SSRI Dose Response

Peter Forster Major Depression, Treatments of Depression

It has long been unclear whether higher doses of SSRIs are associated with greater response. What has been clear is that higher doses are associated with significantly increased side effects. In fact previous research, whether individual studies or meta-analyses have failed to find a significant dose response with the result that many have felt that there is a flat dose response curve. Higher doses don’t lead to greater effects.

An article by Jakubovski, et al, in the February 2016 the issue of the American Journal of psychiatry evaluated 40 randomized controlled trials. Their study addressed a number of the limitations of previous analyses. They show a modest increase in efficacy for higher doses of SSRIs in major depressive disorder. They replicate previous findings that this modest increase in benefit is associated with a significant reduction in tolerability.

They combine results from all SSRI’s by converting doses into “imipramine equivalents” and conclude that –

Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

In the chart at the right you can see that overall dose-response increased to about 200 – 250 mg of imipramine in a relatively linear fashion and then actually dropped.SSRI Dose Response

Their analysis suggests that these modest benefits may exist for only a portion of patients being treated with SSRIs and point to the importance of methods for identifying those who are more likely to need higher doses, such as the use of genetic markers, including the assessment of cytochrome P450 genotypes (see our article on the Genomind Assay).

An accompanying editorial by Madhukar Trivedi notes both the importance of the finding that higher doses may be useful and highlights the importance of developing new ways of identifying those who are likely to benefit from those higher doses to minimize the risk of adverse side effects in those not likely to need higher doses. The editorialist also points to the importance of repeated measurement of depressive symptoms (a best practice that we have had in our clinic for years) is another way of avoiding excessive doses


“Dose Response for SSRIs.” American Journal of Psychiatry, 173(2), pp. 105–106

Jakubovski E, Varigonda AL, Freemantle N, et al: Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry 2016; 173:174–183