁-adrenergic receptor, the

histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...

H₁ receptor, the

5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₆, and 5-HT₇ receptors, the

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

D₁, D₂, and D₃ receptors, and the

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

s ( M₁– M₅). Like other TCAs, clomipramine weakly blocks voltage-dependent sodium channels as well. Probably all “anticholinergic” side-effects may be successfully reversed in a majority of people with bethanechol chloride, although knowledge of this amenability has unfortunately decreased in medical circles over the decades. Bethanechol supplementation arguably should, however, be seriously considered as an add-on treatment when tricyclics (which often carry significant anti-muscarinic effects, especially for amitriptyline, protriptyline,

imipramine Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth. Common s ...

, and clomipramine) are prescribed, as it may alleviate potentially otherwise-limiting side-effects (blurry vision, dry mouth, urinary hesitancy/retention, etc.). This practice can make drugs of otherwise indispensably potent value more tolerable to certain patients and spare them needless suffering, hence-reducing the overall side-effect burden or concern thereof. Although clomipramine shows around 100- to 200-fold preference in affinity for the serotonin transporter (SERT) over the

norepinephrine transporter The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene. NET is a monoamine transporter and is responsible for the sodium ...

(NET), its major active metabolite, desmethylclomipramine (norclomipramine), binds to the NET with very high affinity (K_i = 0.32 nM) and with dramatically reduced affinity for the SERT (K_i = 31.6 nM). Moreover, desmethylclomipramine circulates at concentrations that are approximately twice those of clomipramine. In accordance, occupancy of both the SERT and the NET has been shown with clomipramine administration in

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...

studies with humans and non-human primates. As such, clomipramine is in fact a fairly balanced SNRI rather than only a

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the drug action, action of the serotonin transporter (SERT). This in turn lea ...

(SRI). The antidepressant effects of clomipramine are thought to be due to reuptake inhibition of serotonin and norepinephrine, while serotonin reuptake inhibition only is thought to be responsible for the effectiveness of clomipramine in the treatment of OCD. Conversely, antagonism of the H₁, α₁-adrenergic, and

s is thought to contribute to its

s. Blockade of the H₁ receptor is specifically responsible for the

effects of clomipramine and side effects like

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

and

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

(sleepiness). Antagonism of the α₁-adrenergic receptor is thought to cause orthostatic hypotension and

. Inhibition of muscarinic acetylcholine receptors is responsible for the

side effects of clomipramine like dry mouth,

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

blurred vision Blurred vision is an ocular symptom where vision becomes less precise and there is added difficulty to resolve fine details. Temporary blurred vision may involve dry eyes, eye infections, alcohol poisoning, hypoglycemia, or low blood pressur ...

, and

cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

memory impairment Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

. In

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

, sodium channel blockade in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

is believed to cause the

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...

and

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s associated with TCAs while blockade of sodium channels in the

heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...

is considered to cause

cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beat ...

cardiac arrest Cardiac arrest (also known as sudden cardiac arrest CA is when the heart suddenly and unexpectedly stops beating. When the heart stops beating, blood cannot properly Circulatory system, circulate around the body and the blood flow to the ...

, and death. On the other hand, sodium channel blockade is also thought to contribute to the

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

effects of TCAs, for instance in the treatment of

neuropathic pain Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuo ...

. The exceptionally strong serotonin reuptake inhibition of clomipramine likely precludes the possibility of its antagonism of

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

s (which it binds to with more than 100-fold lower affinity than the SERT) resulting in a net decrease in signaling by these receptors. In accordance, while

serotonin receptor antagonist A serotonin antagonist, or serotonin receptor antagonist, is a drug used to inhibit the action of serotonin and serotonergic drugs at serotonin receptor, serotonin (5-HT) receptors. Types 5-HT2A antagonists Antagonists of the 5-HT2A, 5-HT2A re ...

s like cyproheptadine and

chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...

are effective as

antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon antidoton)'', "(medicine) given as a remedy". An older term in English which is ...

s against

, clomipramine is nonetheless capable of inducing this syndrome. In fact, while all TCAs are SRIs and serotonin receptor antagonists to varying extents, the only TCAs that are associated with serotonin syndrome are clomipramine and to a lesser extent its dechlorinated analogue

, which are the two most potent SRIs of the TCAs (and in relation to this have the highest ratios of serotonin reuptake inhibition to serotonin receptor antagonism). As such, whereas other TCAs can be combined with

s (with caution due to the risk of hypertensive crisis from NET inhibition; sometimes done in treatment-resistant depressives), clomipramine cannot be due to the risk of serotonin syndrome and death. Unlike the case of its serotonin receptor antagonism, orthostatic hypotension is a common side effect of clomipramine, suggesting that its blockade of the α₁-adrenergic receptor is strong enough to overcome the stimulatory effects on the α₁-adrenergic receptor of its NET inhibition.

Serotonergic activity

Clomipramine is an extremely strong SRI by all accounts. Its

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the SERT was reported in one study using human tissues to be 0.14 nM, which is considerably higher than that of other TCAs. For example, the TCAs with the next highest affinities for the SERT in the study were

, amitriptyline, and dosulepin (dothiepin), with K_i values of 1.4 nM, 4.3 nM, and 8.3 nM, respectively. In addition, clomipramine has a terminal half-life that is around twice as long as that of amitriptyline and imipramine. In spite of these differences however, clomipramine is used clinically at the same usual dosages as other serotonergic TCAs (100–200 mg/day). Some health authorities recommend daily dosage is in the range of 30 to 75 mg in single or divided doses. Initial dosage should be 10 mg/day with gradual increments to 30–150 mg/day in divided doses or as a single dose at bedtime. Health Canada recommends maximum dose for outpatients is preferred at 200 mg/day. Sustained-release 75 mg formulation may be preferable at doses above 150 mg/day (i.e. 200 mg to 250 mg/day). It achieves typical circulating concentrations that are similar in range to those of other TCAs but with an upper limit that is around twice that of amitriptyline and imipramine. For these reasons, clomipramine is the most potent SRI among the TCAs and is far stronger as an SRI than other TCAs at typical clinical dosages. In addition, clomipramine is more potent as an SRI than any

selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

s (SSRIs); it is more potent than paroxetine, which is the strongest SSRI. A positron emission tomography study found that a single low dose of 10 mg clomipramine to healthy volunteers resulted in 81.1% occupancy of the SERT, which was comparable to the 84.9% SERT occupancy by 50 mg

. In the study, single doses of 5 to 50 mg clomipramine resulted in 67.2 to 94.0% SERT occupancy while single doses of 12.5 to 50 mg fluvoxamine resulted in 28.4 to 84.9% SERT occupancy. Chronic treatment with higher doses was able to achieve up to 100.0% SERT occupancy with clomipramine and up to 93.6% SERT occupancy with fluvoxamine. Other studies have found 83% SERT occupancy with 20 mg/day

and 77% SERT occupancy with 20 mg/day

citalopram Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and soci ...

. These results indicate that very low doses of clomipramine are able to substantially occupy the SERT and that clomipramine achieves higher occupancy of the SERT than SSRIs at comparable doses. Moreover, clomipramine may be able to achieve more complete occupancy of the SERT at high doses, at least relative to fluvoxamine. If the ratios of the 80% SERT occupancy dosage and the approved clinical dosage range are calculated and compared for SSRIs, SNRIs, and clomipramine, it can be deduced that clomipramine is by far the strongest SRI used medically. The lowest approved dosage of clomipramine can be estimated to be roughly comparable in SERT occupancy to the maximum approved dosages of the strongest SSRIs and SNRIs. Because their

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

was originally not known and dose-ranging studies were never conducted, first-generation

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

s were dramatically

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

d in patients. It has been suggested that the same may have been true for clomipramine and other TCAs. Nonetheless, there is little doubt that many may, indeed, benefit from much higher doses. 250 mg/d, as mentioned elsewhere, is the typical maximum recommended dose but some people may need as much as 300 mg/d or more to benefit from all clomipramine has to offer beyond its potent SNRI capacity alone.

Obsessive–compulsive disorder

Clomipramine was the first drug that was investigated for and found to be effective in the treatment of OCD. In addition, it was the first drug to be approved by the in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

for the treatment of OCD. The effectiveness of clomipramine in the treatment of OCD is far greater than that of other TCAs, which are comparatively weak SRIs; a

found pre- versus post-treatment

effect size In statistics, an effect size is a value measuring the strength of the relationship between two variables in a population, or a sample-based estimate of that quantity. It can refer to the value of a statistic calculated from a sample of data, the ...

s of 1.55 for clomipramine relative to a range of 0.67 for imipramine and 0.11 for desipramine. In contrast to other TCAs, studies have found that clomipramine and SSRIs, which are more selective SRIs, have similar effectiveness in the treatment of OCD. However, multiple meta-analyses have found that clomipramine nonetheless retains a significant effectiveness advantage relative to SSRIs; in the same meta-analysis mentioned previously, the effect sizes of SSRIs in the treatment of OCD ranged from 0.81 for

to 1.36 for

(relative to 1.55 for clomipramine). However, the effectiveness advantage for clomipramine has not been apparent in head-to-head comparisons of clomipramine versus SSRIs for OCD. The differences in effectiveness findings could be due to differences in methodologies across non-head-to-head studies. Relatively high doses of SSRIs are needed for effectiveness in the treatment of OCD. Studies have found that high dosages of SSRIs above the normally recommended maximums are significantly more effective in OCD treatment than lower dosages (e.g., 250 to 400 mg/day sertraline versus 200 mg/day sertraline). In addition, the combination of clomipramine and SSRIs has also been found to be significantly more effective in alleviating OCD symptoms, and clomipramine is commonly used to augment SSRIs for this reason. Studies have found that

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

clomipramine, which is associated with very high circulating concentrations of the drug and a much higher ratio of clomipramine to its metabolite desmethylclomipramine, is more effective than oral clomipramine in the treatment of OCD. There is a

case report In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrenc ...

of complete remission from OCD for approximately one month following a massive

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

of fluoxetine, an SSRI with a uniquely long

duration of action Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

. Taken together, stronger serotonin reuptake inhibition has consistently been associated with greater alleviation of OCD symptoms, and since clomipramine, at the clinical dosages in which it is employed, is effectively the strongest SRI used medically (see table above), this may underlie its unique effectiveness in the treatment of OCD. In addition to serotonin reuptake inhibition, clomipramine is also a mild but clinically significant antagonist of the

D₁, D₂, and D₃ receptors at high concentrations. Addition of

s, which are potent dopamine receptor antagonists, to SSRIs, has been found to significantly augment their effectiveness in the treatment of OCD. As such, besides strong serotonin reuptake inhibition, clomipramine at high doses might also block dopamine receptors to treat OCD symptoms, and this could additionally or alternatively be involved in its possible effectiveness advantage over SSRIs. For this reason, it may also be that augmentation with neuroleptics (a common procedure in the occurrence of inadequate response to monotherapy with an SRI) is needed with less frequency with clomipramine relative to SSRIs, the latter of-which apparently lack significant activity as dopamine-receptor antagonists. Although clomipramine is probably more effective in the treatment of OCD compared to SSRIs, it is greatly inferior to them in terms of tolerability and

safety Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings The word 'safety' entered the English language in the 1 ...

due to its lack of selectivity for the SERT and promiscuous pharmacological activity. In addition, clomipramine has high

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

in overdose and can potentially result in death, whereas death rarely, if ever, occurs with overdose of SSRIs. It is for these reasons that clomipramine, in spite of potentially superior effectiveness to SSRIs, is now rarely used as a first-line agent in the treatment of OCD, with SSRIs being used as first-line therapies instead and clomipramine generally being reserved for more severe cases and as a second-line agent.

Pharmacokinetics

The

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of clomipramine is approximately 50%. Peak plasma concentrations occur around 2–6 hours (with an average of 4.7 hours) after taking clomipramine orally and are in the range of 56–154 ng/mL (178–489 nmol/L). Steady-state concentrations of clomipramine are around 134–532 ng/mL (426–1,690 nmol/L), with an average of 218 ng/mL (692 nmol/L), and are reached after 7 to 14 days of repeated dosing. Steady-state concentrations of the active metabolite, desmethylclomipramine, are around 230–550 ng/mL (730–1,750 nmol/L). The volume of distribution (V_d) of clomipramine is approximately 17 L/kg. It binds approximately 97–98% to

plasma protein Plasma proteins, sometimes referred to as blood proteins, are proteins present in blood plasma. They perform many different functions, including transport of hormones, vitamins and minerals in activity and functioning of the immune system. Other b ...

s, primarily to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

. Clomipramine is metabolized in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

mainly by

. It has a terminal half-life of 32 hours, and its N-desmethyl

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

, desmethylclomipramine, has a terminal half-life of approximately 69 hours. Clomipramine is mostly excreted in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

(60%) and

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

(32%). Although the normal maximum-recommended total daily dosage of clomipramine is 250 milligrams, treatment-resistant cases of depression and obsessive-compulsive disorder may require corresponding doses within the range of 255 to 300 milligrams. Indeed, doses of 375 milligrams per day, sometimes in combination with

aripiprazole Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as ...

, have not only been necessary but, remarkably, relatively well-tolerated. Caution, however, is generally prudent when doing this, as

, which are more likely to occur with clomipramine than every other

besides maprotiline, become more and more of a risk beyond the normally-recommended upper-ceiling. At daily doses ≤ 250 m.g., the incidence of seizures may be reliably estimated to be around the order of 0.48%. (All tricyclic antidepressants technically lower the seizure-threshold but this is only significant with amoxapine, maprotiline and, indeed, clomipramine.) Dose-increases between 25 m.g. and 150 m.g., barring significant drug-drug interactions which may elevate clomipramine blood-levels, should be titrated in doses of 50 m.g. (25 m.g. in the case of

and 10 to 25 m.g. in the cases of premature ejaculation and

narcoleptic Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...

cataplexy) and above 150 m.g. in 25 m.g. increments. Average optimal total daily doses for depression (whether mild or severe), premature ejaculation, cataplexy-narcolepsy, obsessive-compulsive disorder,

and trichotilomania respectively are (in milligrams) 150, 50, 25 - 75, 150 - 250, 50 - 150 and 150 - 200. Some consider the minimum optimally-therapeutic dose of clomipramine in obsessive-compulsive disorder, which often requires much higher levels of serotoninergic concentration than other indications for these drugs, to be 200, rather than 150, milligrams per day. For premature ejaculation, clomipramine can be taken prn 3 to 5 hours before attempted sexual intercourse.

Chemistry

Clomipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a

side chain In organic chemistry and biochemistry, a side chain is a substituent, chemical group that is attached to a core part of the molecule called the "main chain" or backbone chain, backbone. The side chain is a hydrocarbon branching element of a mo ...

attached in its

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

. Other dibenzazepine TCAs include

, desipramine, and trimipramine. Clomipramine is a

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

of imipramine with a chlorine atom added to one of its rings and is also known as 3-chloroimipramine. It is a tertiary amine TCA, with its

-demethylation, demethylated metabolite desmethylclomipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline,

, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of clomipramine is 3-(3-chloro-10,11-dihydro-5''H''-dibenzo[''b,f'']azepin-5-yl)-''N,N''-dimethylpropan-1-amine and its free base form has a chemical formula of C₁₉H₂₃ClN₂ with a molecular weight of 314.857 g/mol. The drug is used commercially almost exclusively as the hydrochloride salt (chemistry), salt; the free base has been used rarely. The CAS Registry Number of the free base is 303-49-1 and of the hydrochloride is 17321–77–6.

History

Clomipramine was developed by Geigy as a chlorinated derivative of

. It was first referenced in the literature in 1961 and was patented in 1963. The drug was first approved for medical use in Europe in the treatment of depression in 1970, and was the last of the major TCAs to be marketed. In fact, clomipramine was initially considered to be a "me-too drug" by the FDA, and in relation to this, was declined licensing for depression in the

. As such, to this day, clomipramine remains the only TCA that is available in the United States that is not approved for the treatment of depression, in spite of the fact that it is a highly effective antidepressant. Clomipramine was eventually approved in the United States for the treatment of OCD in 1989 and became available in 1990. It was the first drug to be investigated and found effective in the treatment of OCD. The benefits in OCD were first reported by Juan José López-Ibor in 1967, and the first double-blind, placebo-controlled clinical trial of clomipramine for OCD was conducted in 1976, with more rigorous clinical studies that solidified its effectiveness conducted in the 1980s. It remained the "gold standard" for the treatment of OCD for many years until the introduction of the SSRIs, which have since largely superseded it due to greatly improved tolerability and safety (although notably not effectiveness). Clomipramine is the only TCA that has been shown to be effective in the treatment of OCD and that is approved by the FDA for the treatment of OCD; the other TCAs failed clinical trials for this indication, likely due to insufficient serotonergic activity.

Society and culture

Generic names

''Clomipramine'' is the English language, English and French language, French generic term, generic name of the drug and its , , and , while ''clomipramine hydrochloride'' is its , , , and . ''Clomipramina'' is its generic name in Spanish language, Spanish, Portuguese and Italian language, Italian and its , while ''clomipramin'' is its generic name in German language, German and ''clomipraminum'' is its generic name in Latin language, Latin.

Brand names

Clomipramine is marketed throughout the world mainly under the brand names Anafranil and Clomicalm for use in humans and animals, respectively.

Veterinary uses

In the US, clomipramine is only licensed to treat separation anxiety in dogs for which it is sold under the brand name Clomicalm. It has proven effective in the treatment of obsessive–compulsive disorders in cats and dogs. In dogs, it has also demonstrated similar efficacy to

in treating tail chasing. In dogs some evidence suggests its efficacy in treating noise phobia. Clomipramine has also demonstrated efficacy in treating urine spraying in cats. Various studies have been done on the effects of clomipramine on cats to reduce urine spraying/marking behavior. It has been shown to be able to reduce this behavior by up to 75% in a trial period of four weeks.

References

{{Authority control Alpha-1 blockers Antihistamines CYP2D6 inhibitors Chloroarenes Dibenzazepines Dimethylamino compounds Dopamine antagonists Drugs developed by Novartis Muscarinic antagonists Serotonin receptor antagonists Serotonin–norepinephrine reuptake inhibitors Treatment of obsessive–compulsive disorder Tricyclic antidepressants Veterinary drugs Wikipedia medicine articles ready to translate World Health Organization essential medicines