Supplementary Material for: Dose Escalation of Antidepressants in Unipolar Depression: A Meta-Analysis of Double-Blind, Randomized Controlled Trials

<p><b><i>Background:</i></b> As many patients with unipolar depression do not respond sufficiently to initial antidepressant monotherapy, a dose increase of the current administered antidepressant (dose escalation, high-dose treatment) is frequently carried out as next treatment measure. <b><i>Methods:</i></b> We conducted a meta-analysis which included all double-blind randomized controlled trials (RCTs) comparing a dose increase of antidepressants directly to continuation of standard-dose treatment in unipolar depressive patients who were non- responders to standard-dose pharmacotherapy. A mean change in the Hamilton Rating Scale for Depression (HAM-D) total score was the primary outcome. Secondary outcomes were response rates and discontinuation rates due to any reason, inefficacy, and adverse effects. Hedges g and risk ratios were calculated as effect sizes. <b><i>Results:</i></b> Seven double-blind RCTs (8 study arms) representing 1,208 participants were included. Fluoxetine (<i>N</i> [number of studies] = 2, <i>n</i> [number of patients] = 448), sertraline (<i>N</i> = 2, <i>n</i> = 272), paroxetine (<i>N</i> = 2, <i>n</i> = 146), duloxetine (<i>N</i> = 1, <i>n</i> = 255), and maprotiline (<i>N</i> = 1, <i>n</i> = 87) were investigated. Dose escalation was not more efficacious in HAM-D total score reduction than maintaining standard-dose treatment, neither for the pooled antidepressant group (<i>N</i> = 7, <i>n</i> = 999; Hedges g = -0.04, 95% CI: -0.20 to 0.12; <i>p</i> = 0.63) nor the individual antidepressants. No differences could be determined for response rates, all-cause discontinuation, and drop-outs due to inefficacy. Significantly more patients in the dose escalation group dropped out due to adverse effects than in the standard-dose continuation group. The metaregressions indicate no influence of baseline symptom severity or amounts of dose increments on effect sizes. <b><i>Conclusions:</i></b> According to our meta-analytic findings, dose escalation after initial non-response to standard-dose pharmacotherapy cannot be regarded as general evidence-based treatment option in unipolar depression.</p>