This is a general piece on uncertainty and thoughtful documentation in a pretty messed up healthcare system, not a comment on any specific case. Mostly pro tips and reminders for trainees on things to consider when documenting.
Someone asked about Auvelity yesterday, and I happened to already be deep into this piece. It walks through the receptor pharmacology in detail and makes the case for why we should be skeptical of Auvelity's proposed NMDA mechanism specifically.
I saw that Auvelity was recently approved for agitation in dementia and was immediately skeptical, so I looked at the underlying studies. Weak.
The ADVANCE-1 trial (n=308) was a 5-week RCT with change from baseline on the Cohen-Mansfield Agitation Inventory (CMAI) as the primary endpoint. The result was statistically significant: -14.9 vs -11.6 for placebo, a treatment difference of -3.3 points (95% CI -5.8 to -0.8). A 3-point difference on a scale that runs to over 200 points is not clinically meaningful by any reasonable standard. This is very similar to the brexpiprazole approval for the same indication.
The more telling finding is ADVANCE-2, which was the larger 5-week parallel-group replication trial (n=408), and it missed its primary CMAI endpoint entirely (-13.8 vs -12.6). This was the trial that was supposed to confirm ADVANCE-1, and it failed.
One 5-week trial hit a 3-point CMAI difference, the larger replication trial failed. Two of the four authors are Axsome Therapeutics employees.