Selective Serotonin Reuptake Inhibitors

Most recently, the selective serotonin reuptake inhibitors (SSRIs) have provided an alternative to the older pharmacologic treatments. Although paroxetine and, very recently, sertraline have FDA-approved indications for the treatment of panic disorder, a significant body of literature exists, as well, for fluvoxamine and, to a lesser extent, fluoxetine. Sheehan and Harnett-Sheehan have comprehensively reviewed the role of SSRIs and Jefferson has reviewed the antidepressants in general in the treatment of panic disorder. As a group, these agents are significantly different from the tricyclic antidepressants, monoamine oxidase inhibitors, and benzodiazepines. They demonstrate little or no abuse potential, orthostatic hypotension, anticholinergic side effects, sedation, or ability to produce hypertension secondary to drug-drug and drug-food interactions. On the whole, they display a profile of CNS-stimulating side effects (e.g., anxiety, insomnia, headaches, nausea, weight loss). Among the serotonin reuptake inhibitors, fluoxetine is the most stimulating and fluvoxamine the least. In addition, paroxetine appears to have some mild anticholinergic properties, and they differ from one another with respect to the drug-drug interactions in which they are involved via P450 isoenzymes. Half-lives of elimination of the parent compounds and their active metabolites constitute another important difference among the four (see Table 2). All four of the SSRIs have been studied in panic disorder with the greatest number of published reports involving fluvoxamine, the largest number of patients treated with paroxetine, and the least number of published reports involving fluoxetine and sertraline.

• Fluoxetine: Based on a total of 195 patients in three open-label studies and one double-blind comparison with desipramine, fluoxetine (10-80 mg/day) has shown some efficacy in the treatment of panic disorder. However, patients appear to be very sensitive to its activating effects, resulting in high dropout rates. Starting doses as low as 2.5 mg/day may be necessary for successful treatment of patients; employing this approach, Schneier et al. reported that 76% of 25 patients with panic disorder markedly improved.

• Fluvoxamine: In multiple double-blind studies, involving over 1,000 patients, fluvoxamine has been shown to be more effective than placebo, maprotiline, and ritanserin (not available in the U.S.) and equal in efficacy to clomipramine and imipramine in the treatment of panic disorder. In one such study, lasting 8 weeks, Black et al. compared fluvoxamine (up to 300 mg/day), cognitive behavior therapy, and placebo in 75 patients. At week 4, 57% of patients taking fluvoxamine, 40% receiving cognitive therapy, and 22% of those taking placebo showed at least moderate improvement. At week 8, 81% of the fluvoxamine group, 53% of the cognitive therapy group, and 29% of the placebo group were free of panic attacks; the difference between the fluvoxamine and placebo groups was statistically significant.

• Sertraline: Sertraline (50, 100, and 200 mg/day fixed doses), in a 12-week, multicenter, placebo-controlled study of 320 patients with panic disorder, significantly reduced the number of panic attacks at the 100 and 200 mg/day doses. Of concern, 22% of patients receiving sertraline discontinued treatment secondary to adverse effects, while there were no dropouts in the placebo group.

• Paroxetine: The efficacy of paroxetine in the treatment of panic disorder has been studied in over 1,200 patients and reported in three published studies and three presentations. All of these trials were double-blind and placebo-controlled, and overall, paroxetine (40-60 mg/day) was found to be superior to placebo and equal to either clomipramine (150 mg/day) or alprazolam (6 mg/day). Onset of action can be slow, however, with a 50% reduction in panic attacks not occurring until week 6 and a reduction to one or zero attacks lasting three consecutive weeks not occurring until week 12. In a 10-week, fixed-dose (10, 20, and 40 mg/day) study of 278 patients, significant differences from placebo were seen only in the patients treated with 40 mg/day.

Conclusions

Currently available data indicate that the serotonin reuptake inhibitors are emerging as distinct options in the treatment of panic disorder. As with the older treatments, onset of action can be slow, effective doses are similar to those needed in treating major depression, and, at times, drug discontinuation secondary to adverse effects can be a significant problem. Overall, however, the SSRIs have a number of advantages over the older options, particularly with respect to adverse effects and abuse and dependence potential, and are already viewed by many prescribers as first-line agents, especially in patients with panic disorder and concomitant major depression. Further information on long-term efficacy as well as comparisons of each of the serotonin reuptake inhibitors with the others would be helpful in fully assessing their place in the treatment of panic disorder.

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