The next study was recently published in the New England Journal of Medicine, and it compared not ketamine but esketamine, Spervato, to quatypine in 676 patients with treatment resistant depression. It was sponsored by Janssen, the manufacturer of esketamine. Both drugs were used as augmentation of SNRIs or SSRIs, and in the end, esketamine was the clear winner, if only by a small margin. Specifically, those on esketamine were one and a half times more likely to experience remission than quatypine, 27% versus 18%. Now in some ways, this isn't surprising, as esketamine has already proven its benefits in the kind of treatment resistant depression studied here. The real kind, where they had to fail two or more, antidepressant trials. Chylo-quatypine has mainly shown its benefits in patients who failed just one antidepressant. But we were a little surprised. Quatypine has unique benefits in anxiety and sleep that could have swayed the data in its direction here. But alas, it did not. Also, as we'll soon see, this trial involved esketamine, which is likely not as effective as ketamine. The bottom line, esketamine is more effective than quatypine in treatment resistant depression, not quite by a factor of two to one, but one and a half to one. And while esketamine leaves many patients in the undesirable position of requiring ongoing maintenance therapy, we have to concede that quatypine is not much better in the long-term risk department. As professionals, we may shy away from long-term esketamine because it is a controlled substance. But for patients, the diabetes, weight gain, tartive dyskinesia may be more of a deal-breaker.

Our second question is ketamine really all that effective? Earlier, we quoted a recent meta-analysis that registered an ultra-high effect size for intravenous ketamine. 1.5. That was across 79 different trials. This study is not alone in finding a big hit for ketamine. It's just the latest in a string of meta-analyses that arrived at similar conclusions. So to get a sense of that 1.5, by comparison, SSRIs have an effect size around 0.3 to 0.4 in depression, and stimulants like VIVANs ring in at 0.8 to 0.9 in ADHD. Now effect size is a measure of the difference between the placebo response and the medication response. And there is a problem in comparing effect sizes across different trials. Remember, ketamine studies are smaller, and smaller trials tend to yield bigger effects. More critically, ketamine is a dissociative anesthetic. It has immediate, profound psychological effects. Don't you think that people should be able to guess whether they got ketamine or a saline drip? And if they did guess correctly, wouldn't that blow the whole placebo cover? That possibility was tested out in two new studies. The first one looked at all the controlled ketamine trials and divided them into two groups. Those that used a saline drip as the placebo. And those that used an IV benzodiazepine, medazalam, as the placebo. They used that one in an effort to better disguise ketamine's fingerprint. When compared to a saline drip, ketamine's benefits are loud and clear, with a large effect size of 1.7. But when it's compared to medazalam, that caused the effect to shrink by more than 50% down to 0.7, which is in the medium range and closer to the effect for the average psychiatric treatment, which is 0.5, where most psych treatments fall, including psychotherapy. Now that analysis to me is a pretty harsh takedown for ketamine. And perhaps it's too harsh. I mean, after all, other medications cause side effects that might clue study participants into whether they received a sugar pill or not. Think of the sedation on quatypine or the high energy on medaphanyl. And that is where this next study comes in. It tried to blind participants to the placebo in a most dramatic and unusual

way.