Clomipramine

Clomipramine

Systematic (IUPAC) name
3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine
Clinical data
Trade names	Anafranil, Clofranil
AHFS/Drugs.com	monograph
MedlinePlus	a697002
License data	US FDA: Clomipramine
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	Oral, IV[1]
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	50%
Protein binding	97-98%
Metabolism	Hepatic (CYP2D6-mediated)
Biological half-life	32 hr (69 hr for active metabolite)
Excretion	Renal (60%), faeces (32%)
Identifiers
CAS Number	303-49-1
ATC code	N06AA04 (WHO)
PubChem	CID 2801
IUPHAR/BPS	2398
DrugBank	DB01242
ChemSpider	2699
UNII	NUV44L116D
KEGG	D07727
ChEBI	CHEBI:47780
ChEMBL	CHEMBL415
Chemical data
Formula	C19H23ClN2
Molar mass	314.9 g/mol
SMILES ClC1=CC(N(CCCN(C)C)C2=C(CC3)C=CC=C2)=C3C=C1
InChI InChI=1S/C19H23ClN2/c1-21(2)12-5-13-22-18-7-4-3-6-15(18)8-9-16-10-11-17(20)14-19(16)22/h3-4,6-7,10-11,14H,5,8-9,12-13H2,1-2H3 Key:GDLIGKIOYRNHDA-UHFFFAOYSA-N
(verify)

Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA).^[2] It is used for the treatment of obsessive compulsive disorder, panic disorder, major depressive disorder, and chronic pain. It may decrease the risk of suicide in those over the age of 65. It is taken by mouth.^[2]

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 in those under the age of 25, seizures, mania, and liver problems. If stopped suddenly a withdrawal syndrome may occur with headaches, sweating, and dizziness. 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.^[2]

Clomipramine was discovered in 1964 by the Swiss drug manufacturer Ciba-Geigy.^[3] It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.^[4] It is available as a generic medication.^[2] The wholesale price is between 0.11 and 0.21 per day as of 2014.^[5] In the United States a typical dose costs about 1.20 USD per day.^[2] It was made from imipramine.^[3]

Medical uses

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

• Obsessive–compulsive disorder (OCD) which is its only U.S. FDA-labelled indication.^[6][7] Other regulatory agencies (such as the TGA of Australia and the MHRA of the UK) have also approved clomipramine for this indication.^{[8][9][10][11]}
• Major depressive disorder (MDD) a popular off-label use in the US. It is approved by the Australian TGA and the United Kingdom MHRA for this indication.^{[8][9][10][11]} Some have suggested the possible superior efficacy of clomipramine compared to other antidepressants in the treatment of MDD, although at the current time the evidence is insufficient to adequately substantiate this claim.^[12]
• Panic disorder with or without agoraphobia.^[13][14]
• Body dysmorphic disorder^[15]
• Cataplexy associated with narcolepsy. Which is a TGA & MHRA-labelled indication for clomipramine.^[10][11]
• Premature ejaculation^[16]
• Depersonalization disorder^[17]
• Chronic pain with or without organic disease, particularly headache of the tension type.^[18]
• Sleep paralysis, with or without narcolepsy
• Enuresis (involuntary nightly urinating in sleep) in children and adolescents.^[19]
• Trichotillomania^[20][21][22]

In a meta-analysis of various trials involving fluoxetine (Prozac), fluvoxamine (Luvox), and sertraline (Zoloft) to test their relative efficacies in treating OCD, clomipramine was found to be the most effective.^[23]

Pregnancy and lactation

Clomipramine use during pregnancy is associated with congenital heart defects in the newborn.^[11][24] It is also associated with reversible withdrawal effects in the newborn.^[25] Clomipramine is also distributed in breast milk and hence nursing while taking clomipramine is advised against.^[7]

Adverse effects

Adverse effects by frequency:^[6][7][8][9]
Very common (>10% frequency):

• Accommodation (eye)
• Blurred vision
• Nausea
• Dry mouth
• Constipation
• Fatigue
• Weight gain
• Increased appetite
• Dizziness
• Tremor
• Headache
• Myoclonus
• Drowsiness
• Somnolence
• Restlessness
• Micturition disorder
• Sexual dysfunction (erectile dysfunction and loss of libido)
• Hyperhidrosis (profuse sweating)

Common (1-10% frequency):

• Weight loss
• Orthostatic hypotension
• Sinus tachycardia
• Clinically irrelevant ECG changes (e.g. T- and ST-wave changes) in patients of normal cardiac status
• Palpitations
• Tinnitus (hearing ringing in one's ears)
• Mydriasis (dilated pupils)
• Vomiting
• Abdominal disorders
• Diarrhoea
• Decreased appetite
• Transaminases increased
• Alkaline phosphatase increased
• Speech disorders
• Paraesthesia
• Muscle hypertonia
• Dysgeusia
• Memory impairment
• Muscular weakness
• Disturbance in attention
• Confusional state
• Disorientation
• Hallucinations (particularly in elderly patients and patients with Parkinson's disease)
• Anxiety
• Agitation
• Sleep disorders
• Mania
• Hypomania
• Aggression
• Depersonalisation
• Insomnia
• Nightmares
• Aggravation of depression
• Delirium
• Galactorrhoea (lactation that is not associated with pregnancy or breastfeeding)
• Breast enlargement
• Yawning
• Hot flush
• Dermatitis allergic (skin rash, urticaria)
• Photosensitivity reaction
• Pruritus (itching)

Uncommon (0.1-1% frequency):

• Convulsions
• Ataxia
• Arrhythmias
• 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).
• Leucopenia — a low white blood cell count.
• Agranulocytosis — basically a worse form of leucopaenia; a dangerously low white blood cell 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 — an abnormally low amount of platelets 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 — 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 [low blood sodium], hypokalaemia [low blood potassium], hypocalcaemia [low blood calcium]).
• Glaucoma
• Oedema (local or generalised)
• Alopecia (hair loss)
• Hyperpyrexia (a high fever that is above 41.5 °C)
• Hepatitis (liver swelling) with or without jaundice — 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 (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:
  • Tremor
  • Muscle rigidity
  • Mental status change (such as confusion, delirium, mania, hypomania, agitation, coma, etc.)
  • Hyperthermia (high body temperature)
  • Tachycardia (high heart rate)
  • Blood pressure changes
  • Diaphoresis (sweating profusely)
  • Diarrhoea
• Alveolitis allergic (pneumonitis) with or without eosinophilia
• Purpura

• Conduction disorder (e.g. widening of QRS complex, prolonged QT interval, PQ changes, bundle-branch block, torsade de pointes, particularly in patients with hypokalaemia)

Withdrawal

Withdrawal symptoms may occur during gradual or particularly abrupt withdrawal of tricyclic antidepressant drugs. Possible symptoms include: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, anxiety, dizziness and worsening of psychiatric status.^[8] Differentiating between the return of the original psychiatric disorder and clomipramine withdrawal symptoms is important.^[26] Clomipramine withdrawal can be severe.^[27] Withdrawal symptoms can also occur in neonates when clomipramine is used during pregnancy.^[25] 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 or benztropine mesylate.^[28]

Drug interactions

Clomipramine may interact with a number of different medications, including the monoamine oxidase inhibitors which include isocarboxazid, moclobemide, phenelzine, selegiline and tranylcypromine, antiarrhythmic agents (due to the effects of TCAs like clomipramine on cardiac conduction. There is also a potential pharmacokinetic interaction with quinidine due to the fact that clomipramine is metabolised by CYP2D6 in vivo), diuretics (due to the potential for hypokalaemia (low blood potassium) to develop which increases the risk for QT interval prolongation and torsades de pointes), the selective serotonin reuptake inhibitors (SSRIs; due to both potential additive serotonergic effects leading to serotonin syndrome and the potential for a pharmacokinetic interaction with the SSRIs that inhibit CYP2D6 [e.g. fluoxetine and paroxetine]) and serotonergic agents such as triptans, other tricyclic antidepressants, tramadol, etc. (due to the potential for serotonin syndrome).^[8] Its use is also advised against in those concurrently on CYP2D6 inhibitors due the potential for increased plasma levels of clomipramine and the resulting potential for CNS and cardiotoxicity.^[8]

Contraindications

Contraindications include:^[9]

• Known hypersensitivity to clomipramine, or any of the excipients or cross-sensitivity to tricyclic antidepressants of the dibenzazepine group
• Recent myocardial infarction
• Any degree of heart block or other cardiac arrhythmias
• Mania
• Severe liver disease
• Narrow angle glaucoma
• Urinary retention
• It must not be given in combination or within 3 weeks before or after treatment with an monoamine oxidase inhibitor. (moclobemide included, however, Clomipramine can be initiated 48 hours upon discontinuation of Moclobemide)

Overdose

Clomipramine overdose usually presents with the following symptoms:^[6][8][9]

• Signs of central nervous system depression such as:
  • stupor
  • coma
  • drowsiness
  • restlessness
  • ataxia
• Mydriasis
• Convulsions
• Enhanced reflexes
• Muscle rigidity
• Athetoid and choreoathetoid movements
• Serotonin syndrome - 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
  • cardiac arrest
• Apnoea
• Cyanosis
• Respiratory depression
• Vomiting
• Fever
• Sweating
• Oliguria
• Anuria

There is no specific antidote for overdose and all treatment is purely supportive and symptomatic.^[8] Treatment with activated charcoal may be used to limit absorption in cases of oral overdose.^[8] Anyone suspected of overdosing on clomipramine should be hospitalised and kept under close surveillance for at least 72 hours.^[8] 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 obsessive-compulsive disorder.^[29] In another meta-analysis, however, clomipramine was associated with a significant degree of toxicity in overdose.^[30]

Mechanism of action

Structure of desmethylclomipramine, clomipramine's active metabolite.

Clomipramine is a highly selective (~200x over norepinephrine) inhibitor of serotonin reuptake.^[31] It is also an antagonist/inverse agonist at the histamine H₁ receptor, the muscarinic acetylcholine receptors and the α₁ adrenergic receptor.^[31] These last three actions likely contributes to its adverse effects.^[31]

Clomipramine's binding profile is as follows:^{[32][33][34][35][36]}

Biological protein	SERT	NET	DAT	5-HT1A	5-HT2A	5-HT2C	5-HT3	5-HT6	5-HT7	α1A	α2A	D1	D2	D3	H1	mAChRs
Ki (nM)	0.21	45.85	2,605	>10,000	35.5	64.6	85.1	53.8	127	3.2	525	219	119.8	40.05	31.2	37

In addition clomipramine's active metabolite desmethylclomipramine is known to display the following affinity:

• Norepinephrine transporter (NET) (K_i = <1 nM)^[37]

Pharmacokinetics

Peak plasma concentrations occur around 2–6 hours (with an average of 4.7 hours) after taking clomipramine orally.^[6] Maximum plasma concentrations of clomipramine are around 56-154 ng/mL.^[6] Steady state concentrations of clomipramine are around 134-532 ng/mL (with an average of 218 ng/mL) and are reached after 7–14 days of repeated dosing.^[6] Steady-state concentration of the active metabolite, desmethylclomipramine, are around 230-550 ng/mL.^[6] Its oral bioavailability is 50%.^[6] It binds approximately 97-98% to plasma proteins,^[6][7] primarily albumin.^[6] It is metabolised in the liver primarily by CYP2D6.^[7] It has an elimination half-life of 32 hours, and its N-desmethyl metabolite, desmethylclomipramine, has a half-life of approximately 69 hours.^[7] It is mostly excreted in urine (60%) and faeces (32%).^[7] Its volume of distribution (V_d) is approximately 17 L/kg.^[7]

Veterinary uses

Lick granuloma (also known as acral lick dermatitis) from excessive licking.

In the U.S., clomipramine is only licensed to treat separation anxiety in dogs for which it is sold under the brand name Clomicalm.^[38] It has proven effective in the treatment of obsessive-compulsive disorders in cats and dogs.^[39][40] In dogs, it has also demonstrated similar efficacy to fluoxetine in treating tail chasing.^[41] In dogs some evidence suggests its efficacy in treating noise phobia.^[42]

Clomipramine has also demonstrated efficacy in treating urine spraying in cats.^[43] 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% reduction of the behavior in a trial period of four weeks.^[44]

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43. King, JN; Steffan, J; Heath, SE; Simpson, BS; Crowell-Davis, SL; Harrington, LJ; Weiss, AB; Seewald, W (September 2004). "Determination of the dosage of clomipramine for the treatment of urine spraying in cats". Journal of the American Veterinary Medical Association 225 (6): 881–887. doi:10.2460/javma.2004.225.881.
44. Landsberg, G.M.; Wilson, A.L. (2005). "Effects of clomipramine on cats presented for urine marking". J. Am. Anim. Hosp. Assoc. 41: 3–11. doi:10.5326/0410003.