The side effects of clomipramine (trademarked as Anafranil and Clofranil) are typical of those seen with other TCAs. The literature disagrees on the relationship between side effects and plasma levels. Stern et al. (1980) found no relationship between side effects and serum levels. However, Capstick (1977) felt that the side effects were dose dependent although they, as well as the therapeutic effects, varied from patient to patient. In a recent study, Ackerman et al. (1996) correlated this differential side effect profile as a predictor of clinical response in which the presence of side effects during the first 4 weeks of treatment represented a marker of drug responsiveness. Our own clinical experience seems to indicate that a dose-dependent relationship exists for side effects but that there is considerable individual variability. In a systematic study of diminished dosing of clomipramine, we found that patients could tolerate a 40% drop in dose with no deterioration in symptom improvement but with some decrease in side effects ().
Despite the serotonergic and noradrenergic properties of clomipramine, most of the side effects are anticholinergic in nature (). The most commonly reported side effects are dry mouth, dizziness, tremor, somnolence, constipation, ejaculation failure in men, fatigue, nausea, headache, and increased sweating (Clomipramine Collaborative Study Group 1991). Stern et al. (1980) noted that during the first 4 weeks of a study of clomipramine, patients reported significant side effects, including eye-focusing problems, constipation, dizziness, drowsiness, unsteady hands, dry mouth, and increased sweating. However, by the end of the 7-week study, only unsteady hands, dry mouth, and sweating maintained statistically significant severity.
In general, patients habituate to most of these side effects over time. Dry mouth is considered by some to be the most significant long-term side effect because of the effects of decreased saliva on dental health. Clinicians should recommend good oral hygiene and avoidance of sugared candies to keep the mouth moist; sugarless gum and candies are preferable and saliva substitutes may even be considered.
Constipation can often be handled by having patients stay well hydrated. We often recommend to our patients a minimum of eight glasses of fluid per day, increased fiber in their diet, and a regular schedule of exercise. If this does not work, a stool softener such as docusate sodium (Co-lace), 100-300 mg/day, or psyllium hydrophilic mucilloid (Metamucil) is added.
If patients complain of nausea, therapists can recommend taking the clomipramine with or without food, whichever minimizes the nausea best.
Fatigue is also a problem, and for this reason we often give the full dose of medication at bedtime. If fatigue on awakening is noted, we move the evening dose from bedtime to 8:00 PM and then to 5:00 PM, and this often helps. If this adjustment does not work, decreasing the dose or dividing it to two or three times a day may help, although the major portion of the medicine is still taken at bedtime.
As with other TCAs, patients occasionally develop urinary hesitance or even urinary retention. Hesitancy, if persistent, can usually be managed with a bethanechol derivative of 25 mg up to three times a day; however, severe hesitancy or urinary retention warrants urologic consultation and probably medication discontinuation.
Mental cloudiness or mild memory deficit is a symptom that, although present in many of our patients, is usually well tolerated. Often, reassurance that the symptom is not permanent is enough to put the patient at ease. Occasionally, a patient finds this side effect intolerable, in which case the dose must be decreased or the medication stopped.
Monteiro et al. (1987) reported a high incidence of anorgasmia in patients with obsessive-compulsive disorder who were being treated with clomipramine. They noted that 22 of 24 male and female patients with obsessive-compulsive disorder who had normal sexual function developed anorgasmia while receiving clomipramine. This symptom occurred in most cases within 3 days of starting treatment at very low doses of 25-50 mg. Only 2 of the 22 patients found remission of this symptom within 2-3 months on clomipramine, although all patients had return of normal sexual functioning within 3 days of stopping clomipramine. The authors pointed out that eliciting a history of this side effect was difficult. Patients were reticent to report it; in fact, in 36% of the cases it was not reported on a standardized questionnaire but revealed with direct questioning. A retrospective chart review of male patients receiving several different antidepressants found sexual dysfunction, including decreased libido, erectile difficulties, and impairment in orgasm and ejaculation, in 12 of 39 men receiving TCAs (clomipramine was not evaluated individually) (). Although quite common, the dysfunction was reported less often for TCAs (30.8%) than for the SSRIs fluoxetine, paroxetine, and sertraline (50%; 24 of 48 cases) (). In our clinical experience, many patients experience some decrease in orgasm or sex drive, but we have found that decreasing the dose lessens the severity of this side effect in many patients (see case examples at the end of this chapter). However, clomipramine might be helpful in those patients who experience premature ejaculation because it causes delayed ejaculation.
Sexual dysfunction associated with clomipramine as well as other serotonin reuptake inhibitors in some cases can be counteracted with additional pharmacologic agents. Clomipramine-induced anorgasmia has been reported to be successfully treated with either the alpha-2 antagonist yohimbine () or cyproheptadine, a 5-HT2 antagonist with antihistaminergic and adrenolytic properties ().
Clomipramine: Case Example
E.M. was a 42-year-old married man and amateur athlete with a 20-year history of OCD. His compulsions included a need to pick up glass and matches on the street because of a sense of overresponsibility that if he did not, a child would get hurt. He also had an obsession that his copy of the newspaper contained national secrets and had to be destroyed and that the plastic bag in which it came might suffocate a child. He would tear the paper and bag into little pieces and then throw them away. He would often avoid reading the newspaper to avoid this obsession and its consequent compulsion. E.M. estimated that symptoms resulted in his functioning at 60% of his potential.
Within 2 months of starting clomipramine at 250 mg/day his symptoms had reduced significantly. As he described it, “The medicine chokes off the anxiety so that the obsessions or compulsions don’t have a chance to get started.” His obsessions about the newspaper disappeared completely, and he had only an occasional need, not even daily, to pick up a match or piece of glass he saw on the street. His global assessment of his improvement was 80%. Side effects, however, included difficulty with orgasm and ejaculation, excessive sweating, a 10- to 15-lb weight gain, mild dry mouth, and mild constipation. The side effect most bothersome to him was a sense of heaviness in his legs that resulted in decreased exercise tolerance. Thus, instead of being able to run 10 miles a day, he was down to 3-5 miles a day.
Clomipramine (Anafranil) was discontinued in a double-blind fashion. Within 4 weeks, marked deterioration was noted. Obsessive thoughts about national secrets had returned almost to the point of causing panic attacks, and E.M. felt that it was taking a significant effort to resist the compulsions to pick up glass or matches. He also complained of some psychomo-tor agitation, increased appetite, and difficulty with sleep. Side effects improved, however. In particular, E.M. noticed improved exercise tolerance. Within 7 weeks of discontinuation, he had developed a new obsession: a fear that he had been contaminated by the AIDS virus even though his risk was quite low. He could also no longer resist the urge to pick up glass off the street. His sleep problems had subsided, and he reported no specific neurovegetative symptoms.
Clomipramine (Anafranil) was reinstituted at 150 mg/day in an attempt to minimize the exercise intolerance. Within 3 weeks, E.M. noted a remission of his symptoms — obsessions about national security in the newspaper and about AIDS and compulsions to pick up matches and glass. He was still avoiding reading some parts of the newspaper, but his anxiety had diminished significantly. However, side effects, particularly increased sweating, dry mouth, mild constipation, and problems with orgasm remained, as did some exercise intolerance, although it was less severe. At 4 months, clomipramine dose was decreased further to 125 mg. This brought no deterioration in his symptom relief, which he now rated at 90%-95% improved, but did reduce his side effects. His constipation cleared completely, he had only minor dry mouth and much less sweating, and he felt that his ability to exercise was within 80%-90% of his pretreatment level. After 10 months on clomipramine, a further decrease to 100 mg/ day was attempted, but this was followed by mild but notable deterioration in improvement. Total time on obsessions and compulsions increased from 30 to 90 minutes per day, with a more irritable and anxious mood. A return to 125 mg brought a quick remission of symptoms to the 90%-95% improvement level within 4 weeks.
Selections from the book: “Current treatments of obsessive-compulsive disorder” (2001).