June 7, 2019

expert reaction to systematic review and dose-response meta-analysis of antidepressants

Research published in Lancet Psychiatry demonstrates that for the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves optimal balance between efficacy, tolerability, and acceptability in the treatment of depression.

Prof Sir Munir Pirmohamed, Professor of Molecular and Clinical Pharmacology and Department of Health Sponsored Chair in Pharmacogenetics and Director of MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, University of Liverpool, said:

“Paracelsus, more than 500 years ago, said that the dosage is either the remedy or poison.  Unfortunately, these wise words have largely not been translated into how we develop medicines and how we use medicines.  Medicines are developed on a one-dose-fits-all strategy, and typically the dosing instructions state that the dose should be titrated to the maximum tolerated doses, which inevitably ends up as the maximum licensed dose. 

“This is reflected in this important study by Furukawa et al.  They have undertaken a careful meta-analysis of almost 20,000 participants focusing on how dose affects efficacy, tolerability and acceptability. Their findings, which are important, suggest that maximal efficacy may be at the lower end of licensed doses of the antidepressants that they evaluated. Inevitably, this will also improve tolerability because the risk of adverse reactions increases with the dose administered – again this is shown by their analysis.   This is biologically plausible based on the mechanisms of actions of these drugs.  The authors call for changes to guidelines on how these medicines are dosed in everyday clinical practice.

“This study highlights the importance of dosing.  However, a limitation is that this is based on data at a population level rather than at an individual level.  We need to start developing methodology for personalising dosing for patients, not only for drugs used for psychiatry, but also in many other conditions.   This is because there is large inter-individual variability in the dose required to achieve the maximal benefit-risk ratio: some patients require low doses while other require higher doses to achieve the same degree of efficacy.  Many factors determine this inter-individual variability in dosing including age, gender, comorbidities, genetic factors, and drug-drug interactions.  Taking into account all of these factors is complicated, but is essential to move treatment from the current one-dose-fits-all strategy (20th century) to a more precision (21st century) dosing strategy. “

‘Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis’ by Toshi A Furukawa and Andrea Cipriani et al. was published in Lancet Psychiatry at 23:30 UK time on Thursday 6th June.

Declared interests

Prof Sir Munir Pirmohamed: No conflicts of interest.