Online clinics delivered at-home ketamine throughout the pandemic, and we’re just becoming aware of the consequences. 

Publication Date: 2/27/2023 

Duration: 19 mins, 15 seconds

Transcript:

CHRIS AIKEN: In 2019, the FDA released esketamine with more REMS regulations than any psychiatric drug of past, but they left its racemic cousin ketamine practically laying on the table, and online start-ups are delivering the drug with unregulated speed.

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

KELLIE NEWSOME: Joyous. Mindbloom. NueLife. WonderMed. These are the hyperbolic names of a new kind of mental health clinic that has cropped up during COVID: At-home Ketamine therapy. In early 2020, the DEA issued a waiver that relaxed restrictions in the Ryan Haight Act, allowing clinicians to prescribe controlled substances by telemedicine, without ever meeting the patient in person. For patients on Concerta, Ambien, and Suboxone, it allowed treatment to continue as usual, but it also opened up new markets and new modes of treatment. That emergency waiver is coming to an end in May 2023, but we’ll be dealing with the after effects for a while.

Last month we covered one of those after effects: the Adderall shortage. Telehealth companies cropped up during lockdown, offering easy access to stimulant medications. Prescriptions rose, but production didn’t change – stimulant quantities are regulated at the factory level – and when a labor shortage hit the main supplier of generic Adderall the system collapsed, creating a domino effect of shortages throughout the stimulant category.

CHRIS AIKEN: Today we’re going to cover another side effect of the loosened regulation: At-home ketamine. But first, a preview of the CME quiz for this episode.

What limits the efficacy of oral ketamine?

A. It has a slow speed of onset

B. It has low bioavailability

C. It has a high rate of gastrointestinal side effects

D. It does not contain enough esketamine

CHRIS AIKEN: Ketamine is FDA-approved as a surgical anesthetic, but that’s not how it was used in the online-only ketamine clinics that have flourished during the pandemic. The FDA allows off-label prescribing, and ketamine has a sizeable evidence-base for treatment-resistant depression. Depression is a clinical syndrome, but it’s also a universal emotion. The logical conclusion of these facts is that – without regulation – everyone is eligible for a dose of ketamine from time to time.

The surge in off-label use is not just driven by the feel-good intentions that drive much of the overprescription of psychiatric meds. There are valid clinical reasons to prefer ketamine over esketamine. For one, ketamine has a large effect size, while esketamine’s is surprisingly smaller  – several meta-analyses have placed it around 0.3. We don’t have enough head-to-head data to know if this is a real difference, but animal studies also suggest that they got the wrong isomer when they isolated and branded esketamine. The other isomer is arketamine, and it’s under development for depression but not currently available. Two give arketamine, you have to use the racemic ketamine – which is 50% esketamine and 50% arketamine.

KELLIE NEWSOME: Besides the efficacy debate, there is a clear financial difference. Most patients can’t afford the $5,000 a month cost of esketamine unless it is covered by their insurance, and that’s just the cost of the med, not the 2 hour office visits that are required to deliver it. Oral ketamine can be obtained for $130 a month through online clinics and compounding pharmacies. 

Public health experts question whether esketamine brings any societal good at this cost. A quality of life analysis in the American Journal of Psychiatry concluded that the cost of esketamine/Spravato would have to drop by 40% to justify its cost in treatment-resistant depression. That cost-benefit lag is why the UK health system declined to endorse esketamine in their NICE guidelines this year.

These debates are part of why IV ketamine clinics still operate in the Spravato era, and we have no qualms with IV Ketamine clinics. If given responsibly in person for patients who need it, IV ketamine is about as safe as intranasal esketamine. Some clinics even give IV ketamine at home, but it’s still a supervised treatment with in person meetings – the patients aren’t delivering the drug themselves.

What does concern us is the rise in oral, at-home ketamine clinics. The DEA has strict regulations around the use of esketamine in depression. Patients have to be monitored for two hours after taking it to prevent diversion and abuse as well as psychiatric and cardiovascular complications. Oral ketamine does not have those requirements, existing in the kind of legal loophole that regulators too often leave open.

CHRIS AIKEN: But what could possibly go wrong? For one thing, does it work? There are a few small studies supporting oral ketamine in depression, but the effects are less reliable because oral ketamine suffers a bioavailability problem. Only 20-30% of the gets absorbed. In contrast, most psychiatric drugs we prescribe – stimulants, benzos, antidepressants, lamotrigine, lithium – have bioavailabilities over 80%, meaning more than 80% of the med gets into their system. Esketamine has the same limitations, which is why the FDA approved form was developed as an intranasal. By giving esketamine/Spravato through the capillary rich nasal mucosa, 50% of it gets absorbed. That’s better than the 20-30% for oral, but far short of the 100% bioavailability of intravenous ketamine. Everything that goes in the vein gets in the vein.

But what concerns us even more is the risk of misuse. Ketamine is a rewarding drug, which makes it difficult for patients to take reliably on their own. It was discovered in the early 1960’s as a replacement for the first dissociative anesthetic: PCP. PCP was heralded as a wonder drug for surgery upon its debut in the 1950’s, but it caused too many psychiatric problems for human use, and ketamine came about as a safer alternative. Ketamine is still used in anesthesia, and it did a fine job until supplies started to leak to the streets. Ketamine use disorders spread in the 1970’s, and has ranked as the #1 misused drug in some countries. When the drug is used for a long time at recreational doses – like 400 mg/day of oral ketamine – it can cause bladder damage, neurotoxicity, psychosis, and cognitive problems. 

And there are withdrawal problems. These didn’t show up in the clinical trials, but case reports are popping up from ketamine clinics, including a recent in one the American Journal of Psychiatry by our Carlat Addictions Editor Noah Capurso. Noah writes that “regular ketamine users can experience dysphoria, anxiety, and cravings on stopping use” and describes possible withdrawal symptoms of agitation, tremor, sweating, irritability, and insomnia.

KELLIE NEWSOME: Last week the New York Times painted a vivid picture of these problems in an article titled “A Fraught New Frontier in Telehealth.” The Times interviewed over 40 patients and two dozen medical professionals

The doctors they spoke with were confident that oral ketamine was safe and rarely if ever lead to misuse – perhaps for only 1 in 1,000 patients at most. But they got a different story when they spoke with the patients of those very same doctors. Some described a compulsive need to take more and more of the medication. They asked for higher doses. Some were prescribed beyond the standard 0.5 mg/kg IV equivalents for depression. Others just raised it on their own or took it rectally to enhance the rush. When they ran out early, the did did not tell their physician for fear of losing further refills. Several developed bladder problems, but kept this well-known ketamine side effect hidden from their online physicians for fear of losing access. 

The details are telling. A 50 year old man now has to use a catheter to empty his bladder. A 37-year-old woman who wears adult diapers. And all the while they kept taking the ketamine.

Some of our own patients may be taking oral ketamine from online providers and not telling us, perhaps those who could not afford esketamine therapy. You can detect it on a urine drug screen, but not the standard one – ketamine screens need a special order.

CHRIS AIKEN: One comment in the times struck me. When asked about abuse, a physician said “just because there’s a handful of people that don’t follow directions, that does not mean that this medicine is not safe for the rest of the population of competent adults.” That sounds a lot like the propaganda spread by the opioid industry in the 1990’s. Citing an informal letter to the editor that appeared in a very formal journal – the New England Journal of Medicine – industry sponsored experts argued that misuse of opioids was a rare phenomenon among pain patients, seen only in those with personality problems. Not something that the rest of us need to worry about. 

The opioid crisis that sprung from that logic has shown that there is no “us and them” when it comes to substance use disorders. This is why our field is moving away from stigmatizing words like “addiction” and “abuse”, which set up a world where everyone is either a bad actor or a clean and sober citizen. But misuse is something we are all capable of, and people with severe depression are even more vulnerable – depression does not make people follow directions or take good care of themselves. 

KELLIE NEWSOME: These are not “competent” patients who are in need of ketamine, as the doctor described it in his defense of at-home treatment. The Times makes the point that people with severe depression seem drawn to online clinics because of this poor judgment. They want a “hands off” treatment where they don’t have to interact with anyone or engage in a potentially therapeutic relationship. 

And that is what they got. Many of these clinics are stocked with pain specialists or primary care physicians rather than psychiatrists. Patients send in rating scales by text and get back computer generated dosing schedules without any human involvement. It’s medicine without the medical care. Some patients described reaching out for suicidal crises, only to receive automated replies directing them to the national 988 hotline.

CHRIS AIKEN: Ketamine is not a cure for depression. It does not correct any underlying pathophysiology, and it's not known to prevent future episodes. It works quickly, but we don’t know what to do after the relief wears off. We’re not even sure if continued dosing is effective – in a meta-analysis of the FDA registration trials for esketamine the drug lost its efficacy as the weeks progressed, and was no different from placebo by week 4. Many drugs have been tried to pick up where ketamine left off, including lithium and ketamine-esque glutamatergics like cycloserine, but all have failed.

KELLIE NEWSOME: The only treatment we know of that successfully sustained ketamine’s benefits in a randomized controlled trial is cognitive behavioral therapy, and that points to something we need to pay more attention to psychiatry: The difference between acute and preventative treatment.

When someone is having a heart attack, we give nitroglycerin to quickly dilate the blood vessels and blood thinners to stop the clotting. We don’t rush in with statins, we use those to prevent heart attacks. 

Turning back to depression, it’s pretty clear that ketamine is an acute treatment. It works within hours and wears off after a few days. Psilocybin and other psychedelics have a similar time course, but what about antidepressants?

CHRIS AIKEN: Antidepressants sit in an uncomfortable middle ground. They are not fast acting, and not particularly robust in their long-term effects either. One of the best real-world studies came out in the New England Journal in 2021. They randomized 500 patients on long-term antidepressants who felt ready to come off to either stay on the antidepressant or secretly switch it with a placebo. The antidepressant group did better, but not by much – relapse rates were 39% with continuation vs. 56% with placebo.

We see better results with psychotherapy. In a 2021 meta-analysis from Toshi Furukawa and colleagues, psychotherapy was 1.5 times more likely to prevent depression than pharmacotherapy. And a 2000 study of aerobic exercise from Ranga Krishnan’s group at Duke pushes the needle even further. They randomized patients with depression to either sertraline or group aerobic exercise. After 4 months, both treatments worked equally well, but after 10 months the ones who were trained in exercise were 4-times less likely to relapse. Not everyone continued to exercise on their own after the group program ended, but the ones who did were 50% less likely to relapse.

That is the approach we need with the ketamines: To start the treatment with a clear end-point in mind, and set up that expectation with the patient. “Ketamine will get you better quickly, but it won’t keep you better. You’ll need to do something else to maintain the progress – Either active, weekly psychotherapy, or 45 minutes every other day of aerobic exercise. People rarely exercise on their own. They need to buy a gym membership, join a group, and get a doctor’s order.

KELLIE NEWSOME: And now for the study of the day:

Dr. Aiken is still posting a study a day in his LinkedIn and Twitter feed, and today’s is Adjunctive Lumateperone in Bipolar Depression by Trisha Suppes and colleagues.

Lumateperone is FDA approved as Caplyta in bipolar depression, but so far all the studies have tested the drug as monotherapy, which is not how people are likely to use it in practice. This is the first study to test lumateperone as an add-on treatment in bipolar depression, either to lithium or valproate. Over 500 patients with bipolar I or II depression were randomized to 3 treatment arms: Lumateperone 28mg, 42mg, or placebo. The FDA-approved dose is 42mg, but the company recently released lower doses, cutting it in half to 21 mg and again in half to 10.5mg, which we appreciate because we’ve seen a lot of side effects when patients start with 42.

In this study, the full 42 mg dose separated from placebo with an effect size of 0.3, but the lower 28 mg dose was only marginally effective – barely separating from placebo or not at all depending on the outcome measure. Somnolence, dizziness, and nausea were the main side effects.

That makes 4 industry sponsored studies of lumateperone that we’re aware of, and here’s the score: two positive, one negative, and one – in depressive mixed states – whose results are pending. 

The bottom line: 42 mg is still the target dose for lumateperone, as lower doses are only marginally effective. And by the way, they don’t even make a 28mg dose – the next level down is 21 mg – and we have little confidence that will work for most patients.

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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.