Clomipramine

Source: Wikipedia, the free encyclopedia.

Clomipramine
Skeletal formula of clomipramine
Ball-and-stick model of the clomipramine molecule
Clinical data
Trade namesAnafranil, Clomicalm, others
Other namesClomipramine; 3-Chloroimipramine; G-34586[1]
AHFS/Drugs.comMonograph
MedlinePlusa697002
License data
Pregnancy
category
  • AU: C
intravenous[2]
ATC code
Legal status
Legal status
Renal (51–60%)[4]
Feces (24–32%)[4]
Identifiers
  • 3-(3-Chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine
JSmol)
  • CN(C)CCCN1c2ccccc2CCc2ccc(Cl)cc21
  • 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 checkY
  • Key:GDLIGKIOYRNHDA-UHFFFAOYSA-N checkY
  (verify)

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

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.

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

generic medication.[5]

Medical uses

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

Although lithium is most-associated with the treatment of

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

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):

  • Weight loss
  • Dystonia
  • Cognitive impairment
  • 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
  • Increased
    transaminases
  • Increased Alkaline phosphatase
  • 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)
  • 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).
  • Leukopenia — a low white blood cell count.
  • Agranulocytosis — a more severe form of leukopenia; a dangerously low neutrophil count which leaves one open to life-threatening infections due to the role of the white blood cells in defending the body from invaders.
  • 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.
  • 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
    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

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.,

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.

benztropine mesylate.[87]

Overdose

Main article: Tricyclic antidepressant overdose

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

  • 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.

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

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

See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Clomipramine (and metabolite)[91]
Site CMI
DMC
Tooltip Desmethylclomipramine		 Species Ref
SERTTooltip Serotonin transporter 0.14–0.28 40 Human/rat [92][93][94]
NETTooltip Norepinephrine transporter 38–53.7 0.32 Human/rat [92][93][94]
DATTooltip Dopamine transporter ≥2,190 2,100 Human/rat [92][93][94]
5-HT1A ≥7,000 19,000 Human/und [95][93][94]
5-HT1B >10,000 ND Human [93]
5-HT1D >10,000 ND Human [93]
5-HT2A 27–35.5 130 Human/und [95][93][94]
5-HT2B ND ND ND ND
5-HT2C 64.6 ND Human [93]
5-HT3 460–985 ND Rodent [93][96][97]
5-HT6 53.8 ND Rat [98]
5-HT7 127 ND Rat [99]
α1 3.2–38 190 Human/und [93][100][94]
α2 525–3,200 1,800 Human/und [93][100][94]
β
 22,000 16,000 Undefined [94]
D1
 219 320 Human/und [96][94]
D2
 77.6–190 1,200 Human/und [93][100][94]
D3
 30–50.1 ND Human [93][96]
D4
 ND ND ND ND
D5
 ND ND ND ND
H1 13–31 450 Human/und [101][100][94]
H2 209 ND Human [101]
H3 9,770 ND Human [101]
H4 5,750 ND Human [101]
mACh
Tooltip Muscarinic acetylcholine receptors		 37 92 Human/und [100][94]
σ1 546 ND Rat [102]
hERG
Tooltip Human Ether-à-go-go-Related Gene		 130 (
IC50
Tooltip Half-maximal inhibitory concentration)		 ND Human [103]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Clomipramine is a

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

desmethylclomipramine (norclomipramine), binds to the NET with very high affinity (Ki = 0.32 nM) and with dramatically reduced affinity for the SERT (Ki = 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,

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


Comparison of SERT-active antidepressants[118]
Medication SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter Dosage
(mg/day)
t1/2
Tooltip Terminal half-life (M)
(hours)		 Cp
(ng/mL)		 Cp / SERT
ratio
Amitriptyline 4.3 34.5 100–200 16 (30) 100–250 23–58
Amoxapine 58.5 16.1 200–300 8 (30) 200–500 3.4–8.5
Butriptyline[92] 1,360 5,100 ? ? ? ?
Clomipramine 0.14–0.28 37 100–200 32 (70) 150–500 536–3,570
Desipramine 17.5 0.8 100–200 30 125–300 7.1–17
Dosulepin[119][120][121] 8.3 45.5 150–225 25 (34) 50–200 6.0–24
Doxepin 66.7 29.4 100–200 18 (30) 150–250 2.2–3.7
Imipramine 1.4 37 100–200 12 (30) 175–300 125–214
Iprindole[92] 1,620 1,262 ? ? ? ?
Lofepramine[92] 70.0 5.4 ? ? ? ?
Nortriptyline 18.5 4.4 75–150 31 60–150 3.2–8.1
Protriptyline 19.6 1.4 15–40 80 100–250 5.1–13
Trimipramine[92] 149 2,450 75–200 16 (30) 100–300 0.67–2.0
Citalopram 1.4 5,100 20–40 36 75–150 54–107
Escitalopram 1.1 7,840 10–20 30 40–80 36–73
Fluoxetine 0.8 244 20–40 53 (240) 100–500 125–625
Fluvoxamine 2.2 1,300 100–200 18 100–200 45–91
Paroxetine 0.34 40 20–40 17 30–100 300–1,000
Sertraline 0.4 417 100–150 23 (66) 25–50 83–167
Duloxetine 1.6 11.2 80–100 11 ? ?
Milnacipran 123 200 ? ? ? ?
Venlafaxine 9.1 535 75–225 5 (11) ? ?
The values for the SERT and NET are Ki (nM). Note that in the Cp / SERT ratio,
free versus protein-bound drug concentrations are not accounted for.

SERT occupancy by SRIs at clinically approved dosages
Medication Dosage range
(mg/day)[122]		 ~80% SERT
occupancy
(mg/day)[123][124]		 Ratio (dosage /
80% occupancy)
Citalopram 20–40 40 0.5–1
Escitalopram 10–20 10 1–2
Fluoxetine 20–80 20 1–4
Fluvoxamine 50–300 70 0.71–5
Paroxetine 10–60 20 0.5–3
Sertraline 25–200 50 0.5–4
Duloxetine 20–60 30 0.67–2
Venlafaxine 75–375 75 1–5
Clomipramine 50–250 10 5–25

Clomipramine is an extremely strong SRI by all accounts.

terminal half-life that is around twice as long as that of amitriptyline and imipramine.[118][127] In spite of these differences however, clomipramine is used clinically at the same usual dosages as other serotonergic TCAs (100–200 mg/day).[118]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.[128] Sustained-release 75 mg formulation may be preferable at doses above 150mg/day (i.e 200mg to 250mg/day).[129][130] 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.[118] 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.[125][126] In addition, clomipramine is more potent as an SRI than any selective serotonin reuptake inhibitors (SSRIs); it is more potent than paroxetine, which is the strongest SSRI.[118]

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 fluvoxamine.[112] 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.[112] 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.[112] Other studies have found 83% SERT occupancy with 20 mg/day paroxetine and 77% SERT occupancy with 20 mg/day citalopram.[112][131] 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.[112][123] Moreover, clomipramine may be able to achieve more complete occupancy of the SERT at high doses, at least relative to fluvoxamine.[112]

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.

overdosed in patients.[123] It has been suggested that the same may have been true for clomipramine and other TCAs.[123] 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.[132]

Obsessive–compulsive disorder

Clomipramine was the first drug that was investigated for and found to be effective in the treatment of OCD.[15][133] In addition, it was the first drug to be approved by the FDATooltip Food and Drug Administration in the United States for the treatment of OCD.[134] The effectiveness of clomipramine in the treatment of OCD is far greater than that of other TCAs, which are comparatively weak SRIs; a meta-analysis found pre- versus post-treatment effect sizes of 1.55 for clomipramine relative to a range of 0.67 for imipramine and 0.11 for desipramine.[135] 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.[135] However, multiple meta-analyses have found that clomipramine nonetheless retains a significant effectiveness advantage relative to SSRIs;[136] in the same meta-analysis mentioned previously, the effect sizes of SSRIs in the treatment of OCD ranged from 0.81 for fluoxetine to 1.36 for sertraline (relative to 1.55 for clomipramine).[135] However, the effectiveness advantage for clomipramine has not been apparent in head-to-head comparisons of clomipramine versus SSRIs for OCD.[136] The differences in effectiveness findings could be due to differences in methodologies across non-head-to-head studies.[135][136]

Relatively high doses of SSRIs are needed for effectiveness in the treatment of OCD.

duration of action.[139]
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

D3 receptors at high concentrations.[118][136][140] Addition of antipsychotics, which are potent dopamine receptor antagonists, to SSRIs, has been found to significantly augment their effectiveness in the treatment of OCD.[136][141] 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.[142][143]
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

safety due to its lack of selectivity for the SERT and promiscuous pharmacological activity.[136][144] In addition, clomipramine has high toxicity in overdose and can potentially result in death, whereas death rarely, if ever, occurs with overdose of SSRIs.[136][144] 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.[144]

Pharmacokinetics

The

terminal half-life of 32 hours,[145][146] and its N-desmethyl metabolite, desmethylclomipramine, has a terminal half-life of approximately 69 hours.[18] Clomipramine is mostly excreted in urine (60%) and feces (32%).[18]

Although the normal maximum-recommended total daily dosage of clomipramine is 250 milligrams, treatment-resistant cases of depression

seizures, which are more likely to occur with clomipramine than every other tricyclic antidepressant 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%.[149] (All tricyclic antidepressants technically lower the seizure-threshold but this is only significant with amoxapine, maprotiline and, indeed, clomipramine.[150]
)

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

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

molecular weight of 314.857 g/mol.[1] The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely.[1][159] The CAS Registry Number of the free base is 303-49-1 and of the hydrochloride is 17321-77-6.[1][159]

History

Clomipramine was developed by

Geigy as a chlorinated derivative of imipramine.[15][160] It was first referenced in the literature in 1961 and was patented in 1963.[160] The drug was first approved for medical use in Europe in the treatment of depression in 1970,[160] and was the last of the major TCAs to be marketed.[4] 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 United States.[4] 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.[161]

Clomipramine was eventually approved in the United States for the treatment of OCD in 1989 and became available in 1990.

placebo-controlled clinical trial of clomipramine for OCD was conducted in 1976,[133] with more rigorous clinical studies that solidified its effectiveness conducted in the 1980s.[15] 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).[164][165] 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.[166][167]

Society and culture

Generic names

Clomipramine is the

Latin.[159][169]

Brand names

Clomipramine is marketed throughout the world mainly under the brand names Anafranil and Clomicalm for use in humans and animals, respectively.[159][169]

Veterinary uses

In the U.S., clomipramine is only licensed to treat separation anxiety in dogs for which it is sold under the brand name Clomicalm.[170] It has proven effective in the treatment of obsessive–compulsive disorders in cats and dogs.[171][172] In dogs, it has also demonstrated similar efficacy to fluoxetine in treating tail chasing.[173] In dogs some evidence suggests its efficacy in treating noise phobia.[174]

Clomipramine has also demonstrated efficacy in treating

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.[176]

References

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    ISBN 978-1-4757-2085-3. Archived
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  2. ISBN 978-0-470-97948-8
    .
  3. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  4. ^
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