Date: 29 Apr 2005

Is dose escalation of antidepressants a rational strategy after a medium–dose treatment has failed?

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Maximizing the dose of antidepressants is widely recommended in cases of non–response to medium–dose treatment. However, scientific evidence supporting high–dose treatment is scarce. Systematic studies comparing dose escalation with alternative strategies for refractory depression (i. e. augmentation or change of compound) are lacking. The aim of this publication is to review available direct and indirect evidence concerning dose increase of antidepressants after a medium–dose trial has failed.


We performed a systematic literature search of Medline (1966–2003) and reviewed studies and publication references for available evidence.

Data sources and study selection

Studies of the following types were included: 1) dose increase studies in treatment refractory patients, 2) comparative dose studies, 3) therapeutic drug monitoring studies.


Available data suggest differential efficacy of various pharmacological classes at more than medium–dosage. Direct evidence shows no increase of efficacy with high–dose selective serotonin reuptake inhibitor (SSRI) treatment; however, indirect evidence suggests enhanced therapeutic efficacy with high–dose tricyclic antidepressants. Few clinical data show ultra–high–dose treatment with the irreversible monoamine–oxidase–(MAO–) inhibitor tranylcypromine to be effective for refractory depression. Data concerning other selective compounds are insufficient to allow any definitive conclusion on the benefit of high–dose treatment.


Based on available data highdose antidepressant treatment of patients refractory to medium–dose treatment is recommended for tricyclic compounds but not for SSRI. Some data suggest beneficial efficacy of ultra–high doses of the irreversible MAOI tranylcypromine. Research on other substance groups is limited and inconclusive. Prospective studies comparing dose escalation with alternative strategies for treatment of non–responding patients are needed.