Steven Levine, MD: Your notes of caution, guidance, and advice to look toward the data are very welcome. In the off-label prescription of ketamine over the last decade, we’ve seen a lot of excitement and enthusiasm—at some points, ahead of the data. Although there have been many studies looking at racemic IV [intravenous] ketamine for treatment-resistant depression, they are primarily relatively small studies. There are still some unanswered questions. The availability of data gathered in a rigorous way answers more questions for us, including what we do in the longer term beyond the treatment of the acute episode, is really important.

With esketamine, the phase 3 TRANSFORM studies gave us an opportunity to see how glutamatergic medicines perform in this population. They gave us some more reason for hope and optimism but also some cautionary notes. They showed us that this is an efficacious medicine that can help a lot of people. It didn’t help everyone. These are still relatively short-term studies that don’t necessarily answer the questions about the management of patients in the long term.

Something that maybe happens with the community prescription of IV ketamine is a lack of full appreciation of short-term adverse effects. Those are some of the things that also get highlighted in rigorous phase 3 trials, like the TRANSFORM studies with esketamine. It’s perhaps not particularly dangerous to patients, but it’s certainly clinically meaningful. In the short term, patients have dissociation and some sedation. Then there’s the potential for divergence or misuse, hence the embedding of this therapy within a REMS [Risk Evaluation and Mitigation Strategy] program. That means that patients and providers need a lot of information prior to starting people on esketamine. Lisa, perhaps you can speak about what information you need prior to starting someone on intranasal esketamine.

Lisa Harding, MD: The first thing is an understanding. What we didn’t mention was that with racemic ketamine, we have both the S and the R portion of the ketamine. With esketamine, it is just the S part of it. As you pointed out, we need an understanding clinically of the evidence that we do know vs what we don’t. A lot of it is the long-term efficacy. It starts with good screening. As with everything in medicine, we are moving away from throwing spaghetti at a wall and seeing what sticks. A good comprehensive diagnostic interview is important. I really like the phrase and the reframing of saying that patients haven’t failed a medication, but that the medication has failed them. We sometimes don’t understand the burden of our words.

In selecting the correct patient with the correct diagnosis, to then choose this modality of treatment, I completely agree with the sentiment that we sometimes just need to wait longer. Last year showed us how to portray some level of patience with the way things move in life. Sometimes we also need to exhibit that same patience when it comes to the treatment of depression. I conceptualize to my patients that there’s a 4-pronged approach. We have the biologic, genetic, environmental, and the internal and external psychological. I can park the ketamine truck outside your house. If you’re in a bad relationship and that’s what’s causing this, then I don’t really know where the intervention lies. The overarching answer is that you have to select the right patient, and you really have to do a deep dive and diagnostic into that patient to make sure this is the right treatment for them.

Steven Levine, MD: Those are really important points, Lisa. Continuing along that thread, Patricia, could you speak to what patient types you see responding best to this therapy?

Patricia Ares-Romero, MD, FASAM: Definitely. The patients I usually see doing really well are the ones who come to the clinic after failing 2 trials of medications. Patients who have done ECT [electroconvulsive therapy] and other modalities usually don’t do as well. A good clinical history is very important. We don’t treat anyone unless we do a consultation with them. Whether they’re referred from the community or not, we want to make sure we’re ruling out any other diagnoses that might be misdiagnosed. The big 1, where a lot of patients are misdiagnosed, is bipolar disorder. When they’re bipolar, they’re not going to respond to this treatment, of course.

The response in our clinic has been great with patients. It’s important that they understand the expectation of treatment as well. It has to be explained that not everybody responds right away, and the expectation is that we’re going to be doing this for 3 months. It’s very important to set good expectations for our patients and to be clear with the treatment options as well.

Transcript Edited for Clarity