Clomipramine


Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant. It is used in the treatment of various conditions, most notably obsessive–compulsive disorder but also many other disorders, including hyperacusis, panic disorder, major depressive disorder, trichotillomania, body dysmorphic disorder and chronic pain. It has also been notably used to treat premature ejaculation and the cataplexy associated with narcolepsy.
It may also address certain fundamental features surrounding narcolepsy besides cataplexy. The evidence behind this, however, is less robust. As with other antidepressants, it may paradoxically increase the risk of suicide 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 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 and norepinephrine.
Clomipramine was discovered in 1964 by the Swiss drug manufacturer Ciba-Geigy. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.

Medical uses

Clomipramine has a number of uses in medicine, including in the treatment of:
  • Obsessive–compulsive disorder, which happens to be its only US -labeled indication. Other regulatory agencies have also approved clomipramine for this indication.
  • Major depressive disorder, 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. 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, at a dosage of 50 mcg. In the case of clomipramine specifically, this may also be the case with obsessive-compulsive disorder.
  • Panic disorder with or without agoraphobia.
  • Body dysmorphic disorder
  • Repetitive self-injurious/self-harming behaviours in those with intellectual disability specifically.
  • The subtype of systemised paranoia characterised by somatic phenomena.
  • Compulsive nail-biting.
  • Cataplexy associated with narcolepsy. This is a TGA and MHRA-labeled indication for clomipramine.
  • Self-bloodletting
  • Premature ejaculation, where it may be more effective than paroxetine
  • Depersonalization-derealization disorder
  • Chronic pain with or without organic disease, particularly headache of the tension type.
  • Developmental stuttering
  • Sleep paralysis, with or without narcolepsy
  • Enuresis 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 with anticholinergic medication may be more effective for treating enuresis than the tricyclic alone.
  • Trichotillomania
  • In combination with lithium 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 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.
  • Isolated cataplexy unto itself, admittedly a rare condition
  • There is anecdotal and tentative, as-yet-undocumented information suggesting that clomipramine may address certain core features of hyperacusis, and possibly misophonia. In the case of hyperacusis, 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, it may have a certain place in the management of treatment-resistant depression. In these cases it is often prescribed alongside SSRIs, venlafaxine and various of the tricyclics, 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. In any case, it is not necessary to have a diagnosis of bipolar affective disorder, or even to be considered to have subtle elements of it, to benefit from lithium in the context of treatment with clomipramine.
In a meta-analysis of various trials involving fluoxetine, fluvoxamine, and sertraline 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:
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 effects listed below:
Very common :
Common :
Uncommon :
Very rare :
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.
Topiramate has been used to off-set the weight-gain induced from various antidepressants and antipsychotics, and more broadly for general weight-loss. 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. 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 should they require or opt for treatment with an antidepressant which reduces the seizure-threshold significantly.
In the case of seizures occurring due to overdose of tricyclic antidepressants, intravenous lorazepam 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. 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.