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You are 4 weeks into a trial of fluoxetine for a patient with severe depression, and there has been no improvement on 20 mg daily. What’s your next move? Wouldn’t nearly all of us think about increasing to, say, 40 mg for at least another 2 weeks, preferably 4 weeks if the patient and their symptoms allow? Yet, is increasing the dose supported by available data? Well, let’s have a look at some data and see.
Hi! Jim Phelps for the Psychopharmacology Institute. The authors of a new meta-analysis, Cora Braun and colleagues, note that previous studies of dose-response relationships for SSRIs—the serotonin reuptake inhibitors—are largely based on indirect evidence. So, they compiled and analyzed randomized trials that directly compared different SSRI doses, and their conclusion was “no statistically significant trend emerged for efficacy at higher doses.” Let’s take some examples.
Escitalopram: Most people start with a dose of 10 mg, and if that doesn’t work, the temptation is to increase it to 20 mg before judging it ineffective. In this new meta-analysis, Dr. Braun and colleagues found 3 studies which directly compared 10 mg vs 20 mg in a total of 650 patients, and there was no difference in outcomes at those 2 different doses. Let’s look at how those studies were conducted. Patients were randomized to 10, 20, or in some of these studies 40 mg, and this was citalopram back in 2002, before the QT prolongation issue was recognized. In that set of studies, indeed, 10 mg was as effective as 40 mg for citalopram.
These studies are direct dose comparisons. Everybody starts out on a given dose, so-called fixed dose studies. So, they don’t really map directly onto the question that we face clinically. If your patient does not respond to, say, 10 mg of escitalopram, should you raise the dose to 20?
Let’s try this again with fluoxetine. Dr. Braun and colleagues found 7 studies comparing 40 mg vs 20 mg. Again, the findings were the same in those 7 studies: Higher doses produced no better outcomes than lower ones. But unlike clinical practice, patients simply started on the different doses and then their outcomes were compared.
The authors of this new meta-analysis offer 3 conclusions. First, they found no differences in outcome for low, medium, and high SSRI doses. Second, they did not observe a dose-response relationship in 56 studies. That really ought to give us pause when we consider increasing the dose of a medication that is not working, if there really is no dose-response relationship. Their third point is more straightforward and unsurprising: Medium and high doses had more dropouts due to side effects.
Notice that we’re talking about SSRIs here and not SNRIs, although even there the advantage of the higher doses is more in doubt, which I also found by reviewing a broader literature on this issue in 2015. In that review, Drs. Solvason and DeBattista from Stanford concluded that increasing dosages in patients who don’t respond to an initial dose is not unreasonable. But they also stated that “simply remaining on the minimum therapeutic dose may improve response as much as increasing the dose.” In that review, I also referenced the study that found that 80% of our colleagues would increase the dose after nonresponse to an initial antidepressant dose. If this is your routine, you certainly have plenty of company. Of course, that doesn’t mean it’s the best thing to do. Side effects are clearly more common at higher doses. And when you taper, you have that much farther to go down, which means a longer period of time of going nowhere while you’re clearing the decks.
In conclusion, this new meta-analysis should make us wonder once again, are we really improving outcomes by increasing antidepressant dosages? I’d say the jury is out.
For more on this, I’d invite you to examine my 2015 review, as well as the references in that review, which we’ll link here at Psychopharmacology Institute.
Abstract
In search of a dose-response relationship in SSRIs-a systematic review, meta-analysis, and network meta-analysis C Braun, A Adams, L Rink, T Bschor, K Kuhr, C Baethge
Objective: Recent meta-analyses on dose-response relationships of SSRIs are largely based on indirect evidence. We analyzed RCTs directly comparing different SSRI doses.
Method: Systematic literature search for RCTs. Two raters independently screened articles and extracted data. Across SSRIs, doses defined as low, medium, and high doses, based on drug manufacturers’ product monographs, were analyzed in pairwise random-effects meta-analyses and in a sensitivity network meta-analysis with regard to differences in antidepressive efficacy (primary outcome). We also analyzed all direct comparisons of different dosages of specific SSRIs. (Prospero CRD42018081031).
Results: Out of 5333 articles screened, we included 33. Comparisons of dosage groups (low, medium, and high) resulted in only small and clinically non-significant differences for SSRIs as a group, the strongest relating to medium vs low doses (SMD: -0.15 [95%-CI: -0.28; -0.01) and not sustained in a sensitivity analysis. Among different doses of specific SSRIs, no statistically significant trend emerged for efficacy at higher doses, but 60 mg/day fluoxetine are statistically significantly inferior to 20 mg/day. Paroxetine results are inconclusive: 10 mg/day are inferior to higher doses, but 30 and 40 mg/day are inferior to 20 mg/day. Meaningful effects cannot be ruled out for certain drugs and dosages, often investigated in only one trial. Dropout rates increase with dose-particularly due to side effects. Network meta-analyses supported our findings.
Conclusions: There is no conclusive level I or level II evidence of a clinically meaningful dose-response relationship of SSRIs as a group or of single substances. High SSRI doses are not recommended as routine treatment.
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Reference
Braun, C., Adams, A., Rink, L., Bschor, T., Kuhr, K., & Baethge, C. (2020). In search of a dose-response relationship in SSRIs-a systematic review, meta-analysis, and network meta-analysis. Acta Psychiatrica Scandinavica, 142(6), 430–442.
Related References
Phelps, J. (2015, October 15). What is an adequate dose of an antidepressant? Psychiatric Times. https://www.psychiatrictimes.com/view/what-adequate-dose-antidepressant
