Background: In cases where patients with unipolar depression do not respond to a standard dose of selective serotonin reuptake inhibitors (SSRIS), treatment guidelines often recommend a higher dose. A systematic review of the literature revealed uncertainty about the efficacy of dose escalation and pointed to methodological weaknesses in earlier research.

Aim: To review current practice and results concerning dose-escalation of SSRIS.

Method: We made a summary of previously published English articles that systematically reviewed previous SSRI-dose-escalation studies in depressed patients and present the results of a recent double-blind randomised dose-escalation study of paroxetine. By means of a 123I-β-cit-spect study in a subgroup of the patients in the recent dose-escalation study it was possible to measure the amount of paroxetine bound to serotonin transporters. This provided combined clinical and pharmacological outcomes.

Results: The study with paroxetine provided clinical evidence that dose-escalation of paroxetine in depression was not effective and that adverse effects increased. The occupancy of the serotonin-transporters did not increase significantly after dose-escalation, despite increases in paroxetine serum levels.

Conclusion: Dose-escalation of ssris for patients with unipolar depression who did not respond to a standard dose, does not improve response or the chance of remission. The pharmacological explanation for this is that the occupancy of the serotonin-transporters does not increase following dose-escalation.