Clomipramine dosing

The tricyclic antidepressant clomipramine also has been studied for PMDD. In placebo-controlled trials, both continuous daily dosing and luteal phase administration proved effective.17 Compared with the SSRIs, however, clomipramine has a less desirable side-effect profile with low tolerability. 

Tricyclic Antidepressants (TCAs). The TCAs, particularly imipramine (Tofranil), were also discovered soon after their introduction to be effective in the treatment of panic attacks. Imipramine, the best-studied TCA in the treatment of panic disorder, is most often helpful at daily doses of 150-250 mg, though it must be started at 10-25 mg, usually at bedtime, and gradually increased over 2-4 weeks. Although they are not as well studied, many clinicians prefer to use the secondary amine TCAs, desipramine (Norpramin) and nortriptyline (Pamelor), because they have milder side effects than imipramine. Clomipramine (Anafranil), though probably the TCA with the greatest side effect burden, is often said to be most effective in patients with refractory disease. 

The effective dose range for treating OCD is 150-300 mg/day. Side effects associated with clomipramine are similar to or slightly more severe than those observed with other TCAs and are described in more detail in Chapter 3. 

CLOMIPRAMINE /-/YDROC/-/LOR/DE Administer in divided doses with meals to reduce Gl side effects. After titration, the total daily dose may be given once/day at bedtime to minimize daytime sedation. 

Serotonin syndrome Some TCAs inhibit neuronal reuptake of serotonin and can increase synaptic serotonin levels (eg, clomipramine, amitriptyline). Either therapeutic or excessive doses of these drugs, in combination with other drugs that also increase synaptic serotonin levels (such as MAOIs), can cause a serotonin syndrome consisting of tremor, agitation, delirium, rigidity, myoclonus, hyperthermia, and obtundation. 

Venlafaxine is a serotonin and noradrenaline reuptake inhibitor (SNRI). It shares these properties with the TCAs amitriptyhne, clomipramine and imip-ramine, but it is the first selective SNRI, with low affinity for muscarinic, histaminic and a-adrenergic receptors. At low doses serotonergic effects predominate, but at higher doses the reuptake of noradrenaline is significantly blocked (Melichar et al. 2001). It is available as immediate and extended release (XR) preparations. 

Extensive databases [see Table 24-1) have now shown that paroxetine and sertraline can reduce panic attacks to zero and prevent relapse. Paroxetine studies constitute the largest data set more than 700 patients have been treated for periods ranging from 10 to 36 weeks. In the placebo-controlled comparisons with clomipramine, paroxetine had an earlier onset of action and was better tolerated than clomipramine. Paroxetine was significantly better than placebo from week 4 onward, whereas no separation was seen between clomipramine and placebo until the end of the study. Fewer withdrawals occurred as a result of adverse events with paroxetine (7.3%) than with either clomipramine (14.9%) or placebo (11.4%). The minimum dose shown to be superior to placebo was 40 mg/day. 

Citalopram and fluoxetine also have been studied in panic disorder (Michelson et al. 1998 Wade et al. 1997). Citalopram was compared with clomipramine. At the most effective citalopram dose (20-30 mg/day), approximately 58% of patients were panic-free compared with 50% of patients receiving clomipramine and 32% of placebo patients. All rating scales suggested that 20 or 30 mg/day of citalopram was more effective than 40 or 60 mg/day of citalopram. Finally, data support the efficacy of fluoxetine in panic disorder. In a study comparing 10 and 20 mg/day of fluoxetine and placebo, fluoxetine treatment, particularly the 20-mg daily dose, was associated with more improvement than placebo across multiple measures, including functional impairment. 

Imipramine, amitriptyline, doxepin, desipramine, clomipramine, and trimipramine therapy can be initiated at 25-50 mg/day. Divided dosing may be used at first to minimize side effects, but eventually the entire dose can be given at bedtime. The dose can be increased to 150 mg/day the second week, 225 mg/day the third week, and 300 mg/ day the fourth week. The dose of clomipramine should not exceed 250 mg/day because of an increased risk of seizures at higher doses. 

A dose-related risk of seizures has been found with clomipramine, which has led to the recommendation that the total daily dose of this drug not exceed 250 mg. Overdoses of TCAs, particularly amoxa-pine and desipramine, are associated with seizures. Whether therapeutic doses of TCAs lower the seizure threshold is controversial. Nonetheless, other classes may be safer options for individuals with epilepsy. 

The TCA clomipramine and the SSRls provide the foundation of the pharmacological treatment for OCD. Although pharmacotherapy is effective against many other Axis 1 disorders, most patients with OCD experience only a 35%-60% improvement in symptoms. In addition, medication responses may not be apparent until treatment has been administered for 10 weeks, and some patients will require higher doses than are typically used to treat depression. As in the treatment of depression, SSRls tend to be better tolerated than TCAs (clomipramine is the only effective TCA for OCD). 

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