Ketamine: Now By Prescription

By Scott Alexander

Last week the FDA approved esketamine for treating depression.

Let’s review how the pharmaceutical industry works: a company discovers and patents a potentially exciting new drug. They spend tens of millions of dollars proving safety and efficacy to the FDA. The FDA rewards them with a 10ish year monopoly on the drug, during which they can charge whatever ridiculous price they want. This isn’t a great system, but at least we get new medicines sometimes.

Occasionally people discover that an existing chemical treats an illness, without the chemical having been discovered and patented by a pharmaceutical company. In this case, whoever spends tens of millions of dollars proving it works to the FDA may not get a monopoly on the drug and the right to sell it for ridiculous prices. So nobody spends tens of millions of dollars proving it works to the FDA, and so it risks never getting approved.

The usual solution is for some pharma company to make some tiny irrelevant change to the existing chemical, and patent this new chemical as an “exciting discovery” they just made. Everyone goes along with the ruse, the company spends tens of millions of dollars pushing it through FDA trials, it gets approved, and they charge ridiculous prices for ten years. I wouldn’t quite call this “the system works”, but again, at least we get new medicines.

Twenty years ago, people noticed that ketamine treated depression. Alas, ketamine already existed – it’s an anaesthetic and a popular recreational drug – so pharma companies couldn’t patent it and fund FDA trials, so it couldn’t get approved by the FDA for depression. A few renegade doctors started setting up ketamine clinics, where they used the existing approval of ketamine for anaesthesia as an excuse to give it to depressed people. But because this indication was not FDA-approved, insurance companies didn’t have to cover it. This created a really embarrassing situation for the medical system: everyone secretly knows ketamine is one of the most effective antidepressants, but officially it’s not an antidepressant at all, and mainstream providers won’t give it to you.

The pharmaceutical industry has lobbyists in Heaven. Does this surprise you? Of course they do. A Power bribed here, a Principality flattered there, and eventually their petitions reach the ears of God Himself. This is the only possible explanation for stereochemistry, a quirk of nature where many organic chemicals come in “left-handed” and “right-handed” versions. The details don’t matter, beyond that if you have a chemical that you can’t patent, you can take the left-handed (or right-handed) version, and legally pretend that now it is a different chemical which you can patent. And so we got “esketamine”.

Am I saying that esketamine is just a sinister ploy by pharma to patent and make money off ketamine? Yup. In fact “esketamine” is just a cutesy way of writing the chemical name s-ketamine, which literally stands for “sinister ketamine” (sinister is the Latin word for “left-handed”; the modern use derives from the old superstition that left-handers were evil). The sinister ploy to patent sinister ketamine worked, and the latest news says it will cost between $590 to $885 per dose.

(regular old ketamine still costs about $10 per dose, less if you buy it from a heavily-tattooed man on your local street corner)

I’ve said it before: I don’t blame the pharma companies for this. Big Government, in its infinite wisdom, has decided that drugs should have to undergo tens of millions of dollars worth of FDA trials before they get approved. No government agencies or altruistic billionaires have stepped up to fund these trials themselves, so they won’t happen unless some pharma company does it. And pharma companies aren’t going to do it unless they can make their money back. And it’s not like they’re overcharging; their return to investment on R&D may already be less than zero. This is a crappy system – but again, it’s one that occasionally gets us new medicines. So it’s hard to complain.

But in this case, there are two additional issues that make it even worse than the usual serving of crappiness.

First, esketamine might not work.

Johnson & Johnson, the pharma company sponsoring its FDA application, did four official efficacy studies. You can find the summary starting on page 17 of this document. Two of the trials were technically negative, although analysts have noticed nontechnical ways they look encouraging. Two of the trials were technically positive, but one of them was a withdrawal trial that was not really designed to prove efficacy.

The FDA usually demands two positive studies before they approve a drug, and doesn’t usually count withdrawal trials. This time around, in a minor deviation from their usual rules, they decided to count the positive withdrawal trial as one of the two required positives, and approve esketamine. I suspect this was a political move based on how embarrassing it was to have everyone know ketamine was a good antidepressant, but not have it officially FDA-approved.

But if ketamine is such a good antidepressant, how come it couldn’t pass the normal bar for approval? Like, people keep saying that ketamine is a real antidepressant, that works perfectly, and changes everything, unlike those bad old SSRIs which are basically just placebo. But esketamine’s results are at least as bad as any SSRI’s. If you look at Table 9 in the FDA report, ketamine did notably worse than most of the other antidepressants the FDA has approved recently – including vortioxetine, an SSRI-like medication.

One possibility is that ketamine was studied for treatment-resistant depression, so it was only given to the toughest cases. But Table 9 shows olanzapine + fluoxetine doing significantly better than esketamine even for treatment-resistant depression.

Another possibility is that clinical trials are just really tough on antidepressants for some reason. I’ve mentioned this before in the context of SSRIs. Patients love them. Doctors love them. Clinical trials say they barely have any effect. Well, now patients love ketamine. Doctors love ketamine. And now there’s a clinical trial showing barely any effect. This isn’t really a solution to esketamine’s misery, but at least it has company.

Another possibility is that everyone made a huge mistake in using left-handed ketamine, and it’s right-handed ketamine that holds the magic. Most previous research was done on a racemic mixture (an equal mix of left-handed and right-handed molecules), and at least one study suggests it was the right-handed ketamine that was driving the results. Pharma decided to pursue left-handed ketamine because it was known to have a stronger effect on NMDA receptors, but – surprise! – ketamine probably doesn’t work through NMDA after all. So there’s a chance that this is just the wrong kind of ketamine – though usually I expect big pharma to be smarter than that, and I would be surprised if this turned out to be it. I don’t know if anybody has a right-handed ketamine patent yet.

And another possibility is that it’s the wrong route of administration. Almost all previous studies on ketamine have examined it given IV. The FDA approved esketamine as a nasal spray – which is a lot more convenient for patients, but again, not a lot of studies showing it works. At least some studies seem to show that it doesn’t. Again, usually I expect big pharma not to screw up the delivery method, but who knows?

Second in our litany of disappointments, esketamine is going to be maximally inconvenient to get.

The big problem with regular ketamine, other than not being FDA-approved, was that you had to get it IV. That meant going to a ketamine clinic that had nurses and anesthesiologists for IV access, then sitting there for a couple of hours hallucinating while they infused it into you. This was a huge drawback compared to eg Prozac, where you can just bring home a pill bottle and take one pill per day in the comfort of your own bathroom. It’s also expensive – clinics, nurses, and anesthesiologists don’t come cheap.

The great appeal of a ketamine nasal spray was that it was going to prevent all that. Sure, it might not work. Sure, it would be overpriced. But at least it would be convenient!

The FDA, in its approval for esketamine, specified that it could only be delivered at specialty clinics by doctors who are specially trained in ketamine administration, that patients will have to sit at the clinic for at least two hours, and realistically there will have to be a bunch of nurses on site. My boss has already said our (nice, well-funded) clinic isn’t going to be able to jump through the necessary hoops; most other outpatient psychiatric clinics will probably say the same.

This removes most of the advantages of having it be intranasal, so why are they doing this? They give two reasons. First, they want to make sure no patient can ever bring ketamine home, because they might get addicted to it. Okay, I agree addiction is bad. But patients bring prescriptions of OxyContin and Xanax home every day. Come on, FDA. We already have a system for drugs you’re worried someone will get addicted to, it’s called the Controlled Substances Act. Ketamine is less addictive than lots of chemicals that are less stringently regulated than it is. This just seems stupid and mean-spirited.

The other reason the drugs have to be given in a specially monitored clinic is because ketamine can have side effects, including hallucinations and dissociative sensations. I agree these are bad, and I urge patients only to take hallucinogens/dissociatives in an appropriate setting, such as a rave. Like, yeah, ketamine can be seriously creepy, but now patients are going to have to drive to some overpriced ketamine clinic a couple of times a week and sit there for two hours per dose just because you think they’re too frail to handle a dissociative drug at home?

I wanted to finally be able to prescribe ketamine to my patients who needed it. Instead, I’m going to have to recommend they find a ketamine clinic near them (some of my patients live hours from civilization), drive to it several times a week (some of my patients don’t have cars) and pay through the nose, all so that some guy with a postgraduate degree in Watching People Dissociate can do crossword puzzles while they sit and feel kind of weird in a waiting room. And then those same patients will go home and use Ecstasy. Thanks a lot, FDA.

And the cherry on the crap sundae is that this sets a precedent. If the FDA approves psilocybin for depression (and it’s currently in Phase 2 trials, so watch this space!) you can bet you’re going to have to go to a special psilocybin clinic if you want to get it. Psychedelic medicine is potentially the future of psychiatry, and there’s every indication that it will be as inconvenient and red-tape-filled a future as possible. If you thought it was tough getting your Adderall prescription refilled every month, just wait.

So far, I am continuing to recommend that my patients who want ketamine seek intravenous racemic ketamine at an existing ketamine clinic, since this has a stronger evidence base. Once insurance starts covering esketamine, I may change my mind if money becomes an issue. But I’m annoyed that it’s come to this.