Clomipramine

Clinical data
Trade names	Anafranil, Clomicalm, others
Other names	Clomipramine; 3-Chloroimipramine; G-34586[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a697002
License data	US DailyMed: Clomipramine
Pregnancy category	AU: C
Routes of administration	By mouth, intravenous[2]
ATC code	N06AA04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class C1 (Other controlled substances)[3] CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	~50%[4]
Protein binding	96–98%[4]
Metabolism	Hepatic (CYP2D6)[4]
Metabolites	Desmethylclomipramine[4]
Elimination half-life	CMI: 19–37 hours[4] DCMI: 54–77 hours[4]
Excretion	Renal (51–60%)[4] Feces (24–32%)[4]
Identifiers
IUPAC name 3-(3-Chloro-10,11-dihydro-5H-dibenzoazepin-5-yl)-N,N-dimethylpropan-1-amine
CAS Number	303-49-1 Y
PubChem CID	2801
IUPHAR/BPS	2398
DrugBank	DB01242 Y
ChemSpider	2699 Y
UNII	NUV44L116D
KEGG	D07727 Y
ChEBI	CHEBI:47780 Y
ChEMBL	ChEMBL415 Y
CompTox Dashboard (EPA)	DTXSID6022844
ECHA InfoCard	100.005.587
Chemical and physical data
Formula	C19H23ClN2
Molar mass	314.86 g·mol−1
3D model (JSmol)	Interactive image
SMILES CN(C)CCCN1c2ccccc2CCc2ccc(Cl)cc21
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 Y Key:GDLIGKIOYRNHDA-UHFFFAOYSA-N Y
(verify)

Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA).^[5] It is used in the treatment of various conditions, most-notably obsessive–compulsive disorder but also many other disorders, including panic disorder, major depressive disorder, trichotilomania,^[6] body dysmorphic disorder^[7][8][9] and chronic pain.^[5] It has also been notably used to treat premature ejaculation^[5] and the cataplexy associated with narcolepsy.^[10][11]

It may also address certain fundamental features surrounding narcolepsy besides cataplexy (especially hypnagogic and hypnopompic hallucinations).^[12] The evidence behind this, however, is less robust.

As with other antidepressants (notably including selective serotonin reuptake inhibitors), it may paradoxically increase the risk of suicide in those under the age of 25, at least in the first few weeks of treatment.^[5]

It is typically taken by mouth, although intravenous preparations are sometimes used.^[13][14]

Common side effects include dry mouth, constipation, loss of appetite, sleepiness, weight gain, sexual dysfunction, and trouble urinating.^[5] Serious side effects include an increased risk of suicidal behavior in those under the age of 25, seizures, mania, and liver problems.^[5] If stopped suddenly, a withdrawal syndrome may occur with headaches, sweating, and dizziness.^[5] It is unclear if it is safe for use in pregnancy.^[5] Its mechanism of action is not entirely clear but is believed to involve increased levels of serotonin and norepinephrine.^[5]

Clomipramine was discovered in 1964 by the Swiss drug manufacturer Ciba-Geigy.^[15] It is on the World Health Organization's List of Essential Medicines.^[16] It is available as a generic medication.^[5]

Medical uses

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

• Obsessive–compulsive disorder (OCD), which happens to be its only U.S. FDATooltip Food and Drug Administration-labeled indication.^[17][18] Other regulatory agencies (such as the TGA of Australia and the MHRA of the UK) have also approved clomipramine for this indication.^{[19][20][21][22]}
• 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. In Japan it is also approved for depression.^{[19][20][21][22][23][24]} Some have suggested the possible superior efficacy of clomipramine compared to other antidepressants in the treatment of MDD,^{[25][26][27][28][29]} especially the more severe,^[30][31][32] although at the current time the evidence may be insufficient to more fully substantiate this claim.^[33]
• Panic disorder with or without agoraphobia.^[34][35]
• Body dysmorphic disorder^[36]
• Repetitive self-injurious/self-harming behaviours in those with intellectual disability specifically.^[37][38]
• The subtype of systemised paranoia characterised by somatic phenomena.^[39][40]
• Compulsive nail-biting (onychophagia).^[41]
• Cataplexy associated with narcolepsy. This is a TGA and MHRA-labeled indication for clomipramine.^[21][22]
• Self-bloodletting^[42]
• Premature ejaculation,^[43] where it may be more effective than paroxetine^[44]
• Depersonalization disorder^[45]
• Chronic pain with or without organic disease, particularly headache of the tension type.^[46]
• Developmental stuttering^[47][48]
• Sleep paralysis, with or without narcolepsy
• Enuresis (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.^[49] Combining a tricyclic (such as clomipramine) with anticholinergic medication may be more effective for treating enuresis than the tricyclic alone.^[49]
• Trichotillomania^[50][51][52]
• In combination with lithium and tryptophan for severe, particularly treatment-resistant depression.^[53] This combination, in a similar vein, has also been used for clomipramine-resistant obsessive-compulsive disorder.^[54][55][56] When electro-convulsive therapy is performed alongside this treatment-regime (as may be the case in severe depression and accompanied with thyroxine,^[57][58]) however, great care must be taken with lithium.^[59][60] 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).

Although lithium is most-associated with the treatment of bipolar disorder (where it is known for its general mood-stabilising features and to be especially useful in treating and preventing mania), 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, paroxetine), venlafaxine 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 suicide in general.^[61][62][63] 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 of various trials involving fluoxetine (Prozac), fluvoxamine (Faverin/Luvox), and sertraline (Zoloft) to test their relative efficacies in treating OCD, clomipramine was found to be significantly more effective.^[64][65] Other studies have borne similar results even when risk of bias is eliminated.^[66] 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:^[20]

• 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
• Untreated urinary retention
• It must not be given in combination or within 3 weeks before or after treatment with a monoamine oxidase inhibitor. (Moclobemide 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.^[22][67] It is also associated with reversible withdrawal effects in the newborn.^[68] Clomipramine is also distributed in breast milk and hence nursing while taking clomipramine is advised against.^[18]

Side effects

Clomipramine has been associated with the side effects listed below:^{[17][18][19][20]}

Very common (>10% frequency):

Common (1–10% frequency):

Uncommon (0.1–1% frequency):

• Convulsions
• Ataxia
• Arrhythmias
• Elevated blood pressure
• Activation of psychotic symptoms

Very rare (<0.01% frequency):

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

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 clomipramine and SSRIs.^[69][70]

Topiramate has been used to off-set the weight-gain induced from various antidepressants and antipsychotics,^[71] and more broadly for general weight-loss (likewise with bupropion).^[71] 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, as the weight-loss associated with topiramate may be very impressive indeed.^{[72][73][74][75][76]}

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 or seizures 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, venlafaxine). In the case of seizures occurring due to overdose of tricyclic antidepressants, intravenous lorazepam may successfully abort 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.^[77][78][79]

Tremor may be relieved with a beta-blocker (e.g., pindolol, propranolol, atenolol). 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.^{[80][81][82][83][84]}

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.^[19] Differentiating between the return of the original psychiatric disorder and clomipramine withdrawal symptoms is important.^[85] Clomipramine withdrawal can be severe.^[86] Withdrawal symptoms can also occur in neonates when clomipramine is used during pregnancy.^[68] 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.^[87]

Overdose

Clomipramine overdose usually presents with the following symptoms:^[17][19][20]

There is no specific antidote for overdose and all treatment is purely supportive and symptomatic.^[19] Treatment with activated charcoal may be used to limit absorption in cases of oral overdose.^[19] Anyone suspected of overdosing on clomipramine should be hospitalised and kept under close surveillance for at least 72 hours.^[19] 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.^[88] In another meta-analysis, however, clomipramine was associated with a significant degree of toxicity in overdose.^[89]

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, paroxetine) and serotonergic agents such as triptans, other tricyclic antidepressants, tramadol, etc. (due to the potential for serotonin syndrome).^[19] Its use is also advised against in those concurrently on CYP2D6 inhibitors, due to the potential for increased plasma levels of clomipramine and the resulting potential for CNS and cardiotoxicity.^[19]

Fluvoxamine increases the serotoninergic effects of clomipramine and, likewise, clomipramine increases fluvoxamine levels.^[90]

Pharmacology

Pharmacodynamics

Clomipramine is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin–norepinephrine reuptake inhibitor (SNRI); that is, it blocks the reuptake of these neurotransmitters back into neurons by preventing them from interacting with their transporters, thereby increasing their extracellular concentrations in the synaptic cleft and resulting in increased serotonergic and noradrenergic neurotransmission.^[104][92] In addition, clomipramine also has antiadrenergic, antihistamine, antiserotonergic, antidopaminergic, and anticholinergic activities. It is specifically an antagonist of the α₁-adrenergic receptor, the histamine H₁ receptor, the serotonin 5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₆, and 5-HT₇ receptors, the dopamine D₁, D₂, and D₃ receptors, and the muscarinic acetylcholine receptors (M₁–M₅).^[100][93] Like other TCAs, clomipramine weakly blocks voltage-dependent sodium channels as well.^{[104][15][105]}

Probably all “anticholinergic” side-effects may be successfully reversed in a majority of people with bethanechol chloride,^{[106][107][108]} although knowledge of this amenability has unfortunately decreased in medical circles over the decades. It (bethanechol supplementation) arguably should, however, be seriously entertained when tricyclics which often carry significant anti-muscarinic effects (amitriptyline, protriptyline, imipramine, 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 (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).^[109][110] Moreover, desmethylclomipramine circulates at concentrations that are approximately twice those of clomipramine.^[111] In accordance, occupancy of both the SERT and the NET has been shown with clomipramine administration in positron emission tomography studies with humans and non-human primates.^[112][113] As such, clomipramine is in fact a fairly balanced SNRI rather than only a serotonin reuptake inhibitor (SRI).^[114]

The antidepressant effects of clomipramine are thought to be due to reuptake inhibition of serotonin and norepinephrine,^[104] 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 muscarinic acetylcholine receptors is thought to contribute to its side effects.^[104] Blockade of the H₁ receptor is specifically responsible for the antihistamine effects of clomipramine and side effects like sedation and somnolence (sleepiness).^[104] Antagonism of the α₁-adrenergic receptor is thought to cause orthostatic hypotension and dizziness.^[104] Inhibition of muscarinic acetylcholine receptors is responsible for the anticholinergic side effects of clomipramine like dry mouth, constipation, urinary retention, blurred vision, and cognitive/memory impairment.^[104] In overdose, sodium channel blockade in the brain is believed to cause the coma and seizures associated with TCAs while blockade of sodium channels in the heart is considered to cause cardiac arrhythmias, cardiac arrest, and death.^[104][15] On the other hand, sodium channel blockade is also thought to contribute to the analgesic effects of TCAs, for instance in the treatment of neuropathic pain.^[115]

The exceptionally strong serotonin reuptake inhibition of clomipramine likely precludes the possibility of its antagonism of serotonin receptors (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 antagonists like cyproheptadine and chlorpromazine are effective as antidotes against serotonin syndrome,^[116][117] clomipramine is nonetheless capable of inducing this syndrome.^[114] 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 imipramine,^[114][116] 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).^[118] As such, whereas other TCAs can be combined with monoamine oxidase inhibitors (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.^[104] 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.^[15][104]

Serotonergic activity