Lower-Range Doses of Antidepressants Most Effective for Major Depression

Researchers found data from a dose response meta-analysis that is contrary to the American Psychiatric Association guideline recommendation for titration to the maximum tolerated dose for antidepressant medications.

Lower-range doses of second-generation antidepressants produce the most optimal balance between tolerability, acceptability, and efficacy when used in acute treatment for major depression, according to a study recently published in The Lancet: Psychiatry.

Researchers performed a systematic review and dose-response meta-analysis of double-blind, randomized, controlled trials that examined the effects of antidepressants in fixed doses on adults aged 18 and older diagnosed with major depression. Data for this study were compiled from a number of sources, including the Cochrane Central Register of Controlled Trials, MEDLINE, PsycINFO, and websites of pharmaceutical companies and drug licensing agencies. 

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The antidepressants used in this study were venlafaxine, mirtazapine, and 5 selective serotonin reuptake inhibitors (SSRIs): citalopram, escitalopram, fluoxetine, paroxetine, and sertraline. All doses of the SSRIs were converted to equivalent doses of fluoxetine for analyzing dose dependency. The primary outcomes were tolerability (dropouts as a result of adverse effects), acceptability (dropouts for any reason), and efficacy (defined as a 50% or greater reduction in the severity of depression). After an average of 8 weeks of treatment, these outcomes were evaluated.

Results revealed that the dose efficacy increased gradually between 75- and 150-mg for venlafaxine, up to approximately 30-mg for mirtazapine, and between 20- and 40-mg for fluoxetine equivalents, but efficacy began to decrease gradually or only increased moderately for doses above these. Dropouts due to adverse effects increased steeply with increasing doses for both venlafaxine and mirtazapine, resulting in a dose-acceptability curve that was convex at the lower-licensed range, which approximately corresponded with 20- to 40-mg of fluoxetine equivalents in both cases. All 7 antidepressants evaluated in this study showed optimal acceptability when used in lower-range doses and clear dose dependency in dropouts for adverse effects.

This study had limitations. The findings mainly included patients who were deemed eligible to participate in placebo-controlled trials. A fixed-dose regimen may not properly reflect clinical practice and may overestimate withdrawal, due to adverse effects. There was uncertainty surrounding how to calculate the best dose equivalency among antidepressants. Spline curves for each individual drug were based on a few studies to result in wide confidence intervals. Dropouts for adverse effects from acute-phase treatment was used as an index for tolerability. Because the study years ranged between 1986 and 2013 the search date used for the studies may be considered outdated.

The study investigators concluded that for the majority of patients with major depression who receive venlafaxine, mirtazapine, or SSRIs, the lower range of their licensed dose will likely achieve an optimal balance between tolerability, acceptability, and efficacy.

Multiple researchers report associations with the pharmaceutical industry. Please see the original reference for a full list of disclosures.

Furukawa TA, Cipriani A, Cowen PJ, Leucht S, Egger M, Salanti G. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis [published online June 6, 2019]. Lancet Psychiatry. doi: 10.1016/S2215-0366(19)30217-2