In search of a dose–response relationship in SSRIs—a systematic review, meta‐analysis, and network meta‐analysis

Abstract

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.

Effects of Saffron Extract Supplementation on Mood, Well-Being, and Response to a Psychosocial Stressor in Healthy Adults: A Randomized, Double-Blind, Parallel Group, Clinical Trial

“…Pharmacological treatments exist, but a number of articles have emphasized the inability of antidepressant medication to consistently demonstrate superiority to placebo, in patients with mild or moderate symptoms (3). Side effects of such treatments, including nausea and drowsiness, are also common, especially at medium to high doses in the case of selective serotonin reuptake inhibitors (SSRIs) (4). Alternative treatments, such as natural products or exercise for combating mood disorders, are therefore being explored (5).…”

Dampening antidepressant effects via 5‐HT1A auto‐receptors

“…Although Braun et al 1 showed no significant difference between high and medium doses, if my hypothesis is the case, it seems probable that a further increase in SSRI dose may decrease the effects of SSRIs. In any case, my hypothesis may at least account for the lack of a particularly linear dose–response relationship.…”

“…Braun et al 1 have rigorously performed meta‐analyses on the dose–response relationships of selective serotonin reuptake inhibitors (SSRIs) using all direct comparisons of different dosages of specific SSRIs. They reconfirmed that there were no clinically significant differences among SSRI doses at the low, medium, and high dose category levels, which is consistent with the results of the meta‐analyses performed by Furukawa et al 2 using indirect comparisons and those reported by Dold et al 3 showing nonefficacy of dose escalation after initial nonresponse to standard‐dose pharmacotherapy.…”

“…Although the findings of Braun et al 1 are important, regarding the mechanism(s) of the lack of a dose–response relationship with SSRIs, they cite a SPECT study 4 where at the lower dose of paroxetine, approximately 80% of the individual's serotonin transporters were blocked, and after dose increase, the occupancy rate remained at 80%. Similarly, the antidepressant effects of both paroxetine doses were identical.…”

Guideline advice on second‐step antidepressant treatment: The evidence for IDAS in MIDAS

“…Such a relationship should show in trials randomizing patients to different doses. When scientists did just that, results turned out to be mostly negative: In meta‐analyses we were unable to detect clinically meaningful or statistically significant dose–effect gradients at the level of substance groups—be it SSRIs 3 or SNRIs (manuscript in submitted)—or consistent and positive evidence for specific substances. For example, 225 mg venlafaxine was not statistically significantly inferior to 375 mg, when we summarized three homogeneous studies (SMD: 0.1 [−0.15; 0.37]), neither was 75 mg venlafaxine relative to 150 mg.…”