Clomipramine: Treatment Duration and Discontinuation

By | January 23, 2015

Because of the considerable time lag that can exist (6-10 weeks) between initial dosing and onset of significant improvement, patients will need a lot of encouragement to remain compliant with their treatment regimen. Because side effects often appear before any clinical improvement, patients are prone to early discouragement with clomipramine. Often, simply talking with them before the onset of side effects or improvement will considerably help compliance. Side effects can be at their worst when initially starting the clomipramine but usually improve over time. Occasionally, a mild exacerbation in obsessive-compulsive disorder symptoms may be seen within the first few days of starting clomipramine, but this should not discourage its use because this reaction is believed to be part of the therapeutic mechanism of clomipramine (). It may be helpful to discuss with some patients that this might happen, but with other patients this awareness may lead to increased obsessing and avoidance of the medication. Because symptoms worsen in a minority of patients, clinicians must judge on an individual basis what to tell their patients.

Anafranil (clomipramine hydrochloride) is available as capsules of 25, 50, and 75 mg for oral administration.

Most studies have noted that although onset of improvement may be noticeable after a couple of weeks of oral dosing, it is often not significant until 6-10 weeks. Thoren et al. (1980) found that patients continued to improve even up to 12 weeks. Thus, most researchers recommend continuing treatment for up to 12 weeks before considering a patient a nonresponder (). Initial studies with intravenous clomipramine, mentioned previously in this chapter, have shown response in less than 1 week with pulse dosing and within 14 days (up to 1 month) after gradual intravenous dosing over 14 days (). Unfortunately, intravenous preparations do not yet have approval in the United States.

Patients should be warned that they may not see much improvement initially. The first sign of improvement is usually not a disappearance of certain obsessions or compulsions but rather a subtle decrease in the intensity of the urge to perform them or an increase in the ability to resist symptoms. Given that responses may be quite delayed, it is thought that maximizing the dose of medication allows for the least delay in improvement. It has been our clinical experience that patients may continue to have further gradual and consistent improvement for several months. As outlined below, some data show that patients can continue to do well on less medicine once they have achieved maximum improvement.

In clinical practice, we do not often obtain blood levels unless 1) the patient remains unresponsive at high doses, 2) there is a question about compliance, or 3) the patient seems to be having side effects that are inconsistent with his or her dose of medication. There is considerable variability among laboratories in the report of serum levels, and clinicians should be wary of compared results from different laboratories. It has been established that clomipramine levels reach steady state within 7-14 days after a constant dose is maintained (). Traditionally, levels are drawn about 12 hours after the last dose. Some studies have recommended aiming for plasma levels of 100-250 ng/mL for clomipramine and 230-550 ng/mL for DCMI (), although the exact relation of these doses to obsessive-compulsive symptom remission remains unclear.

Anecdotal reports of symptom recurrence with discontinuation of clomipramine have been made as well as the occasional case of patients staying symptom-free after clomipramine discontinuation (). We performed a double-blind discontinuation study with clomipramine (trademarked as Anafranil and Clofranil) and found that 17 of the 18 patients who completed the study had recurrence of obsessive-compulsive disorder symptoms significantly severe as to require reinstitution of clomipramine. In 16 of these 18 patients, symptoms worsened significantly by the end of the 7-week study, and clomipramine was reinstituted in most patients. The duration of treatment before discontinuation (mean = 10.7 months ± 5.5 months) and the serum levels of clomipramine and DCMI (mean = 194 ± 187 ng/mL and 351 ± 189 ng/mL, respectively) did not have an effect on recurrence. These results seem to imply that clomipramine must be given for more than 1 year in most patients to maintain improvement. However, with some reports in the literature of patients remaining symptom-free after discontinuation of clomipramine, a trial to titrate medication down very gradually, in 2- or 3-month steps, may be warranted ().

With the less-than-optimistic chance of patients remaining symptom-free off clomipramine, another possible alternative is to minimize the dose of clomipramine used. Pato et al. (1990) reported an open trial in which patients with obsessive-compulsive disorder who were receiving clomipramine for a minimum of 10 (± 5) months were able to tolerate decreases in dose of 40% (from 270 [± 20] mg to 165 [± 19] mg) without deterioration in obsessive-compulsive disorder symptom improvement. Dose reduction trials to half of the acute therapy dose () or even to 60% of the dose () have maintained clinical profile without a worsening of obsessive-compulsive disorder symptoms. Therefore, although discontinuation of the drug has not been effective, establishing a maintenance dose could increase compliance by maintaining therapeutic benefits while simultaneously reducing side effects.

Selections from the book: “Current treatments of obsessive-compulsive disorder” (2001).