Indications And Efficacy Depression

Comparison With Other Agents Tricyclic and tetracyclic antidepressants

The efficacy of paroxetine in major depression has been established in several randomized, placebo-controlled studies, as well as in studies comparing the effects of paroxetine with those of active comparators, including fluoxetine, TCAs, and other agents. The preponderance of early data with paroxetine in establishing efficacy in depression was in comparison trials with TCAs, particularly imipramine and amitriptyline, and placebo. The earliest placebo-controlled trials used 10-50 mg of paroxetine and were 6 weeks in duration. Outcome variables typically used were the Hamilton Rating Scale for Depression (Ham-D), the Montgomery-Ásberg Depression Rating Scale (MADRS), and the

Clinical Global Impressions (CGI) Scale. These trials demonstrated the clear superiority of paroxetine over placebo in the treatment of major depression (Claghorn et al. 1992; Kiev 1992; Rickels et al. 1989; Smith and Glaudin 1992).

A meta-analysis by Montgomery (2001) compared the efficacy and tolerability of paroxetine with those of TCAs, including amitriptyline, imipramine, clomipramine, doxepin, and nortriptyline, and the tetracyclic antidepressants mianserin and maprotiline. Studies included in the meta-analysis were randomized, double-blind, and parallel-group in design; were 6 weeks or less in duration; and employed the Ham-D as the primary outcome measure. Results from the pooled data of 3,758 hospitalized and ambulatory patients from 39 studies showed no overall significant difference in antidepressant response rates between paroxetine and TCAs or tetracyclics, based on a >50% reduction in the Ham-D total score or in remission rates, defined as an endpoint Ham-D score of s8. Clearly, paroxetine is better tolerated than the TCAs and related heterocyclic antidepressants in terms of lower rates of discontinuation attributed to adverse events. In addition, paroxetine had a greater effect on concomitant anxiety associated with depression, compared with all other studied medications, except clomipramine, which was equally efficacious with regard to anxiolysis.

Despite the overwhelming evidence supporting the equivalent antidepressant efficacy of paroxetine and TCAs, one notable exception exists. The Danish University Antidepressant Group (1990) conducted a multicenter double-blind, placebo-controlled, fixed-dose investigation comparing efficacy and tolerability of paroxetine (30 mg/day) with clomipramine (150 mg/day) and found nonresponder rates to be significantly greater in the paroxetine group. Whereas most of the data supporting the clinical superiority of paroxetine are derived from outpatient studies, the Danish University Antidepressant Group (1990) study comprised only inpatients. These data appear to argue for relative greater efficacy of clomipramine in severe depression; however, two notable confounds exist here. First, higher dosages of paroxetine (e.g., 50-60 mg/day) might well show equivalent efficacy with clomipramine, especially in view of the NET findings described above. Second, Ham-D scores reported in this study were no more severe than those in the outpatient trials, making it difficult to draw any conclusions regarding relative superiority of clomipramine based on severity of depression. All other published studies comparing paroxetine with clomipramine have shown no difference in efficacy in outpatients with depression; paroxetine is, of course, uniformly better tolerated (Guillibert et al. 1989; Pelicier and Schaeffer 1993; Ravindran et al. 1997).

Other SRIs

Because the SRIs, as a class, have become the first-line pharmacological agents in the treatment of depression and a number of anxiety disorders, the results of a large number of studies, mostly sponsored by the pharmaceutical industry, are available. To date, fluoxetine, fluvoxamine, and sertraline have been compared with paroxetine in the treatment of major depression. In addition, given the favorable response of SRIs in several anxiety disorders, clinical trials have compared the clinical ameliorative effects of paroxetine with those of other SRIs on anxiety symptoms associated with depression.

De Wilde et al. (1993) found, at various time points during the trial, statistically significant advantages of paroxetine (20-40 mg/day) over fluoxetine (20-60 mg/day) in total Ham-D score and anxiety subscore. However, by the end of the 6-week study, there was no difference noted in any outcome variable. Geretsegger et al. (1994) studied a group of geriatric patients with severe depression (n = 106) and found a significantly greater proportion of patients treated with paroxetine (20-40 mg/day) than fluoxetine (20-60 mg/day) to have a >50% reduction in total Ham-D and MADRS scores by the end of the study; however, no difference was observed in terms of response based on the CGI Scale or between-group differences in MADRS or Ham-D at the termination of the study. Other studies have found paroxetine and fluoxetine to be equally effective in the treatment of major depression and associated anxiety (Chouinard et al. 1999; Fava et al. 1998, 2000; Tignol 1993).

Similar results have been observed in trials comparing paroxetine and sertraline. Zanardi et al. (1996) studied a small group (n = 46) of hospitalized patients with psychotic depression and found rates of response to both medications among study completers to be comparable. The intent-to-treat analysis in this trial revealed sertraline (150 mg/day) to be more effective than paroxetine (50 mg/day). The authors suggested that the difference might be attributable to the disproportionately high dropout rate (41%) in the paroxetine group, likely caused by the rapid paroxetine dose titration, compared with the dropout rate in the sertraline group. In the only published study comparing paroxetine and sertraline in a 6-month trial, the two medications had similar antidepressant efficacy and similar ratings on quality-of-life measures (Aberg-Wistedt et al. 2000).

Kiev and Feiger (1997) reported that paroxetine (20-50 mg/day) and fluvoxamine (50-150 mg/day) had equivalent efficacy in the treatment of depression.

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