Panic disorder with or without agoraphobia. 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.
In a metaanalysis 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.
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.
Adverse effects by frequency: Very common (>10% frequency):
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]).
Hepatitis (liver swelling) with or without jaundice — the yellowing of the eyes, the skin, and mucous membranes due to impaired liver function.
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:
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 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. 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 or benztropine mesylate.
There is no specific antidote for overdose and all treatment is purely supportive and symptomatic. Treatment with activated charcoal 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 obsessive-compulsive disorder. In another meta-analysis, however, clomipramine was associated with a significant degree of toxicity in overdose.
Mechanism of action
Structure of desmethylclomipramine, clomipramine's active metabolite
Peak plasma concentrations occur around 2–6 hours (with an average of 4.7 hours) after taking clomipramine orally. Maximum plasma concentrations of clomipramine are around 56-154 ng/mL. 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. Steady-state concentration of the active metabolite, desmethylclomipramine, are around 230-550 ng/mL. Its oral bioavailability is 50%. It binds approximately 97-98% to plasma proteins, primarily albumin. It is metabolised in the liver primarily by CYP2D6. It has an elimination half-life of 32 hours, and its N-desmethyl metabolite, desmethylclomipramine, has a half-life of approximately 69 hours. It is mostly excreted in urine (60%) and faeces (32%). Its volume of distribution (Vd) is approximately 17 L/kg.
In the US, clomipramine is currently only licensed to treat separation anxiety in dogs for which it is sold under the brand name clomicalm. It has also proven itself effective in the treatment of obsessive-compulsive disorders in cats and dogs. In dogs it has also demonstrated similar efficacy to fluoxetine in treating tail chasing. In dogs some evidence suggests its efficacy in treating noise phobia. It has also demonstrated efficacy in treating urinary spraying in cats.
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