Ketamine. Esketamine. They may not be fire from the Gods, but they have left some burning questions that new research is starting to answer. Whether you prescribe those drugs or not, these new studies will help you guide your patients.

KELLIE NEWSOME: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

CHRIS AIKEN: Over the past two decades, we’ve figured out that ketamine treats depression, but we still have a lot of unanswered questions about the drug. How long does it work? How does it compare to other treatments? And who responds best? While we don’t have full answers for any of those questions yet, we do have new studies to share with you that clarify the picture. But first, the basics.

KELLIE NEWSOME: Ketamine’s discovery grew out of an effort to create a safer version of phencyclidine (also known as PCP or Angel Dust). PCP was released as a dissociative anesthetic in 1956, but it soon fell out of favor because of its high risk of psychiatric side effects like violence and psychosis. Ketamine was a safer alternative, and entered the US market as a dissociative anesthetic for short-term surgical procedures in 1970. It was widely used in the Vietnam War, and many soldiers came home with ketamine use disorders. Ketamine also has analgesic properties and is used for refractory pain.

Ketamine’s antidepressant effects were discovered in 2000, and it stands out for both its rapid action – people feel better within a day – and large effect size: 1.5. To put that in perspective, the largest effect size for commonly used psych meds is 0.9 for Vyvanse, but we’re going to present some data today that call that effect size into question. Ketamine also has acute anti-suicidal effects, and its intranasal enantiomer esketamine is FDA approved for rapid relief of suicidality in depression. But while ketamine is rapid acting, we don’t know how to keep its benefits up, so many patients remain on maintenance treatments with the doses spaced out to every 1-4 weeks, much like with maintenance ECT.

CHRIS AIKEN: Like many medications – think citalopram and escitalopram, or modafinil and armodafinil – ketamine is a mixture of two enantiomers: Esketamine and Arketamine. The original ketamine is a mixture of those two, called racemic ketamine, but that drug is long generic, so the only way they could bring it to market in psychiatry was to copyright the enantiomers. One of those, esketamine, was released as Spravato in 2019, and the other, arketamine, is still undergoing testing.

Ketamine is traditionally given as an intravenous IV medication because it has low bioavailability, meaning it’s difficult to get it into the bloodstream. IV is the straightest route for medications like this. After that comes intranasal, which is how esketamine (Spravato) is delivered. 

Both Ketamine and esketamine are schedule III controlled substances. Esketamine can only be delivered under monitoring in a provider’s office, in part to make sure the drug is not diverted but also to monitor their blood pressure and mental state during treatment. To prescribe esketamine for depression, providers must also register with a REMS program – which usually includes inspection of their office to make sure the drug is locked away properly. 

Ketamine and esketamine can cause hypertension, dissociation. Use can escalate to abuse, and they can be used as date rape drugs. They carry medical risks of irreversible bladder ulcers, a problem that so far has only occurred in people who regular dose beyond the antidepressant level.

KELLIE NEWSOME: Let’s pause for a preview of the CME for this episode. Earn CME through the link in the show notes

1. In a 2023 study from the New England Journal of Medicine, ketamine outperformed ECT with greater efficacy in which population?

A. Outpatients with treatment resistant depression

B. Hospitalized patients with treatment resistant depression

C. Patients with a mix of severe and psychotic depression

D. Patients with mild to moderate depression

CHRIS AIKEN: Now for the updates. We’re going to present them as six questions, because although the new studies fill in some of the picture, we still have a long way to go and we want to keep these questions open.

Question 1. How does ketamine compare to other treatments?

Two recent studies compared ketamine to ECT – one that got a lot of press and another that is barely talked about. In the first, ECT came out slightly ahead in terms of efficacy, and in the second ketamine took the prize. It’s that second study that got the most press – likely because its results challenge the conventional wisdom that holds up ECT as the gold standard. So which is right?

Both were large, randomized trials, although the study favoring ketamine was about twice as large – 365 vs 186 patients. But what really separates them is the type of patients enrolled and the quality of the ECT.

The study that favored ECT enrolled inpatients, while the one that favored ketamine was done in an outpatient setting, and its recruitment procedures favored ketamine. Patients were allowed to drop out after being randomized to ECT or ketamine – 31 dropped out when they found out they’d be getting ECT, compared to only 4 who dropped out after getting the ketamine card. There’s no way to blind them to the treatment, so ketamine’s expectancy bias may have enhanced that effect.

The other difference is that the ketamine-friendly study excluded people with psychotic depression, while the ECT-friendly study allowed them in. That’s a big strike against ECT, which is non-psychotic outpatients, and ECT for inpatients and those with psychotic depression.

KELLIE NEWSOME: The next study was recently published in the New England Journal of Medicine, and it compared not ketamine but esketamine (Spravato) to quetiapine 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 1.5 times more likely to experience remission than quetiapine - 27% vs. 18%.

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 2 or more antidepressant trials – while quetiapine has mainly shown its benefits in patients who failed just one antidepressant. But we were a little surprised. Quetiapine 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 quetiapine in treatment resistant depression, not quite by a factor of 2 to 1, but 1.5 to 1. And while esketamine leaves many patients in the undesirable position of requiring ongoing maintenance therapy, we have to concede that quetiapine 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, tardive dyskinesia, may be more of a deal breaker.

CHRIS AIKEN:  Our next question: Is ketamine really all that effective?

Earlier we quoted a recent meta-analysis that registered an ultra-high effect size for IV ketamine, of 1.5 across 79 trials. This study is just the most recent and this study is not alone in that. By comparison, SSRIS are around 0.3.0.4 in depression, and stimulants ring in at 0.8-0.9 in ADHD. 

Effect size is a measure of the difference between placebo response and medication response, and there’s a problem in comparing effect sizes across trials. Ketamine’s studies are smaller, and smaller trials tend to yield big effects. More critically, ketamine is a dissociative anesthetic with immediate, profound effects. Don’t you think 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 looked at all the controlled ketamine trials and divided them into two types – those that used a saline drip as the placebo, and those that used and IV benzo – midazolam – in an effort to better disguise ketamine’s fingerprint. When compared to a saline drip, ketamine’s benefits were loud and clear, with a large effect size of 1.7. But comparing it to midazolam caused that 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 (0.5 is where psych treatments fall on average, including psychotherapy). 

That’s a pretty harsh take down for ketamine, and perhaps too harsh. After all, other meds cause side effects that might clue study participants in to whether they received a sugar pill or not – think of sedation on quetiapine or high energy on modafinil. There’s where this next study comes in. It tried to blind participants to the placebo in a most dramatic – and unusual – way.

KELLIE NEWSOME: Last month, researchers at Stanford published a small randomized controlled trial of IV ketamine vs saline placebo in depression. To make sure that no one could tell which treatment they received, they only enrolled depressed patients who happened to be undergoing surgery, and gave either the ketamine or saline while the patient was unconscious from anesthesia. The blind worked. When they woke up, they correctly guessed which infusion they received at a rate that was, well, worse than chance. And with this blinding intact, ketamine worked no better than placebo.

But after that, the trials results get confusing, raising more questions than it ultimately answers. Even though there was no difference between the groups, both groups had significant improvements after the surgery, of the type we normally see in ketamine trials – dramatic responses that last a few days and then sink back into depression. Our first thought was, “Oh, they must have all thought they received ketamine, and that jolted them into recovery.” But no. The authors reanalyzed the data, this time dividing the patients into those who thought they received ketamine and those who thought they received placebo, and there was no difference between the groups.

Our next thought was, “Having that surgery must have jolted them out of depression, overriding any benefit from the medication.” But the authors cite studies showing the opposite – if anything, people tend to get more depressed after surgery, whether from the pain, discomfort, and ordeal of it all or the rise in inflammation that occurs when the body is sliced open.

Which leaves us with…We don’t know why this study turned out the way that it did. But it does suggest that patients need to be conscious to experience the benefits of ketamine, adding some weight to the debate over whether ketamine’s benefits are purely biological – the type that could be conferred by delivering the med during surgery – or psychological – the type that evolves from new insights obtained through a transcendent, psychedelic experience.

CHRIS AIKEN: The bottom line: Ketamine is the new panacea. I mean, not many psych meds make it to the cover of Time magazine, but this one did. And with that distinction comes an expectancy effect that cannot be ignored. All trials of ketamine and psychedelics need to assess whether the patients could accurately guess the blind, in fact let’s make that standard for trials of all meds. It’s a simple question. Just ask.

KELLIE NEWSOME: A now for the study of the day: Use of rapid fentanyl test strips among young adults who use drugs by Maxwell Krieger and colleagues. This is an older study - from 2018 but – but last week it lead to a new FDA clearance: the first over-the-counter fentanyl urine test. No, this isn’t a test so that parents can check if the child is taking fentanyl. This is a harm-reduction approach for people with opioid use disorder that will help them figure out if their supply is getting laced with the high-potency high-lethality fentanyl. Since it’s a urine stick test, it will tell them after the fact, but the harm-reduction idea here is that something is better than nothing, and that is what this 2018 study showed.

CHRIS AIKEN: The researchers gave a similar test to 93 young adults in Rhode Island who used heroin, cocaine, or illicitly obtained prescription pills. Around half of them found out that their supply was laced with fentanyl bank in 2018, and the reality check lead to significant changes toward safer drug use. 77% said they would use the test strips again, and now thanks to the FDA, they can.

KELLIE NEWSOME: Join us next week for the final 3 updates, where you’ll learn which version works better – ketamine or esketamine; how to sustain the benefits; and whether psychotherapy assistance is necessary.

We’re excited to announce a new Carlat book – the fourth edition of Psychiatry Practice Boosters by Zachary Davis and Jesse Koskey. Inside are 63 of the most clinically relevant studies in psychiatry from the last three years –so if you enjoyed the last edition you’ll find all new studies in this one. Your support helps us stay free of industry influence and bring you the unbiased information you can trust.

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The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one quarter (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.