Clomipramine

5

Obsessive-compulsive disorder affects about 2 percent of the U.S. population and can be quite disabling. Clomipramine is the only drug approved for the treatment of obsessive-compulsive disorder. its efficacy is unique among tricyclic antidepressants and may be related to its relatively high potency in affecting serotonergic neurotransmission. The drug has many anticholinergic effects, but it is relatively well tolerated by the patients for whom it is effective. A 0.4 percent incidence of seizures, a potentially serious side effect, has been observed. Other antidepressants that are relatively selective for serotonergic (as opposed to noradrenergic) transmission may be as effective as clomipramine in the treatment of this disorder; controlled studies are under way. Clomipramine at low doses is also effective in the treatment of panic disorder and has been used successfully in the treatment of premature ejaculation.

Obsessive-compulsive disorder occurs in 1.5 to 2.5 percent of men and women (lifetime prevalence), making it much less common than major depression but more common than schizophrenia. (1) Clomipramine (chlorimipramine; Anafranil) is the only drug approved by the U. S. Food and Drug Administration for the treatment of obsessive-compulsive disorder. The drug is a tricyclic antidepressant and has been available for more than 20 years. While clomipramine may be useful in the treatment of obsessive-compulsive disorder, studies have shown that most other antidepressants are ineffective. Clomipramine has been found to be effective even when patients are not significantly depressed.(2,3) Clomipramine has also been shown to be effective in the treatment of panic attacks.(4,5)

Mechanism of Action

Clomipramine is a potent inhibitor of serotonin reuptake by presynaptic neurons, with relatively little effect on norepinephrine reuptake. Metabolism of clomipramine, which includes demethylation to desmethylclomipramine, resembles that of other tertiary amine tricyclics, such as amitriptyline (Elavil, Endep). The relatively selective effect of clomipramine on serotonergic neurons is thought to be the reason it is more effective than other tricyclics in the treatment of obsessive-compulsive disorder.(6) However, there appear to be other factors involved, since "pure" serotonin reuptake blockers may be less effective, or even ineffective, in the treatment of obsessive-compulsive disorder and less effective in the treatment of endogenous depression. (7,8)

The hypothesis that an abnormality in serotonergic transmission causes the symptoms of obsessive-compulsive disorder is based on two observations: (1) clomipramine is significantly more effective than other tricyclic antidepressants and more effective than monoamine oxidase inhibitors (MAOIs) in the treatment of obsessive-compulsive disorder and (2) clomipramine is far more potent than other drugs in inhibiting the neuronal reuptake of serotonin. Clomipramine has been compared with the tricyclic antidepressants imipramine (Janimine, Tofranil), nortriptyline (Aventyl, Pamelor) and amitriptyline, with the MAOI clorgyline and with desipramine (Norpramin, Pertofrane), a tricyclic with virtually no effect on serotonin reuptake, and has been found to be significantly more effective in treating obsessive-compulsive disorder.(6)

The efficacy of clomipramine in the treatment of obsessive-compulsive disorder led to studies of other relatively selective inhibitors of serotonin reuptake. Most of the studies have not been double-blind, placebo-controlled studies, such as those with clomipramine. However, there is good reason to believe that fluoxetine (Prozac) will be effective in patients with obsessive-compulsive disorder. (9-12) Fluvoxamine now in phase 3 premarketing trials in the United States, has also shown promise.(12,13)

Pharmacokinetics

Oral clomipramine is rapidly and almost completoly absorbed from the gastrointestinal tract. Peak blood levels are reached two to four hours after the ingestion of a single dose.(5,14) As with other tricyclic antidepressants, no clear relationship between steady-state plasma concentration and dosage has been found.(5,15)

The half-life of clomipramine is 20 to 24 hours. Despite this long half-life, the manufacturer recommends giving the drug in several divided doses per day. Therapy is initiated in a dosage of 25 mg two or three times daily. About half of the patients in a large multicenter trial responded to a total daily dosage of 200 mg or less. Nearly all of those responding did so at a dosage of 250 mg or less per day, the recommended maximum daily dosage.(16)

Adverse Reactions

Both clomipramine and its metabolite desmethylclomipramine are strongly anticholinergic, accounting for many of the side effects, including dry mouth, constipation and paralysis of ocular accommodation. These effects are shared with other tricyclic antidepressants. Clomipramine can also cause nausea, an effect it shares with fluoxetine; this effect may reflect serotonergic stimulation. Clomipramine may also retard or inhibit ejaculation. (The side effect of failure to ejaculate may be related to the effectiveness of the drug in the treatment of premature ejaculation(17,18); for this purpose, a dosage of about 75 mg per day is required.)

Seizures have been reported in 0. 7 percent of approximately 5,000 patients in clinical trials. The effect is dose-related: 0.5 percent of patients taking 250 mg or less per day had a seizure, whereas more than 2.1 percent of patients taking 300 mg or more per day had a seizure.(5) Even at daily dosages of 250 mg or less, seizures are more frequent with clomipramine than with imipramine.(19)

Clinical Use

Patients with obsessive-compulsive disorder respond to clomipramine with steady improvement, which may not plateau for three to five months. Patients begin to improve from the first week of treatment, but most of the clinically significant changes occur after about five weeks of treatment.(16,20)

This improvement has been shown to be maintained for up to one year.(16)

While most patients improve, they do not become free of all symptoms, even though some patients no longer meet the diagnostic criteria for obsessive-compulsive disorder. In addition, response to behavioral therapy is not usually complete. Patients treated with drugs tend to relapse when therapy is stopped, while those responding to behavioral therapy tend to maintain some degree of clinical improvement.

Clomipramine has also been found to be effective in the treatment of panic disorder (and agoraphobia with panic attacks) in several open and double-blind trials.(4,5,21) It was equal to imipramine, a standard drug for the treatment of panic attacks, after six weeks of treatment.(21) In other trials, clomipramine was shown to be superior to placebo.(5) Most patients responded to far lower doses of clomipramine than are usually necessary for the treatment of depression.(4)

As noted, clomipramine has long been known to be an effective antidepressant, although it is not approved for this indication in the United States. Clomipramine can relieve the symptoms of endogenous depression after one or two relatively high doses. In a series of studies conducted over several years, high doses (150 to 200 mg) of clomipramine, given once daily, were found to relieve the symptoms of endogenous depression in adults and adolescents.(22,23) The same effects were present whether the drug was given by mouth or by intravenous infusion.(24) The critical variable seemed to be the magnitude of the dose, rather than the route of administration.(25) The mechanism of this unusually rapid antidepressant effect is not known.

Clomipramine, like some other tricyclic antidepressants, can be safely given with MAOIs,(26) but this potentially lethal combination should probably be prescribed only by physicians who are experienced with this approach.(27) Clomipramine has also been used safely in combination with antipsychotic drugs.(28), The antipsychotic drug should have a low incidence of anticholinergic side effects.

Clomipramine has been combined with other drugs that are thought to enhance serotonergic transmission. For example, in one study,(29) it was used with tryptophan and lithium in the treatment of depression. In another study, (30) clomipramine was given with fenfluramine, an indirectly acting serotonergic agonist, to augment the response of obsessive-compulsive patients who had a partial response to clomipramine. All of these combinations were found to be safe and effective in case reports of individual patients or in small studies of patients who failed to respond to clomipramine alone.

Clomipramine is also effective in the treatment of trichotillomania, a relatively unusual disorder in which patients pull out, and sometimes eat, their own hair. The irresistible impulse to pull out hair may be considered a type of compulsion. In one controlled study,(31) patients responded to clomipramine but not desipramine.

Final Comment

Clomipramine is effective and relatively safe in the treatment of obsessive-compulsive disorder. The drug is probably not unique in its efficacy: other serotonin-reuptake inhibitors have been effective in clinical trials, although some may be less effective than clomipramine. Evidence suggests that fluoxetine is also effective and may be better tolerated than clomipramine.

Many patients tolerate the side effects of clomipramine quite well, especially when they experience profound relief of symptoms. Some patients may prefer clomipramine to fluoxetine, especially if fluoxetine causes anxiety or gastrointestinal distress. Clomipramine is currently unique in its effectiveness in the treatment of premature ejaculation and in its rapid onset of antidepressant action when given in larger-than-usual daily doses. It is also a good alternative treatment for panic disorder.

COPYRIGHT 1991 American Academy of Family Physicians
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