The use of biomarkers in psychiatric research: how serotonin transporter occupancy explains the dose-response curves of SSRIs.

This column reviews why signal detection in psychiatric research has been problematic, how the use of biomarkers can help, how and why fixed dose studies are done, and how these studies differ from what clinicians do in practice. The fixed dose studies done with selective serotonin reuptake inhibitors (SSRIs) are used to illustrate general points about clinical trial research methodology relevant to clinical practice. Studies with SSRIs have yielded flat dose-response curves with regard to efficacy but ascending dose-response curves with regard to discontinuation due to adverse effects. These clinical trial findings are explained by studies using serotonin transporter inhibition or occupancy as a surrogate marker for SSRI efficacy and tolerability. Initially, these studies were conducted ex vivo using human platelets as the model system; however, they have now been extended to in vivo measurement of serotonin transporter occupancy in patients using positron emission tomography. The conclusion from this work is that the usually effective, minimum dose of each marketed SSRI produces 70%-80% inhibition or occupancy (depending on the methodology used) of the serotonin transporter; higher rates of inhibition or occupancy do not on average increase efficacy but instead increase early discontinuation rates due to adverse effects. These increased discontinuation rates offset any gain in efficacy when the results are analyzed using the last-observation-carried-forward approach. An understanding of these principles also provides an explanation for what initially may appear to be a conundrum: why some patients can benefit from a dose increase even though, in fixed dose clinical trials, the drug had a flat dose-efficacy curve.