Clomipramine is used in the treatment of obsessive-compulsive disorder when obsessions or compulsions cause marked distress, are time-consuming (take longer than 1 hour daily), or interfere substantially with the patient's normal routine, occupational or academic functioning, or usual social activities or relationships. Obsessions are recurrent and persistent thoughts, impulses, or images that, at some time during the disturbance, are experienced as intrusive and inappropriate (i.e., ''ego dystonic'') and that cause marked anxiety or distress but that are not simply excessive worries about real-life problems. Compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) performed in response to an obsession or according to rules that must be applied rigidly (e.g., in a stereotyped fashion). Although the behaviors or acts are aimed at preventing or reducing distress or preventing some dreaded event or situation, they either are not connected in a realistic manner with what they are designed to neutralize or prevent or are clearly excessive. At some time during the course of the disturbance, the patient, if an adult, recognizes that the obsessions or compulsions are excessive or unreasonable; children may not make such recognition.
The efficacy of clomipramine for the management of obsessive-compulsive disorder has been established in several multicenter, placebo-controlled, parallel-group studies, including 2 studies of 10 weeks' duration in adults and one study of 8 weeks' duration in children and adolescents 10-17 years of age. In these clinical studies, clomipramine was more effective than placebo in reducing the severity of obsessive-compulsive manifestations in patients with moderate to severe obsessive-compulsive disorder. The drug produced substantial improvement in scores on both the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and the National Institute of Mental Health (NIMH) Clinical Global Obsessive-Compulsive Scale (NIMH-OC), while the response with placebo was clinically insignificant. Scores on the YBOCS decreased by an average of approximately 10 from baseline values of 26-28, representing an average improvement of 35-42% in adults and 37% in children and adolescents treated with clomipramine. Scores on the NIMH-OC were reduced by an average of 3.5 units from a mean baseline of 10 in adults, children, and adolescents treated with clomipramine, which represents an improvement in obsessive-compulsive disorder from severe at baseline to subclinical after treatment with the drug. The maximum dosage of clomipramine hydrochloride was 250 mg daily for most adults and 3 mg/kg (up to 200 mg) daily for children and adolescents.
Although obsessive-compulsive manifestations often persist to some extent in patients who respond to clomipramine, responders generally find it easier to resist the manifestations and spend less time engaged in the associated behavior. Data from a retrospective analysis suggest that clomipramine may be more effective in patients who developed obsessive-compulsive disorder during middle age (35-62 years of age) than in those in whom onset occurred during early adulthood (16-23 years old), independent of the length of illness.
Therapeutic response to clomipramine in patients with obsessive-compulsive disorder generally is evident within 2-6 weeks but may not be maximal until 3-4 months after beginning therapy with the drug. Thus, it is essential that patients receive an adequate trial of clomipramine at a therapeutic dosage in order to determine efficacy.
Many clinicians consider clomipramine or a serotonin-reuptake inhibitor (e.g., fluoxetine, fluvoxamine) to be the drugs of choice in obsessive-compulsive disorder. In addition, behavior therapy often is recommended in patients with obsessive-compulsive disorder even when pharmacologic therapy alone has been partially effective.
Results from comparative studies to date suggest that clomipramine is more effective than other tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) and as or more effective than selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine) in the management of obsessive-compulsive disorder. In a pooled analysis of separate short-term (10-13 weeks) studies comparing clomipramine, fluoxetine, fluvoxamine, or sertraline with placebo, clomipramine was calculated as being more effective (as determined by measures on the YBOC scale) than selective serotonin-reuptake inhibitors, although all drugs were superior to placebo. Like clomipramine, selective serotonin-reuptake inhibitors reduce but do not completely eliminate obsessions and compulsions. The decision whether to initiate therapy with clomipramine or a selective serotonin-reuptake inhibitor often is made based on the adverse effect profile of these drugs. For example, some clinicians prefer clomipramine in patients who may not tolerate the adverse effect profile of selective serotonin-reuptake inhibitors (nausea, headache, overstimulation, sleep disturbances) while selective serotonin-reuptake inhibitors may be useful alternatives in patients unable to tolerate the adverse effects (anticholinergic effects, cardiovascular effects, sedation) associated with clomipramine therapy. Consideration of individual patient characteristics (age, concurrent medical conditions), the pharmacokinetics of the drug, potential drug interactions, and cost of therapy may also influence clinicians when selecting between clomipramine and selective serotonin-reuptake inhibitors as first-line therapy in patients with obsessive-compulsive disorder. Although not clearly established, it has been suggested that the mechanism of action of clomipramine and other drugs (fluoxetine, fluvoxamine) used in the management of obsessive-compulsive disorder may be related to their serotonergic activity. Clomipramine also has been effective when used in combination with clonidine in several patients with obsessive-compulsive disorder; however, additional experience is needed to confirm the safety and efficacy of this combination.
The manufacturers state that the efficacy of clomipramine for long-term use (i.e., longer than 10 weeks) in the treatment of obsessive-compulsive disorder has not been established in placebo-controlled studies. After 36 weeks of treatment with clomipramine, improvement compared with placebo was observed on measures of rituals, mood, and social adjustment, although such effects were more substantial after 18 weeks of treatment. At follow-up 22 weeks after treatment ended, clomipramine differed from placebo on one measure of rituals. Clomipramine was not distinguishable from placebo in efficacy at follow-up 6 years after the conclusion of treatment. The combination of clomipramine or placebo with the same behavioral therapy resulted in greater improvement with clomipramine on measures of rituals, mood, and social adjustment at 8 weeks of treatment, but thereafter through the last 15 weeks of treatment and at follow-up through 52 weeks, clomipramine was indistinguishable from placebo. However, clomipramine has been used in some patients for prolonged periods (e.g., up to 1 year) without apparent loss of clinical effect. If clomipramine is used for extended periods, dosage should be adjusted so that patients are maintained on the lowest effective dosage, and the need for continued therapy with the drug should be reassessed periodically.
Discontinuance of clomipramine frequently results in a progressive recurrence of symptoms in patients with obsessive-compulsive disorder, and therefore long-term continued therapy with the drug may be advisable on an individual basis. In a study conducted under double-blind conditions, most patients with obsessive-compulsive disorder who had improved clinically following 5-27 months of clomipramine therapy experienced profound worsening of manifestations after discontinuance of the drug. This worsening started at 4 weeks and continued for the rest of the 7-week placebo period and appeared to be unrelated to the duration of clomipramine therapy or to the type of obsessive-compulsive manifestations originally present. However, readministration of clomipramine resulted in clinical improvement similar to that obtained prior to discontinuance of the drug.
Disorders with an Obsessive-Compulsive Component
Depressive episodes may be associated with obsessive-compulsive disorder. Clomipramine and selective serotonin-reuptake inhibitors are effective antidepressants when obsessive manifestations accompany an episode of major depression. However, the antiobsessional effectiveness of clomipramine does not appear to depend on the presence of depression.
Clomipramine also may reduce obsessive-compulsive manifestations in some patients with schizophrenia and such accompanying manifestations. However, exacerbation of psychosis has been reported in some patients treated with clomipramine. Therefore, the possibility of exacerbating psychosis should be considered in patients with obsessive-compulsive manifestations and schizophrenia, and such patients receiving clomipramine should be observed closely for early signs of worsening psychosis.
There is a high incidence of obsessive-compulsive disorder in patients with Tourette's disorder (Gilles de la Tourette's syndrome), and clomipramine can reduce obsessive-compulsive manifestations associated with Tourette's and suppress associated motor and vocal tics. However, in at least one controlled study, clomipramine did not differ from placebo in the number of tics observed during 4 weeks of treatment.
Obsessive thoughts were decreased with the combination of clomipramine and lithium carbonate in a limited number of patients who had obsessive manifestations that previously failed to respond to clomipramine therapy alone. However, in a study of patients with obsessive-compulsive disorder treated with clomipramine for at least 6 months and who were partial responders to the drug, the addition of lithium carbonate for 4 weeks did not result in improvement in scores on the YBOCS.
Clomipramine has been used effectively for the treatment of panic disorder with or without agoraphobia. In an uncontrolled study, clomipramine reduced both the weekly frequency and severity of panic attacks when given in an average dosage of 45 mg daily (range: 6.25-75 mg daily). In many patients, complete or nearly complete relief from panic attacks was reported during therapy. The number of days that panic attacks occurred was less with clomipramine (mean dosage of 83 mg daily) than with placebo after 8 weeks of treatment in one study. Therapeutic response generally is seen within about 1-3 weeks but may take up to 6 weeks. Although clomipramine therapy generally is well tolerated, a transient increase in the number and intensity of panic attacks may occur during initial therapy with the drug.
(See Dosage and Administration: Dosage.)Clomipramine (mean dosage of 109 mg daily; range: 25-200 mg daily) was at least as effective as imipramine (mean dosage of 109 mg daily; range: 25-200 mg daily) in patients with panic disorder and had a faster onset of action in reducing panic attacks and improving phobic avoidance and associated anxiety.
Clomipramine generally is equally effective in patients with panic disorder with or without agoraphobia. In a limited number of patients whose panic disorder with agoraphobia did not respond to exposure-based behavioral treatment, measures of fear (i.e., fear of bodily incapacitation, fear of losing control), state and trait anxiety, depression, severity of condition, and avoidance of separation situations indicated improvement compared with placebo after receiving clomipramine for about 5 weeks (3 weeks at the maximum dosage of 150 mg daily). Despite such improvement, the efficacy of clomipramine in the treatment of such patients was uncertain. A clinical response, as indicated by improvement by at least 50% on assessment of avoidance of separation situations with the Phobic Avoidance Rating Scale, was produced by clomipramine in 29% of the patients, while such response was observed with behavioral treatment in 47% of the patients.
Preliminary results from an uncontrolled study suggest that clomipramine is effective in patients with panic disorder or agoraphobia with panic attacks who have concurrent mitral valve prolapse.
Although it has been suggested that the mechanism of action of clomipramine in patients with panic disorder may be related to the drug's serotonergic activity, the absence of clear superiority compared with less selective antidepressants (e.g., desipramine) suggests that this may not be the case.
For further information on treatment of panic disorder, .
Major Depressive Disorder
Clomipramine has been used effectively in the treatment of major depressive disorder. Clinical studies have shown that the antidepressant effect of clomipramine exceeds that of placebo and is comparable to that of usual dosages of other tricyclic antidepressants (e.g., amitriptyline, doxepin, imipramine) or selective serotonin-reuptake inhibitors (e.g., fluoxetine, paroxetine). Several (e.g., 4-6) weeks may be required for optimal antidepressant effect at a given clomipramine dosage. Despite comparable efficacy, the adverse effect profile (e.g., anticholinergic effects) of clomipramine may limit its usefulness relative to other antidepressants, and antidepressant therapy should be individualized based on patient response and tolerance. Clomipramine appears to offer no substantial advantage over other tricyclic antidepressants for the management of typical depression in the absence of obsessive-compulsive manifestations and may be more poorly tolerated, particularly compared with tricyclics exhibiting only mild to moderate anticholinergic effects. Although some clinicians have preferred clomipramine to other tricyclic antidepressants for atypical depression (e.g., because of clomipramine's dopaminergic activity), other agents (e.g., selective serotonin-reuptake inhibitors such as fluoxetine) generally have replaced this preference for clomipramine in such depression.
For further information on treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidal risks, .
Like other tricyclic antidepressants, clomipramine has been used for the treatment of chronic pain, including central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, and pain of other neuropathic origin (e.g., cancer pain). Antidepressants have been used alone or as adjuncts to conventional analgesics in the management of such pain. In patients with central pain (e.g., phantom or stump pain, post-herpetic neuralgia, deafferentation pain secondary to posttraumatic nerve lesions), reduction in pain intensity, as indicated by scores on a visual analog scale for pain, was greater during treatment with clomipramine for 3 weeks than with placebo. Treatment of idiopathic pain disorder with clomipramine (mean dosage of 97 mg daily) for 6 weeks resulted in improvement, as indicated by the physicians' global assessment, in 63% of patients. The patients' scores on visual analog scales that included assessment of pain also were improved. In patients with tension headache, a greater decrease in headache pain, as indicated by scores on a visual analog scale, occurred with clomipramine administered for 6 weeks than with placebo. Treatment of diabetic peripheral neuropathy with clomipramine for 2 weeks resulted in a greater decrease compared with placebo in the severity of symptoms overall, as evaluated by a physician through use of a scale that quantified pain, paresthesia, dyesthesia, numbness, nightly deterioration, and sleep disturbances.
Cataplexy and Associated Narcolepsy
Clomipramine has been used for the symptomatic management of cataplexy in a limited number of patients with cataplexy and associated narcolepsy. Cataplexy attacks and sleep paralysis resolved or were reduced in frequency during clomipramine therapy (25-200 mg daily); however, the drug did not consistently improve sleep attacks. Although the precise mechanism of clomipramine's anticataplectic action is not known, it has been suggested that its serotonergic and REM-suppressing activity may be involved.
Clomipramine has been effective in a limited number of patients with autistic disorder. In a double-blind study, clomipramine therapy (mean dosage: 152 mg daily) was superior to both desipramine and placebo in improving standardized ratings of autistic manifestations, including repetitive and obsessive-compulsive behaviors and hyperactivity in a limited number of pediatric outpatients aged 6-18 years with autistic disorder. However, in an open study involving younger inpatients aged 3-9 years with autistic disorder but with relatively low intellectual functioning and without prominent obsessive-compulsive manifestations, clomipramine was not found to be effective and was commonly associated with adverse effects, including acute urinary retention.
Clomipramine has been used in a limited number of patients with trichotillomania (an urge to pull out one's hair). In one double-blind, crossover study, clomipramine (mean dosage of 181 mg daily; range: 100-250 mg daily) was shown to be more effective than desipramine (mean dosage of 173 mg daily; range: 150-200 mg daily) in the short-term management of trichotillomania. However, relapse has been reported in some patients receiving long-term treatment with clomipramine.
Clomipramine has been used in a limited number of patients with severe onychophagia (nail biting) and no history of obsessive-compulsive disorder. In one study, the severity of nail biting decreased in patients treated with clomipramine hydrochloride 25-200 mg daily for 5 weeks. However, the relatively high dropout rate secondary to adverse effects and drug intolerance suggests that clomipramine should not be considered as first-line therapy in most patients with onychophagia.
Clomipramine has been used in a limited number of patients with stuttering. Following 5 weeks of therapy (mean dosage: 147 mg daily), clomipramine improved the severity of stuttering, preoccupation with thoughts about stuttering, amount of energy spent resisting stuttering, and expectancy of stuttering. Additional study of the efficacy of clomipramine in the management of stuttering is necessary.
Clomipramine has been used in a limited number of patients with anorexia nervosa. In a placebo-controlled study, clomipramine therapy was associated with increased appetite, hunger, and calorie consumption during initial therapy; however, the drug was not associated with improved eating behavior after 8 weeks of therapy or greater weight gain. In addition, body weight did not differ between the clomipramine and placebo groups at 1-year follow-up and a measure of outcome based on nutritional status, sexual adjustment, socioeconomic adjustment, and mental state did not differ between the 2 groups at 4-year follow-up. Few controlled studies on the pharmacotherapy for anorexia nervosa have been published, and results with most drugs have been unimpressive. Because malnourished depressed patients may be particularly susceptible to the adverse cardiovascular effects or other severe toxicities (including death) of tricyclic antidepressants, the American Psychiatric Association (APA) states that tricyclic antidepressants should be avoided in underweight individuals and in those exhibiting suicidal ideation. For further information on use of antidepressants in the treatment of eating disorders
Clomipramine has been used with some success in the treatment of premature ejaculation. In a controlled study, mean ejaculatory latency was prolonged in patients receiving 25 or 50 mg of the drug daily. Sexual and relationship satisfaction also was improved. A trial with drug therapy may be particularly useful in patients who fail or refuse behavioral or psychotherapeutic treatment or when partners are unwilling to cooperate with such therapy.
Clomipramine has been used in the management of premenstrual syndrome. In a limited number of women with severe premenstrual irritability and/or depressed mood, clomipramine given either continuously or intermittently (i.e., premenstrual administration) during 3 menstrual cycles at a dosage of 25-75 mg daily was more effective than placebo in reducing premenstrual irritability and depressed mood. However, preliminary data suggest that patients with premenstrual syndrome may be particularly sensitive to the adverse effects associated with the drug.