Hearts and souls: An opinionated take on NEJM highlights for October and November 2022

A psychedelic for refractory depression

While major depression is awful, treatment-resistant depression (as defined not responding to at least two different courses of therapy) is worse with sufferers stuck in a long dark tunnel of anguish without a light at the end of it. Since psilocybin (the psychedelic agent in so-called magic mushrooms) has shown some effectiveness in depression, it seemed reasonable to test its differentiated mechanism of action in this high need patient population.  In this study that was mostly Europe-based but included sites in the US (finally), patients were given a single dose of psilocybin in three groups (1 mg vs. 10 mg vs. 25 mg) and then monitored for the next 12 weeks. Response rate (29%) was significant in the 25 mg group at 3 weeks but faded below statistical significance at 12 weeks. Definitely not a panacea, but certainly worth continued exploration. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression;


The story of A-beta and AD continues…

Merely two months after the initial press release, the lecanemab study is peer-reviewed and just out online (I am guessing it will come out in print late December). A few initial reactions. It appears to be a very clean, carefully done study. The clinical effect on cognition is undoubtedly real, though relatively small in the 18-month timeline of the trial – roughly, it appears to be equivalent to a 6-month delay in disease progression, a similar effect to what is observed with acetylcholinesterase inhibitors such as donepezil (aka Aricept) which are not considered disease modifying agents.  Is lecanemab a disease modifying agent? Those who believe in the beta-amyloid hypothesis will think so… but the clinical data does not really say one way or the other. To unearth the most intriguing (to me!) finding of this study, you have to go to the supplementary materials where an exploratory analysis compares patient groups based on ApoE4 status:  non-carriers appear to get significantly more benefit than homozygotes with heterozygotes in-between (though confidence intervals overlap).  If that holds, it may turn out that lecanemab has a very meaningful clinical effect on the non-carrier population, well-worth the bi-weekly burden of infusions, while the risk/burden/benefit for carriers is much more equivocal. Lecanemab in Early Alzheimer’s Disease


A new shocking approach to cardiac arrest

Out-of-the hospital cardiac arrest is common and leads to poor outcomes. A notable increase in survival rates has occurred with advances in defibrillator equipment, but even when there is a shockable rhythm, in 20-40% of cases standard defibrillation procedures are not effective leading to a dismal survival rate of ~13%. An interesting randomized study from Canada tested alternative vs. standard defibrillation strategies once the standard 3 shocks have been administered. In one arm placing leads back and front (instead of the normal upper right chest to lower left chest), in another combining the back to front and left to right in a rapid shock succession (yes this requires 4 pads and two machines). What they found is that the front to back strategy led to 22% survival to hospital discharge and the double shock strategy led to 30% survival, with statistical significance of the latter versus standard approach (~13% survival). This could be a major advance, but what’s disheartening is that this approach is probably not going to make it to an EMS near you (if you are in the US) anytime soon. A lukewarm, nitpicky editorial, limited incentives to pursue the evidence further, and a big dose of medical inertia – I don’t see this getting traction anytime soon, whereas if a cancer drug achieved similar results, there would be clamoring for access. Defibrillation Strategies for Refractory Ventricular Fibrillation; Defibrillation after Cardiac Arrest — Is It Time to Change Practice?


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.