KELLIE NEWSOME: Today, three more burning questions about ketamine and esketamine and the new research that attempts to answer them

CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report.

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

Ketamine and esketamine treat depression, but they leave a lot of questions unanswered. Last week we covered 3 of them. How does it compare to quetiapine – it works a little better. How does it compare to ECT – depends on the setting – we’re seeing better responses to ECT in hospitalized and psychotic depression, and better responses to ketamine in outpatient depression. And how effective is it? That depends on which placebo you compare it to – compared to intravenous saline the effect is huge, but when compared to an intravenous benzo it’s a lot smaller but still in the respectable large range.  And that brings us to question 4: Which version is more effective, ketamine or esketamine?

CHRIS AIKEN: In the animal models, there was some suggestion that the R enantiomer arketamine had stronger antidepressant effects than esketamine – but then I saw studies showing the opposite, so it’s not clear. 

KELLIE NEWSOME: Besides being different enantiomers, they also have different routes of delivery – ketamine is IV and esketamine intranasal. On that alone I’d expect better responses with the more direct IV route. 

CHRIS AIKEN: In meta-analyses, ketamine scores a much larger effect size – 0.7 to 1.7 – while esketamine rings in at 0.3, and that’s not including a recent industry sponsored controlled trial from China where esketamine did not work at all. But these are not exactly comparing apples to apples – I mean we tend to see smaller effect sizes in large, rigorous, industry sponsored trials than we do in the smaller, independent trials that made ketamine famous. 

KELLIE NEWSOME: Were the two ever compared head-to-head in the same trial?

CHRIS AIKEN: There are two small trials that did that, and they both came up equal. One looked at acute antidepressant effects, and the other at acute anti-suicide effects. 

KELLIE NEWSOME: The bottom line: Ketamine might be more effective than esketamine – but we can’t say for sure. In practical terms, both have their downsides. Ketamine requires IV delivery, and esketamine is brand-only and very expensive. During the pandemic, some companies sprouted up dispensing compounded oral ketamine for depression, but last month the FDA issued a warning against that practice.

CHRIS AIKEN: If you want to learn more about those problems, scroll back to our Feb 26 2023 episode Ketamine Comes Home, which is based on investigative reporting from the New York Times and the Wall Street Journal. The details they uncovered are lot more shocking than the tepid proclamation from the FDA. The FDA’s October statement focuses on the fact that oral ketamine is being used off-label without their approval – as if off-label use is some kind of rarity in medicine – and then briefly mentions that there have been reports of “misuse, psychiatric events, increases in blood pressure, respiratory depression, and lower urinary tract and bladder symptoms.” The warnings they put on antidepressants and benzos sound scarier than that jargony babble. The actual details – which the FDA strangely white washed – are much more concerning than “urinary symptoms”:

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.

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

KELLIE NEWSOME: 

1. What did two recent studies of weight gain on lithium conclude?

A. Lithium is associated with rare cases of severe weight gain, but on average does not cause any

B. Lithium causes initial weight gain but not long-term weight gain

C. There was a trend toward weight gain on lithium, but it was not statistically significant

D. Lithium causes clear weight gain, but less than that of antipsychotic

Question 5: Whether you use esketamine or ketamine, how do you sustain the drug’s benefits?

If we ask the manufacturer of esketamine, we’re pretty sure the answer is going to be, “more esketamine,” and – yep – here it is, the SUSTAIN trial. This trial randomized patients who recovered on esketamine to continue with either long-term esketamine maintenance at a reduced frequency, every 1-2 weeks instead of twice a week, or switch to placebo for about a year. The esketamine group did better, and no new safety concerns rose to the surface. That study is a few years old, and this year a secondary analysis of SUSTAIN-1 provided more reassurance that esketamine does not wear off.

Part of the SUSTAIN protocol was that it allowed rescue treatments for patients who slipped into depression during the long haul of the trial. Both the placebo group and the esketamine group could receive rescue therapy – also known as a second induction. In the esketamine group, this meant doubling or quadrupling their dose frequency for a month: from every 1-2 weeks to twice a week.

The good news to come from this trial is that the rescue treatments worked just as well as the original treatments – both for the placebo group and those on maintenance therapy. What that tells us is that tolerance did not appear to be an issue – or at least not a big enough issue to matter in the context of this study. Otherwise, we’d expect the 2nd and 3rd inductions to have a fading effect. Now, this doesn’t prove that tolerance is not an issue. It could still be that if ketamine is given long enough, or at higher or more frequent dosages, rescues stop working, or the patients start to require more and more rescues and can’t back down to the maintenance doses. Those of us who have seen patients after decades of benzodiazepine treatment are probably familiar with this kind of scenario, and it will take many more years to figure out if ketamine and esketamine are prone to that same pitfall.

CHRIS AIKEN: But does anything else sustain ketamine’s benefits, besides more of the same? Many medications have been tried without success, including lithium and meds that work through the same mechanism as ketamine – glutamatergic agents like cycloserine, lamotrigine, and riluzole. But one treatment has sustained ketamine’s benefits, and that gets into our next question:

Question 6: Should ketamine be delivered as part of a psychotherapy?

The answer is a tentative “yes,” if you want the benefits to last. We can only find two randomized trials that sustained ketamine or esketamine’s benefits other than maintenance with more of the same, and both involved psychotherapeutic techniques. 

The first was a trial of by Sam Wilkinson and colleagues at Yale that tacked on 12 sessions of traditional CBT vs treatment as usual after a successful course of ketamine in treatment resistant depression. It was small – 42 patients – and only marginally positive. For most of the study, there was no difference on the primary outcome measure – the clinician rated MADRS scale – it was only in the last 3 weeks that a difference emerged, which is at least what we’d expect from a treatment with known benefits like CBT. 

Wilkinson speculates that ketamine brings about a state of neuroplasticity that CBT can capitalize on, making cognitions less stubborn and more amenable to change. But other than that theory, the CBT in this study was pretty traditional and did not resemble what is done in the psychedelic assisted therapies, which involve preparatory sessions before the medication, support during the medication delivery, and integration sessions 1-2 days after the dosing where the patient integrates the new awareness they gained during the psychedelic trip.

KELLIE NEWSOME: The next study took a very different approach, delivering subliminal messages during the ketamine treatment to change people’s cognitions. Although it’s a psychological intervention, it did not involve interaction with a therapist. Instead, the patient spent 15-20 minutes twice a day with a computer program that delivered positive messages paired with pictures or words about themselves for 4 days after the ketamine infusion. So they would see a picture of themselves while the words “sweet” or “attractive” flashed both subliminally – below the level of conscious detection – and consciously.

CHRIS AIKEN: After a month, there was a small benefit for those who used the real positive association program along with the ketamine. When I first read the paper, I was excited about the result, but now I have some reservations. The benefit was only seen 4 weeks after the treatment – not at 2 weeks – and it was a small difference. What if that was just random flux? I mean, if this 4-day association training worked, wouldn’t you expect to see a difference early on?

Dr. Eiko Fried and colleagues at Leiden University in the Netherlands have done some digging that suggests this may have been no more than random noise. They went back to the clinical trial registration and – low and behold – the original primary outcome was the depression rating at 2 weeks, not just 4 weeks. This is why pre-registration of trials is so important. It prevents researchers from moving the goal posts after the results are in. 

KELLIE NEWSOME: We’re used to seeing that kind of problem in industry sponsored trials, but why would they do that in a psychotherapy study?

CHRIS AIKEN: The positive association software is under patent, and the first author is named as an inventor on the patent. I should disclose at this point that I too have a conflict in this area.

KELLIE NEWSOME: How so?

CHRIS AIKEN: When I was 12 I created software that would flash subliminal messages on those old IBM PC computers. It was for the science fair – the computer would draw pictures and flash words like “Carrot” at a speed faster than conscious perception. Then I’d ask subjects – basically anyone who came over to our house – to name the first vegetable that came into their mind while watching the computer screen. And you know what? People who got the “Carrot” subliminal message tended to name “Carrot” as the first vegetable that came to their mind. 

KELLIE NEWSOME: Well, software patents only last 20 years and that was – what 

CHRIS AIKEN: 1986

KELLIE NEWSOME: So I think your conflict is long expired. The bottom line: We’d like to think that psychotherapy extends the benefits of ketamine, but so far the area is far too understudied and the meager results are not too inspiring. But any clinician worth their salt will do more than administer a rating scale after completing ketamine – or after giving an antidepressant for that matter. These are people’s lives we’re dealing with – not just their symptoms – and we need to help them translate those early sprouts of recovery into meaningful changes in their lives. Whether you call that psychotherapy or not – it’s just good practice.

KELLIE NEWSOME: And now for the study of the day. It’s 3 studies: A triple feature on weight gain on lithium

CHRIS AIKEN: “I’ll gain weight” is one of the most common fears I hear spoken when I recommend lithium to a patient. But 10 years ago I noticed a meta-analysis that showed the opposite – weight loss in short term placebo-controlled trials of lithium – which got me thinking maybe this problem is rarer than we thought. Last year, another meta-analysis confirmed that – this one was broader, looking at both long and short term trials – 29 in all – and found no significant weight gain on lithium compared to placebo.

OK, I get it I may be losing some people here to disbelief. Don’t people put on a little weight through water retention on lithium? Well, this analysis did find a slight trend toward weight gain, it just wasn’t enough to reach statistical significance.

So on average there’s little or no weight gain on lithium, but what if there are rare cases where people gain a lot? This next study, which came out last month, suggests no.

The study combed through a 30 years of data from a drug safety database that collects reports of severe side effects on psych meds from hospitals in Germany, Austria, and Switzerland. There were 527 reports of severe weight gain and used lamotrigine as the comparator since that mood stabilizer does not cause weight gain – in fact there’s a study from a weight loss clinic that used lamotrigine successfully. Patients appreciate hearing that! 

As with last year’s study, they found a slight trend for weight gain on lithium, but it was not statistically different than lamotrigine, and it was much less than the reports of severe weight gain on other mood stabilizers. 

That’s 3 studies calling to question a popular belief about lithium. Still convinced it causes weight gain? Consider this: Kraepelin found high rates of weight gain in his bipolar patients – by middle age most had developed the apple shape, and modern studies confirm that adverse metabolic direction.

The bottom line: Tell patients that weight gain is very rare on lithium, and some even lose weight on it because untreated mood disorders mess with metabolism. Lithium will likely make them thirsty, and they can avoid weight gain by drinking lots of water – avoiding caloric beverages and diet drinks which cause weight gain indirectly. Staying on top of thyroid will also keep weight gain at bay.

KELLIE NEWSOME: Stay up on the latest research through Dr. Aiken’s social media feed The Daily Psych – search for chrisaikenmd on LinkedIn, Twitter, Facebook, or Threads. Earn CME for this podcast through the link in the show notes, or subscribe online for all our content and get $30 off with the promocode Podcast. Thank you for helping us stay free of commercial support.