Analysis of antidepressant dosage highlights need for new clinical guidelines

Analysis published earlier this month in The Lancet Psychiatry shows that a lower dose of the most commonly used second-generation antidepressants achieves the best balance of effectiveness and tolerability in the acute treatment of adults with major depression.

The study, funded by the National Institute for Health Research, has important clinical implications for guidelines and the daily use of antidepressants in real world settings. It focuses on the most frequently prescribed antidepressants in the UK, including five SSRIs (selective serotonin reuptake inhibitors: citalopram, escitalopram, fluoxetine, paroxetine and sertraline), venlafaxine and mirtazapine. Data from almost 20,000 participants was used to assess efficacy, acceptability and tolerability over a median of 8 weeks treatment.

Optimal acceptability and dose-efficacy for the SSRIs was in the lower licensed range between 20 mg and 40mg fluoxetine equivalents. For both venlafaxine and mirtazapine optimal acceptability was also in the lower range of their licensed dose. However, for venlafaxine efficacy increased up to 150 mg and for mirtazapine dose-efficacy increased only up to about 30 mg.

“When I see patients in my clinic and we agree on prescribing an antidepressant for their depressive episode, the big challenge is not only to prescribe the right medication but also to find the best dosage for each individual, optimising efficacy and reducing side effects. Current practice guidelines provide conflicting recommendations”
Professor Andrea Cipriani, NIHR Research Professor

In the UK the NICE (National Institute for Clinical Excellence) guidelines state that there is no dose dependency within the therapeutic range of SSRIs, in the US guidelines from the American Psychiatric Association recommend slow titration up to the maximum tolerated dose. This new evidence suggests neither of these methods are correct.

“For the majority of patients receiving SSRIs a small increase in dose can be beneficial in terms of efficacy and overall acceptability. It is very interesting (and reassuring) that these results from clinical studies are in line with basic science investigations in psychopharmacology. Mental health research is pushing the boundaries of discovery science and where there’s clear evidence of potential benefits it’s important that this be reflected in the clinical guidelines used by thousands of people every day.”
Professor Andrea Cipriani, NIHR Research Professor

The systematic review and dose-response meta-analysis is based on the largest and most comprehensive dataset of double-blind, randomised controlled trials, published and unpublished. The study was carried out by an international team of experts led by the University of Oxford and was funded by the National Institute for Health Research in the UK, together with the Japan Society for the Promotion of Science and the Swiss National Science Foundation.