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BACKGROUND: In fixed dose antidepressant trials, the lower range of the licensed dose achieves the optimal balance between efficacy and tolerability. Whether flexible upward titration while side effects permit provides additional benefits is unknown. METHODS: We did a systematic review of placebo-controlled randomised trials that examined selective serotonin reuptake inhibitors (SSRIs), venlafaxine or mirtazapine in the acute treatment of major depression. Our primary outcome was response, defined as 50% or greater reduction in depression severity. Secondary outcomes included dropouts due to adverse effects and dropouts for any reason. We conducted random effects meta-analyses to calculate the ratios of odds ratios (RORs) between trials comparing the flexible dose titrating above the minimum licensed dose against placebo and those comparing the fixed minimum licensed dose against placebo. RESULTS: We included 123 published and unpublished randomized controlled trials (29,420 participants). There was no evidence supporting efficacy of the flexible dosing over the fixed low dose of SSRIs (ROR 0.96, 95%CI: 0.73 to 1.25), venlafaxine (1.24, 0.96 to 1.60) or mirtazapine (0.77, 0.33 to 1.78). No important differences were noted for tolerability or for any subgroup analyses except the superior efficacy of venlafaxine flexible dosing between 75-150 mg over the fixed 75 mg (1.30, 1.02 to 1.65). CONCLUSION: There was no evidence to support added value in terms of efficacy, tolerability or acceptability of flexibly titrating up the dosage over the minimum licensed dose of SSRIs or mirtazapine. For venlafaxine, increased efficacy can be expected by flexibly titrating up to 150 mg.

Original publication




Journal article


Acta Psychiatr Scand

Publication Date



Antidepressivee agents, Fixed dosing, Flexible dosing, Major depressive disorder