The efficacy of sertraline in the treatment of MDD was established by a number of placebo-controlled trials for acute-phase therapy (Fabre et al. 1995; Opie et al. 1997; Reimherr et al. 1990). In a multicenter trial, 369 patients were randomly assigned to a fixed dose of sertraline (50 mg, 100 mg, or 200 mg daily) or placebo for 6 weeks (Fabre et al. 1995). Patients at all doses of sertraline showed approximately equivalent improvement, which was greater than placebo for most measures, including the total Hamilton Rating Scale for Depression (Ham-D) score, Beck subscale of the Ham-D, and the Clinical Global Impressions (CGI) Scale score. The combined effect size for sertraline, compared with placebo, was 0.31 (Davidson et al. 2002).
Sertraline was compared with amitriptyline and placebo in a multicenter trial of 448 patients (Reimherr et al. 1990). Sertraline was dosed flexibly up to 200 mg daily, and amitriptyline was administered at dosages as high as 150 mg/day. Both active treatments were superior to placebo, as indicated by Ham-D and CGI scores; similarly, response rates (rates at which patients attained a 50% decrease in the Ham-D or a CGI score of 1 or 2) were higher with the active treatment compared with placebo. Comparisons of sertraline and amitriptyline showed superiority on the Ham-D for amitriptyline until about week 3, after which both treatments were equivalent; response rates were nonsignificantly higher in the amitriptyline group. The effect size for sertraline, compared with placebo, in this study was 0.45 (Davidson et al. 2002).
A recent study sponsored by the National Institute of Mental Health (NIMH) that compared the acute-phase efficacy of Hypericum perforatum (St. John's wort), sertraline, and placebo in the acute-phase treatment of MDD had more equivocal results (Davidson et al. 2002). The study enrolled 340 patients with MDD for 8 weeks of treatment. Average patient age ranged from 40 to 43 years, and 37%-40% were male. The dosage of sertraline was flexibly titrated to 50-150 mg daily, although patients were at the highest dose for no more than 2 weeks. At study endpoint, there were no statistically significant differences in full response, defined as a CGI Scale score of s.2 and a Ham-D score of s8. However, more patients had a partial response (CGI ¿2, 50% improvement on the Ham-D, but not full response) in the sertraline group (26%), compared with the placebo (13%) and Hypericum (16%) groups. Sertraline was also statistically superior to both placebo and Hypericum when the CGI Scale was used as a continuous measure. The effect size for sertraline, compared with placebo, was 0.24 with the Ham-D and 0.41 with the CGI Scale (Davidson et al. 2002). The difference between sertraline and placebo may have failed to achieve significance in some tests because the sample size may have been inadequate given the effect size.
In a multicenter study of 235 men and 400 women with either chronic MDD (enduring at least 2 years) or MDD superimposed on dysthymic disorder, probands were randomly assigned to 12 weeks of either sertraline or imipramine in a 2:1 ratio (Kornstein et al. 2000). Treatment was double-blind, and participants had their medication titrated to a maximum total daily dose of 200 mg of sertraline or 300 mg of imipramine. Full remission was defined as a CGI-Improvement (CGI-I) score of s.2 and a 24-item Ham-D (Ham-D24) score of <7; criteria for satisfactory response were a decrease in the Ham-D24 to 50% of baseline, an absolute score of sl5, a CGI-Severity of Illness (CGI-S) score of s3, and a CGI-I score of s.2, but no full remission. Remission occurred in 36% and 40% of the sertraline and the imipramine groups, respectively. Satisfactory response rates were 22% and 21% for the sertraline and the imipramine groups, respectively.
An interesting finding from this study is that men and women had differential response rates to sertraline and imipramine (Kornstein et al. 2000). The remission and satisfactory response groups were combined for this analysis. When these criteria and an intent-to-treat group were used, it was found that 57% of women, but only 46% of men, responded to sertraline. Response was somewhat better for imipramine, compared with sertraline, among men (62% for imipramine and 45% for sertraline). Response rates were more rapid for men assigned to imipramine and for women given sertraline and did not differ if only completers were used in the analysis. Premenopausal women were more likely to respond to sertraline, while postmenopausal women were equally likely to respond to either agent.
Sertraline has been shown to be effective for maintenance-phase treatment, generally in patients with MDD (Doogan and Caillard 1992) and in patients with chronic MDD (defined as MDD enduring at least 2 years or co-occurring with dysthymic disorder) (Keller et al. 1999). The Doogan and Caillard (1992) study included more than 450 patients with MDD (17-item Ham-D [Ham-D17] >17) who entered 8 weeks of acute-phase treatment with sertraline, dosed flexibly between 50 and 200 mg daily; 68% of those patients responded, and 300 patients entered double-blind, placebo-controlled maintenance therapy. After 44 weeks of maintenance treatment, 13% of sertraline-treated patients, compared with 46% of placebo-treated patients, experienced a relapse.
The utility of sertraline in preventing illness recurrence has been explored using data from the chronic depression maintenance trial discussed above (Keller et al. 1999). Fifty-five percent of the acute-phase responders (378 of the total 426 patients who received sertraline) began continuation-phase treatment, and 169 patients continued to meet the criteria for remission (CGI-I score of 1 or 2 and a Ham-D score of <8); 161 patients entered maintenance treatment and were randomly assigned to 52 weeks of treatment with either placebo or a flexible dose of sertraline (maximum 200 mg daily). More than 60% of those entering maintenance treatment were female and had a current episode of depression that exceeded 8 years in duration. Sertraline significantly outperformed placebo for all outcome measures, which included the Ham-D, CGI Scale, Beck Depression Inventory (BDI), Cornell Dysthymia Scale, and Montgomery-Âsberg Depression Rating Scale; 20% of sertraline-treated patients and 50% of placebo-treated patients experienced illness recurrence.
In addition to the above trials, several studies found sertraline to be at least as effective as TCAs in treating younger adults (Cohn et al. 1990; Lydiard et al. 1997; Moller et al. 1998) and elderly patients (Bondareff et al. 2000; Finkel et al. 1999; Forlenza et al. 2001) with MDD. Sertraline has been shown to be as beneficial as nortriptyline in women with postpartum major depression (Wisner et al. 2006). Furthermore, sertraline may also confer a prophylactic advantage in women at high risk for developing postpartum depression (Wisner et al. 2004). Other trials show roughly equivalent response between sertraline and other SSRIs (Aguglia et al. 1993; Franchini et al. 1997; Nemeroff et al. 1996; Newhouse et al. 2000; Stahl 2000). A recent study suggests that the combination of liothyronine and sertraline enhances the antidepressant effect of the latter and leads to higher remission rates (Cooper-Kazaz et al. 2007).
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