Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder

Abstract

Objective: Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.

Method: The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.

Results: Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54).

Conclusions: Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

Figure 1. Selection of Studies

Figure 1 is a flowchart depicting the procedure for selection of eligible trials from identified references. Abbreviations: MDD=Major Depressive Disorder, SSRI=Selective-Serotonin Reuptake Inhibitor, RCT= Randomized Controlled Trial

Figure 2. Effect of Dosage on Longitudinal Response Curve of SSRIs

Figure 2 depicts the effects of dosage on the longitudinal response curve examining the efficacy of SSRIs compared to placebo over time. Each line represents the typical improvement in depressive symptoms experienced over time in SSRIs compared to placebo at a dosage isoquant. Dosages are expressed in imipramine equivalents. 100mg of imipramine = 120mg of sertraline = 100mg of fluvoxamine = 20mg of paroxetine or fluoxetine=33.3 mg of citalopram=16.7 mg of escitalopram. Abbreviations: SSRI= Selective-Serotonin Reuptake Inhibitor, SMD=Standardized Mean Difference between Active and Placebo

Figure 3. Effect of Dose on Measured Efficacy of SSRIs compared to Placebo at Trial Endpoint

Figure 3A is a scatterplot depicting the association between SSRI dosage in imipramine equivalents and measured effect size of SSRIs compared to placebo (standardized mean difference). Within the scatterplot, circles represent individual studies with the size of the circle corresponding to its weight in the meta-analysis. The regression line reflects the significant positive relationship between SSRI dosage and measured efficacy compared to placebo (β=0.00053, 95% CI 0.00018–0.00088, z = 2.98, p =0.0029). Figure 3B depicts the association between SSRI dose and measured effect size in 4 dose categories of SSRIs. The 4 chosen dose categories of SSRIs: <100mg, 100–199mg, 200–250mg and >250mg were based on a meta-analysis that failed to demonstrate a dose-response relationship in antidepressant medications (not exclusively SSRIs). Dosages are expressed in imipramine equivalents. 100mg of imipramine = 120mg of sertraline = 100mg of fluvoxamine = 20mg of paroxetine or fluoxetine=33.3 mg of citalopram=16.7 mg of escitalopram. Abbreviations: SMD=Standardized Mean Difference. Figure 3C is a scatterplot depicting the association between SSRI dosage in imipramine equivalents and response in SSRIs compared to placebo (Odds Ratio). The regression line reflects the non-significant positive relationship between SSRI dosage and response compared to placebo (β=0.00029, 95% CI −0.00010–0.00066, z = 1.44, p =0.15). Figure 3D depicts the association between SSRI dose and response in 4 dose categories of SSRIs. Abbreviations: SMD=Standardized Mean Difference

Figure 4. Relationship between SSRI Dosage and Likelihood of Dropout

Figure 4A is a scatterplot of a meta-regression analysis that examines the association between SSRI dose and likelihood of all-cause dropout. Higher SSRI dose were associated with a lower rate of all-cause dropouts (β=−0.00093, 95% CI −0.00165– (−0.00021), z = −2.54, p =0.0110). Figure 4B is a scatterplot of a meta-regression analysis that examines the association between SSRI dose and likelihood of dropout due to side-effects. Higher doses of SSRIs were associated with a higher rate of dropouts due to side-effects (β=0.00207 95% CI 0.00071– 0.00342, z = 2.98, p =0.0028). Within the scatterplot, circles represent individual studies with the size of the circle corresponding to its weight in the meta-analysis. Lines represent the results of meta-regression analysis. Figure 4C depicts the association between SSRI dose and all-cause dropouts and dropouts due to side-effects in 4 dose categories. The 4 chosen dose categories of SSRIs: <100mg, 100–199mg, 200–250mg and >250mg were based on a meta-analysis that failed to demonstrate a dose-response relationship in antidepressant medications (not exclusively SSRIs). Dosages are expressed in imipramine equivalents. 100mg of imipramine = 120mg of sertraline = 100mg of fluvoxamine = 20mg of paroxetine or fluoxetine=33.3 mg of citalopram=16.7 mg of escitalopram. Abbreviations: SMD=Standardized Mean Difference, SSRI=Selective-Serotonin Reuptake Inhibitor, LogOR= Logarithm of odds ratio