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Re: Dose increase recommendations vs time for effect?

Posted by Mtom on December 27, 2020, at 10:52:05

In reply to Re: Dose increase recommendations vs time for effect?, posted by rjlockhart37 on December 26, 2020, at 19:59:56

My concern is, if you look at the paper linked in the initial post, including the graphs, SSRIs and Mirtazapine show an inverted u-shaped curve with highest efficacy in the mid-dose ranges, which started reducing in higher dose ranges, i.e. improvements in depression were (on average) lower at higher doses. This is interesting and relevant, and I don't see an explanation for this. Only venlafaxine did not show a strong inverted u-shaped curve for dose vs efficacy. In contrast, dropouts due to adverse effects increased linearly or exponentially with increasing dose for all the antidepressants examined (including venlafaxine).

Which suggests that if doses are being increased, as they often are, early after starting, during the phase in which there may not have been enough time to assess response, some patients may already be at doses in the downward portion of the efficacy curve before efficacy has had a chance to kick in, and all patients would be in the increasing adverse effects slope of the graphs.

The authors note that a previous study showed approximately 80% serotonin transporter occupancy occurs at minimum therapeutic doses of several SSRIs and venlafaxine, and that further dose increments result in only small increases in occupancy . Their data also suggests that increases over 80% occupancy dont result in greater efficacy.

It should be noted that this study was a Meta-Analysis of prior published studies. It sounds like most of those studies analyzed various fixed-doses of anti-depressants with no or rapid titration. They discuss tolerability might then confound efficacy because interventions with high dropouts are likely to show lower endpoint efficacy because the majority of patients leave the study early and therefore have less time to improve. Which still supports my point that a fast titration schedule in real clinical practice, increasing the dose too quickly, could do the same. Either through increasing adverse effects at the higher doses (which may have been more tolerable at lower doses) - or by dipping into the left decreasing slope of efficacy with the higher doses. Or both.

The authors conclude that for the majority of patients receiving SSRIs, venlafaxine, or mirtazapine for acute-phase major depression treatment, the lower range of the licensed dose likely achieves optimal balance between efficacy, tolerability, and acceptability.

The link again: Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis: Lancet Psychiatry. 2019 Jul;6(7):601-609. doi: 10.1016/S2215-0366(19)30217-2.




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