Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder

Selective serotonin reuptake inhibitors are generally accepted as a class of drugs that should be prescribed to those with major depressive disorder, especially in the most severe cases. There is really not much debate about this fact, however, there is still question and uncertainty about how to dose these medications. The APA guidelines today call for optimizing the dose as long as the side effects can be tolerated because it has been shown that the there is a flat dose-response curve within the therapeutic range for antidepressant medications in major depressive disorder. The authors of this meta-analysis believe that this statement may be flawed for two reasons. One, the data that supports this statement includes all antidepressants not just SSRIs, and the researchers from the previous meta-analysis that produced this guideline looked at dose as a categorical outcome instead of continuous which could have reduced their power to determine what the dose-response relationship is really like. This meta-analysis set out to determine whether higher doses of SSRIs really improved outcomes or not.

The authors of this paper only included very specific studies to ensure that they came to the most accurate conclusion. The inclusion criteria were data for both SSRI and placebo treated patients and used standardized, validated outcome measurements for depression. The exclusion criteria included patients less than 19 or older than 60, use of a cross-over design, dual diagnoses, non-SSRIs, not randomized, not placebo-controlled, and psychotherapy was given to either the control or active group. In the end, the team of authors concluded that SSRIs show a significant increase in efficacy when higher doses were administered. The analysis also found that the higher doses are associated with reduced tolerability because more people dropped out of the trials due to side effects at high doses of SSRIs. These results differed from the previous meta-analysis, showing that the dose response curve did not level-off until the very end of the dosing range. This new finding could possibly affect how doctors prescribe SSRIs because there could be evidence to indicate prescribing higher doses than the minimum therapeutic range could be more effective for patients but also more harmful.


Jakubovski E, Varigonda AL, Freemantie N, et al. Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder. Am J Psychiatry. 2016; 173: 174-83.


After reading this article, it makes me wonder how physicians in charge of treating a patient’s major depressive disorder would react. Would more physicians start their patients off at a dose in the middle of the dose response curve, or would they start off higher? If they started in the middle and their patient did not see any improvement, would they feel more comfortable increasing the dose or would the potential side effects still keep them from doing this?

1 thought on “Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder”

  1. This seems like a very tricky class of drugs to deal with when determining what dose to give a patient. By this study showing that higher doses are more effective yet more harmful, I wonder how this will change the way that SSRIs are prescribed. I suppose that physicians will have to weigh the potential for more adverse effects against the greater therapeutic effect from giving the higher dose. Physicians will have to carefully consider and closely monitor each patient if they choose to start on a higher dose.

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