One of the questions that has bedevilled clinicians ever since the introduction of the first SSRI (Prozac, fluoxetine) is whether there is any relationship between SSRI doses and effectiveness. In other words, do higher doses result in greater effectiveness. I can recall about 20 years ago reading the first clinical trial looking at this question. It was an article published in the Journal of Clinical Psychopharmacology. In the study, people with a partial response to fluoxetine 20 mg a day at week four were randomized to either a dose escalation of 20 mg per day every two weeks or no change in dose. At the end of the study those who were in the dose escalation study were at an average dose of roughly 60 mg a day and had a significantly better response at the end of the study compared to the beginning of the study (week four of fluoxetine 20 mg a day). However, those who stayed at 20 mg a day had roughly the same improvement. The main difference was that those in the dose escalation group had many more side effects. In other words, giving the same dose more time was a better strategy than titrating up when 4 weeks of 20 mg a day led to a partial response.
Fast forward to 2020. Braun et al performed a review of all the studies comparing high, medium, or low doses of an SSRI (there are now many studies on this question).
The studies examined six SSRI’s and one agent (vilazodone) which is in a somewhat different category (serotonin modulators). The medications included fluoxetine (n=7 studies), citalopram (n=7), sertraline (n=6), paroxetine (n=6), escitalopram (n=4), vilazodone (n=3) and fluvoxamine (n=1), and the analysis included 12,052 patients (mean age, 42; 58% women). Overall, 33 different doses of SSRIs were examined in 56 comparisons. Few differences were found in effectiveness among high, medium, and low doses (minor benefits for medium over low doses were not statistically significant).
The exceptions to this rule were that paroxetine at 20 mg/day seemed somewhat more effective than 10 mg/day, and fluoxetine at 20 mg/day was modestly more effective than higher doses such as 40 mg a day or 60 mg a day.
Overall, the differences between medium and high doses were negligible. Higher doses were associated with more frequent dropout and side effects.
While these studies only looked at unipolar depression. It is our clinical experience that the conclusion that we should not titrate doses of SSRI upward if there is an inadequate response applies even more strongly to bipolar depression,. The only exception appears to be people with obsessive compulsive disorder who may need significantly higher doses to achieve a robust response.
Dosing SSRIs for Major Depression. Joel Yager, MD reviewing Braun C et al. Acta Psychiatr Scand 2020 Sep 24 in Journal Watch Psychiatry
Braun C et al. In search of a dose-response relationship in SSRIs-a systematic review, meta-analysis, and network meta-analysis. *Acta Psychiatr Scand* 2020 Sep 24; [e-pub].