Clomipramine (Anafranil), a tricyclic antidepressant (TCA) and potent serotonin re-uptake inhibitor, was used in the first controlled pharmacologic treatment trial in children and adolescents for OCD. Nineteen pediatric patients (mean age, 14.5 ± 2.3 years) were studied in a 12-week double-blind placebo-controlled crossover study (5 weeks of active medication) (). Doses of clomipramine targeting 3 mg/kg/day were used, with a mean dose of 141 mg/day. In the 14 patients with obsessive-compulsive disorder who completed the trial, clomipramine was significantly better than placebo in decreasing obsessive-compulsive symptoms at week 5. An improvement in symptoms could usually be seen as early as week 3, and 75% of the patients had a moderate to marked improvement. This hallmark study led the way for subsequent trials, including those of the newer selective serotonin reuptake inhibitors (SSRIs).
Clomipramine (Anafranil) is unique among the TCAs because it significantly inhibits serotonin reuptake. Interestingly, its primary metabolite, desmethyl-clomipramine, is a potent noradrenergic reuptake inhibitor ); thus, clomipramine has both noradrenergic and serotonergic action. Leonard et al. () noted that clomipramine was clearly superior to desipramine (a selective noradrenergic reuptake inhibitor) in a double-blind crossover comparison of 48 children and adolescents with OCD. The comparison drug desipramine was used because of its similar side effect profile and antidepressant efficacy. Thirty-one boys and girls with a mean age of 13.9 years (range, 7-19 years) and a mean age at onset of 10.2 years (range, 5-16 years) were studied using an average dose of 150 mg/day. Clomipramine (Anafranil) was significantly better than desipramine in ameliorating obsessive-compulsive disorder symptoms at week 5. Desipramine was no more effective in improving obsessive-compulsive symptoms than placebo had been in a previous study by Flament et al. (). In fact, when desipramine was given as the second active medication, 64% of the patients had some degree of relapse within several weeks of crossover.
Subsequently, a large 8-week multicenter double-blind parallel comparison of clomipramine versus placebo was completed that led to U.S. Food and Drug Administration (FDA) approval of clomipramine for the treatment of obsessive-compulsive disorder in children and adolescents (aged 10 years or older) (). Clomipramine (Anafranil) was generally well tolerated in these studies and in clinical experience. Long-term clomipramine maintenance has not revealed any unexpected adverse reactions ().
There are anticholinergic, antihistaminic, and alpha-blocking side effects associated with clomipramine. The most common side effects reported by children and adolescents include (in order of decreasing frequency) dry mouth, somnolence, dizziness, fatigue, tremor, headache, constipation, anorexia, abdominal pain, dyspepsia, and insomnia, and they are comparable with (but anecdotally are reported as milder than) those seen in adults (). One recent report indicated that clomipramine did not have any unexpected cardiotoxic effects. Leonard et al. () suggested that baseline and periodic electro-cardiographic monitoring is advisable. Several adolescents who discontinued clomipramine abruptly (during long-term maintenance) experienced withdrawal symptoms of gastrointestinal distress, which appeared to be a cholinergic rebound syndrome like those reported with other antidepressants (). Thus, abrupt discontinuation of clomipramine is not recommended.
Selective Serotonin Reuptake Inhibitors
The SSRIs have been studied extensively over the past decade. Currently, the medications with an FDA-approved indication for obsessive-compulsive disorder in children include clomipramine (in children 10 years or older), sertraline (children 6 years or older), and fluvoxamine (children 8 years or older). The SSRIs are considered selective inhibitors of serotonin because of their limited effect on other monoamines (). They represent a new class of agents with distinct advantages in their side effect profile and their broad therapeutic index over those of the TCAs.
A multisite study of fluvoxamine in 8-17-year-olds with obsessive-compulsive disorder demonstrated safety and efficacy () and led to an FDA indication (for obsessive-compulsive disorder in children 8 years or older) in 1997. The most common side effects of fluvoxamine include sedation, nausea, anorexia, tremor, and sexual dysfunction, and its side effect profile is clearly less anticholinergic than those of the TCAs.
Similarly, a recent multicenter randomized placebo-controlled trial of sertraline in 187 children and adolescents demonstrated safety and efficacy () and led to an FDA indication (for obsessive-compulsive disorder in children 6 years or older). Sertraline was titrated to a maximum of 200 mg/day during the first 4 weeks of double-blind therapy, after which patients continued to receive this dose for 8 more weeks. The most common side effects of sertraline include nausea, dyspepsia, agitation, and tremor.
Riddle et al. () concluded that fluoxetine appeared to be safe, effective, well tolerated, and superior to placebo in a small controlled trial of children and adolescents with OCD. The most common side effects included nervousness, insomnia, and restlessness. Two small controlled trials of fluoxetine in children with obsessive-compulsive disorder and Tourette’s syndrome reported a modest effect on obsessive-compulsive disorder symptoms (improvement from baseline but not superior to placebo) and no exacerbation of tics (). A large trial in children is under way. Although no large, systematic studies have been published for children with obsessive-compulsive disorder (OCD), fluoxetine is widely used (American Academy of Child and Adolescent Psychiatry 1998) and was the first SSRI commercially available in the United States.
Fluoxetine is reasonably well tolerated in children and adolescents (). The most common side effects include nervousness, insomnia, and restlessness. To minimize side effects, lower initial doses are used, sometimes 2.5-5.0 mg/day, depending on the child’s age and weight. Geller et al.’s () open trial of fluoxetine in children used an average dose of 1 mg/kg/day and the therapeutic effect was sustained over time (mean follow-up, 19 months). Occasionally, the younger age group may be started on 10 mg (i.e., one-half the usual adult dose) of fluoxetine in the morning; the suspension offers dose flexibility. Given the long half-life of the parent drug and metabolite, steady state is not reached for 2-3 weeks and the drug is not completely eliminated from the system for up to 6 weeks after discontinuation. Thus, clinicians are advised to increase the dose slowly and to monitor for delayed side effects as late as 2 weeks after a dose increase.
A large multisite study of paroxetine in the treatment of obsessive-compulsive disorder in children and adolescents is under way. Citalopram, the most recently introduced SSRI in the United States, has been studied in 23 subjects in an open fashion. Thomsen () reported a generally favorable response with 11 of 23 subjects improving and only 5 having little or no response. Larger trials will be needed to study the safety and efficacy of paroxetine and citalopram in the pediatric population.
The SSRI advantages of few anticholinergic side effects and limited cardiovascular toxicities are particularly relevant for the pediatric population (). There are no defined indications for electrocar-diographic monitoring or plasma level monitoring. Most of the side effects reported for SSRIs are from adult studies and include complaints of nausea, headache, nervousness, insomnia, diarrhea, and drowsiness ().
Clinicians should begin with lower doses of the SSRIs for children and adolescents than would typically be used for adults. Patients should be monitored during SSRI treatment for energizing, activating side effects, behavioral activation/dyscontrol, motor restlessness, and the more common side effects mentioned earlier. There are some case reports of children and adults developing unusual mental status changes (i.e., hallucinations, mania, psychosis, and frank delirium) that highlight the importance of considering concomitant prescription, over-the-counter, or illegal drug use (). In general, these reports have been rare and it remains unclear whether they were dose related or the result of a drug-drug interaction. Clinicians should inquire about all over-the-counter medications, recreational drugs, and prescription medications used by the patient (especially terfenadine and astemizole [particularly in combination with certain medications, e.g., ketoconozole], which have been shown to prolong the QT interval) (). Additionally, it has been clearly established that a combination of clomipramine and an SSRI may result in disproportionate clomipramine levels because of competitive inhibition.
Although pharmacologic treatment for each patient with obsessive-compulsive disorder must be individualized, there are a few clinical recommendations. Empirical findings suggest that clomipramine and the SSRIs differ considerably with respect to adverse effects; thus, the choice of a particular agent should be based on the side effect profile, the known efficacy of the agent, and the presence or absence of comorbid diagnoses. SSRIs are preferable to clomipramine for patients with suicidal risk. For patients with obsessive-compulsive disorder and comorbid diagnoses such as ADHD, tic disorders, or anxiety disorders, there is no “head-to-head” evidence that a specific SSRI or clomipramine is more efficacious than another. All of the SSRIs should be used cautiously in patients with lowered seizure thresholds but are preferable antidepressant choices over TCAs.
Clinicians should be aware that during early treatment (first 1 to 2 weeks) with SSRIs, some patients may actually develop a worsening of their obsessive-compulsive disorder symptoms or experience particularly annoying side effects (i.e., insomnia, increased psychomotor activity). This has been referred to as an agitated syndrome and has been well described in patients with some doses. Typically, the exacerbation subsides and a positive clinical response ensues. Thus, the patient and family should be educated about and encouraged to report worsening or problematic side effects. Initial worsening in the first week usually is not a reason in and of itself to discontinue the medication. As a matter of caution, children should be started at a low dose.
Headaches are commonly reported as a side effect of treatment with the SSRIs, with an incidence up to 15% (). Because serotonergic dysfunction has been implicated in the pathophysiology of migraine, it is possible that initiation of SSRI treatment may be associated with precipitation of migraine. Thus, the clinician should take a family and personal history of migraines before initiating SSRI pharmacotherapy. If there is a clear history, treatment should begin at lower doses and be increased slowly.
Selections from the book: “Current treatments of obsessive-compulsive disorder”, 2001